In severely ill hospitalised patients with diabetes mellitus (type 1 and type 2) there is an increase in metabolic rate. Insulin requirements are increased and glycaemic control becomes more difficult to achieve. The insulin sliding-scale is a form of „top up‟ therapy used to supplement the patients existing hypoglycaemic medication. In 2002, research at Livingstone Hospital found that 14 different sliding scales were used in 38 patients (Du Plessis, 2002: 79). In 2006 the nurses and doctors working in the general medical wards at Livingstone Hospital indicated that they were willing to use a standardised insulin sliding scale protocol (Smith, 2006: 56). Thus the aim of this study was to assess whether a standardised insulin protocol can be effectively implemented. The objectives of the study were to: 1) assess insulin usage via insulin sliding scales prior to the implementation of the standardised insulin protocol; 2) implement the standardised insulin protocol; and 3) reassess insulin usage after the implementation of the standardised insulin protocol. As the study involved evaluating the use of insulin via the insulin sliding scale and the implemented insulin protocol, it occurred in four phases. The preliminary phase entailed obtaining ethical approval. The pre-intervention phase included data collection in the form of a nursing questionnaire and the auditing of patient medical records using a data collection tool. The intervention phase involved education sessions on the new insulin protocol for the nursing staff, and the implementation of a standardised insulin protocol, while the post-intervention phase comprised of post-intervention data collection, which included a nursing questionnaire, a prescribers questionnaire and the auditing of patient medical records using a data collection tool. The overall impression obtained from the comparison between the pre- and post-intervention nursing questionnaire was conflicting; in some aspects the educational intervention was successful in others not. Regardless the indication obtained was that the nursing staff require more in-service training on a more regular basis as a lack of knowledge regarding diabetes mellitus as a disease state may negatively affect patient outcomes. The overall response from the nursing staff towards the insulin protocol was positive. The prescribers‟ response to the insulin protocol was conflicted. The number of correct insulin sliding scale doses administered in the pre-intervention and post intervention phase improved by 5.25 percent. The number of incorrect insulin sliding scale doses administered during the pre- and post -intervention phase decreased by 5.25 percent. These results are positive and may be due to fewer sliding scales being prescribed in the post-intervention phase and the implemented insulin protocol. Only three (5.55%; n=54) inpatients with Type 1 diabetes mellitus were placed on the implemented protocol that is, the basal bolus regime, and rarely were dose adjustments to their insulin made rendering the effectives of the protocol undesirable. Only four (7.40%; n=54) inpatients with Type 2 diabetes mellitus were placed on the implemented protocol that is, an intermediate- to long-acting insulin (Protophane®). However all four patients experienced immediate improvements in their fasting blood glucose levels. These results indicated that by adding an intermediate- to long-acting insulin (Protophane®) to the therapy of a patient with Type 2 diabetes mellitus fasting blood glucose levels decrease. This would improve patient outcomes and decrease the risk of related diabetic complications. These limited results may indicate a clinical inertia on the part of the prescribers. Unfortunately overall the educational intervention was not successful and the implementation of the protocol was not successful and did not yield the desired results.

Carbamazepine (CBZ) is a first-line drug used for the treatment of partial and tonic-clonic seizures. It is also the drug of choice for use during pregnancy and recommended for the treatment of seizure disorders in children. CBZ possesses the ability to induce metabolism of drugs that are transformed in the liver and has the unique ability to induce its own metabolism by a phenomenon known as ‘auto- induction’, where its biological half-life is significantly reduced during chronic administration. Large doses of CBZ are often prescribed as daily divided doses and this often adversely affects patient compliance, with the result that therapy is ineffective. A sustained-release dosage form containing CBZ is currently marketed as Tegretol® CR and the development of a generic product would provide patients with an equivalent product with a similar dosing frequency, at a reduced cost. Therefore, the development of a polymer-based matrix tablet was undertaken to produce a sustained-release dosage form of CBZ, since these dosage forms are relatively simple and cheap to produce when compared to other, more sophisticated forms of sustained-release technology. Preformulation studies were conducted to assess moisture content of excipients and dosage forms and to identify possible incompatibilities between CBZ and potential formulation excipients. Furthermore, studies were conducted to assess the potential for polymorphic transitions to occur during manufacture. Stability testing was conducted to assess the behaviour of the dosage forms under storage conditions that the product may be exposed to. Dissolution testing was undertaken using USP Apparatus 3, which allowed for a more realistic assessment and prediction of in vivo drug release rates. Samples were analysed using a high performance liquid chromatographic method that was developed and validated for the determination of CBZ. Tablets were manufactured by wet granulation and direct compression techniques, and the resultant drug release profiles were evaluated statistically by means of the f1 and f2 difference and similarity factors. The f2 factor was incorporated as an assessment criterion in the design of an artificial neural network that was used to predict drug release profiles and formulation composition. A direct compression tablet formulation was successfully adapted from a prototype wet granulation matrix formulation and a number of formulation variables were assessed to establish their effect(s) on the dissolution rate profile of CBZ that resulted from testing of the dosage forms. The particle size grade of CBZ was also investigated and it was ascertained that fine particle size grade CBZ showed improved drug release profiles when compared to the coarse grade CBZ which was desirable, since CBZ is a highly water insoluble compound. Furthermore, the impact of the viscosity grade and proportion of rate-controlling polymer, viz., hydroxypropyl methylcellulose was also investigated for its effect on drug release rates. The lower viscosity grade was found to be more appropriate for use with CBZ. The type of anti-frictional agent used in the formulations did not appear to affect drug release from the polymeric matrix tablets, however specific compounds may have an effect on the physical characteristics of the polymeric tablets. The resultant formulations did not display zero-order drug release kinetics and a first-order mathematical model was developed to provide an additional resource for athematical analysis of dissolution profiles. An artificial neural network was designed, developed and applied to predict dissolution rate profiles for formulation. Furthermore, the network was used to predict formulation compositions that would produce drug release profiles comparable to the reference product, Tegretol® CR. The formulation composition predicted by the network to match the dissolution profile of the innovator product was manufactured and tested in vitro. The formulation was further manipulated, empirically, so as to match the in vitro dissolution rate profile of Tegretol® CR, more completely. The test tablets that were produced were tested in two health male volunteers using Tegretol® CR 400mg as the reference product. The batch used for this “proof of concept” biostudy was produced in accordance with cGMP guidelines and the protocol in accordance with ICH guidelines. The test matrix tablets revealed in vivo bioavailability profiles for CBZ, however, bioequivalence between the test and reference product could not be established. It can be concluded that the polymeric matrix CBZ tablets have the potential to be used as a twice-daily dosage form for the treatment of relevant seizure disorders.

Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.

In the present study lanolin alcohol films were investigated as potential drug delivery systems for the controlled release of salicylic acid. A series of experiments were conducted in vitro to study the release of salicylic acid from these films. The effect of changes in film composition and stirrer speed on drug release were examined. Seven film compositions with varying proportions of lanolin alcohol and ethyl cellulose were prepared over the ethyl cellulose concentrations of 0-30% w/w, while keeping the drug concentration at 2.5% w/w. The release data obtained in this study were examined by the Q vs 1/2 relationship and the first-order relationship. This was done to probe deeper into the underlying mechanism of drug release. Upon examination of the release data by the Q vs 1/2 treatment, it was observed that the correlation coefficients were quite high and lag times were only slightly negative in agreement with the observed initial release data. In contrast, the first-order treatment of data showed somewhat lower correlation coefficients and very high negative lag times. These data strongly suggest that the unidirectional release of salicylic acid from the lanolin alcoholethyl cellulose films follows Higuchi's diffusion-controlled granular matrix model. The release rate constant showed an initial increase with inclusion of ethyl cellulose followed by a sharp decline as the ethyl cellulose concentration was further increased reaching a minimum value at about 15-20 percent of ethyl cellulose. Further increases in the concentration of ethyl cellulose increased the rate of drug release with a tendency to level off at about 30 percent ethyl cellulose concentration. The effect of stirring rate on the release rate constant showed that the rates of release of salicylic acid increased with increases in the stirring rate.

PART I: MARKERS OF INFLAMMATION IN DELAYED MUSCLE SORENESS Fifty-five untrained males were assigned to an experimental (E) or a control group (C), to re-examine the concept that DMS represents an acute inflammatory response. Subjects were assigned to receive either Indocin (Id; 100 mg per day) for 2 days prior to the treatment and a placebo (P) for 2 days after (Id-P); or the reverse combination (P-Id); or Id for- 4 days (Id-Id); or placebo (P-P). On the treatment day, to induce DMS, E subjects performed 30 min of bench-stepping with one leg leading throughout; C subjects rested for 30 min. Immediately before and after stepping/resting, all subjects used their right and left leg to perform 19 maximal and 15 submaximal repetitions on the Cybex II. Blood samples were collected -5 min before, immediately after bench stepping (0 h), 2 h after and 24, 48 and 72 h, to evaluate WBC. DMS was also monitored 0, 24, 48 and 72 h. All E subjects experienced a significant amount of DMS (p<.01) which peaked at 48 h after exercise (E=7.58 ± .79 vs 0 for C, X±SEM); however, no significant differences in soreness perception were observed between drug and placebo groups. Total WBC count ( cells/mm³ ) was significantly greater at 0 h (8,340±380) than at -5 min (6,699±365) for both E and C; this increase was most likely a response to Cybex exercise. At 2 h there was a significant increase in total WBC count for E ( 9,603±389) and no change for C ( 8,336±273}. Neutrophils increased significantly at 2 h for E only (6,428±375 vs 4,988±261 for C}. Bench-stepping leads to increases in DMS and increases in WBC count, particularly in neutrophils, 2 h after stepping; this data suggests that inflammation is involved in DMS. PART II: EFFECT OF AN ASPIRIN-LIKE DRUG ON PERCEIVED EXERTION DURING BENCH STEPPING The object of this study was to determine whether perceived exertion (RPE) for the limb performing predominantly positive work was significantly greater than for the limb performing predominantly negative work, during 30 min of bench stepping. A second objective was to determine the effects of indomethacin (Id) on RPE. Thirty-nine males were randomly assigned to a drug (Id) or placebo (P) group and administered 150 mg indomechacin or placebo, beginning 36 h prior to stepping. Results indicated no significant differences between RPE for "concentric" and "eccentric" limbs of the P group inspite of the fact that the metabolic demand of the "concentric" limb was much greater. Indomethacin did not significantly alter RPE during stepping however, when RPE scores were totaled over the entire bench stepping period, the Id condition was associated with a greater (p < .01) psychological cost for the "concentric" leg effort as compared to P; this indicated that indomethacin might alter effort sense related to concentric contractions. / Ph. D.

Natural products are complex mixtures of compounds with therapeutic effects which are often reported to be due to the synergistic action of multiple and sometimes unknown components. Consequently, standardization of these products is complex and a lack of effective quality control (QC) criteria in most countries has led to marketing of commercial products with questionable quality, safety and efficacy (QSE). The aim of this study was therefore to develop qualitative and quantitative analytical methods for use in the QC of Ginkgo biloba solid oral dosage forms. Initially, a micellar electrokinetic chromatography (MEKC) method was developed for the identification of the flavonol glycosides, rutin and quercitrin as well as 3 flavonol aglycones, quercetin, kaempferol and isorhamnetin in crude extracts of 4 Ginkgo biloba solid oral dosage forms using ultraviolet (UV) detection. A reversed-flow cyclodextrin-modified MEKC method was subsequently developed for the simultaneous determination of the aforementioned flavonols as well as ginkgolide A, B, C, J and bilobalide (all positive markers) in Ginkgo commercial products. A non-aqueous capillary electrophoresis (CE) method was also developed for fingerprinting the presence of ginkgolic acids (negative markers) in Ginkgo biloba leaf extracts, which are purported to be associated with toxic properties. This method was also applied to 2 Ginkgo biloba commercial products. Since the flavonols have strong UV absorbing chromophores, a reversed phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated using photo-diode-array (PDA) detection which was then successfully applied to fingerprint commercially available Ginkgo biloba solid oral dosage forms as well as quantify the relevant flavonol markers present in these extracts. Sample preparation was simple, rapid and cost efficient with minimal clean-up and the employment of a minibore column which requires low mobile phase flow rates contributed to the economy of the method. Unlike the conventional QC approach, samples were not hydrolyzed and direct determination of 2 intact flavonol glycosides, together with the usual aglycone markers was facilitated which provided maximal content information for fingerprint comparisons. On the other hand, terpene trilactones possess poor chromophores and an alternative detection method to UV was required in order to obtain suitable sensitivity. RP-HPLC with evaporative light scattering detection (ELSD) was selected for quantification of these non-volatile constituents in Ginkgo dosage forms and this method was deemed suitable for the routine QC analysis of these positive markers in commercial products. Since approximately 33 flavonoids have been identified in Ginkgo biloba leaf extracts, baseline separation using UV/PDA detection normally requires complex gradient programs and long analysis times. In addition, unequivocal identification of the flavonoids with similar UV spectra and elution times cannot be guaranteed. A liquid chromatographic tandem mass spectrometric (LC-MS-MS) method was therefore developed and validated in order to ensure accurate quantification of the selected flavonol marker compounds in Ginkgo commercial products. LC-MS-MS analysis of Ginkgo extracts revealed, in addition to rutin, the possible presence of other quercetin analogues, quercetin-3-Orhamnoside-7-O-glucoside or quercetin-3-O-glucoside-7-O-rhamnoside, previously unreported in Ginkgo biloba leaf extracts or dosage forms. In terms of evaluating the most suitable analytical method for QC, CE shows exceptional potential in the future analysis of Ginkgo biloba dosage forms while HPLC-PDA and HPLC-ELSD are currently the most affordable and practical instruments for the routine analysis of the flavonols and terpenoids, respectively. LC-MS-MS proved to be pivotal for the accurate identification and quantification of the flavonols due to interference by other flavonoid compounds with similar retention times and UV spectra to the peaks of interest. All quantitative and qualitative results revealed large discrepancies in the marker content between the products regardless of which batch was analysed and product labels disclosed little relevant information. Although currently not required by most regulatory agencies, some of the usual quality criteria applied to orthodox medicines was evaluated. In particular, dissolution analysis, disintegration, tablet hardness and weight uniformity were assessed and revealed similar inconsistencies. This thesis emphasises that implementation of effective QC criteria is long overdue and is essential to ensure consistent product QSE of commercially available Ginkgo biloba solid oral dosage forms.

differential scanning calorimetric profile and the generation of much less intense and broader peaks in the powder X-ray diffraction pattern compared to beta-CD. FTIR analysis revealed significant physical interactions between CX oil and beta-CD in the granules, possibly due to complexation. Results from phase solubility measurements and proton nuclear magnetic resonance ( 1H-NMR) analysis of pure 3-butylidenephthalide (3-BDPH), a representative CX component, lend some support for the formation of a 1:1 stoichiometric inclusion complex between 3-BDPH and beta-CD. / Rhizoma chuanxiong (CX), the dried rhizome of Ligusticum Chuangxiong Hort. (Umbelliferae), has been extensively used in mainland China as a traditional herbal medicine for treating cardio-/cerebrovascular diseases and gynecological disorders. However, the active components in CX, which are predominantly essential oils, generally exhibit poor stability (mostly photo-oxidation), high volatility, low aqueous solubility, and extensive gut/hepatic metabolism, all of which can significantly reduce their oral bioavailability and therapeutic efficacy. The present project has investigated the feasibility of utilizing three formulation approaches to circumvent the aforementioned problems associated with the peroral delivery of CX (as crude oil mixture or individual components). / The first approach involved inclusion of CX oil in beta-cyclodextrin (beta-CD) as solid granules using a coprecipitation method optimized with the aid of an orthogonal study design. The resulting CX oil granules were colorless and odorless with a median particle size of 11.38mum; were stable to heat, light and moisture, and readily soluble in simulated gastric and intestinal fluids. The granules were largely amorphous, as evidenced by an absence of the melting endotherm for beta-CD in the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix. / The second approach involved incorporation of CX oil into surfactant micelles and liquid crystals as a self-emulsifying drug delivery system (SEDDS). An optimal formulation was developed through a judicial choice of excipients (lipids and surfactants/cosurfactant) and their proper combination in the correct proportions, as determined by the spontaneity of the emulsification process and the change in emulsion droplet size. The formulation was readily dispersible in water upon mild agitation, free from unpleasant odor, and stable in soft gelatin capsules for a storage period of at least 12 months under ambient condition. The optimal utilization of the lipid and surfactant blends in defined proportions in the formulation was further substantiated by interfacial tension determination and equilibrium phase analysis. / The third approach involved formulation of 3-BDPH (or crude CX oil) into a sustained-release buccoadhesive tablet, based on a systematic evaluation of the adhesive properties of two polymers (Carbopol 974P and hydroxypropyl methylcellulose K4M) used in the formulation. The adhesive properties of the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix. / Gao Yuan. / "April 2005." / Adviser: Albert H. L. Chow. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1585. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 193-223). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Quality by Design (QbD) is a systematic approach that has been recommended as suitable for the development of quality pharmaceutical products. The QbD approach commences with the definition of a quality target drug profile and predetermined objectives that are then used to direct the formulation development process with an emphasis on understanding the pharmaceutical science and manufacturing principles that apply to a product. The design space is directly linked to the use of QbD for formulation development and is a multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide an assurance of quality. The objective of these studies was to apply the principles of QbD as a framework for the optimisation of a sustained release (SR) formulation of salbutamol sulphate (SBS), and for the establishment of a design space using Response Surface Methodology (RSM) and Artificial Neural Networks (ANN). SBS is a short-acting ♭₂ agonist that is used for the management of asthma and chronic obstructive pulmonary disease (COPD). The use of a SR formulation of SBS may provide clinical benefits in the management of these respiratory disorders. Ashtalin®8 ER (Cipla Ltd., Mumbai, Maharashtra, India) was selected as a reference formulation for use in these studies. An Ishikawa or Cause and Effect diagram was used to determine the impact of formulation and process factors that have the potential to affect product quality. Key areas of concern that must be monitored include the raw materials, the manufacturing equipment and processes, and the analytical and assessment methods employed. The conditions in the laboratory and manufacturing processes were carefully monitored and recorded for any deviation from protocol, and equipment for assessment of dosage form performance, including dissolution equipment, balances and hardness testers, underwent regular maintenance. Preliminary studies to assess the potential utility of Methocel® Kl OOM, alone and in combination with other matrix forming polymers, revealed that the combination of this polymer with xanthan gum and Carbopol® has the potential to modulate the release of SBS at a specific rate, for a period of 12 hr. A central composite design using Methocel® KlOOM, xanthan gum, Carbopol® 974P and Surelease® as the granulating fluid was constructed to fully evaluate the impact of these formulation variables on the rate and extent of SBS release from manufactured formulations. The results revealed that although Methocel® KlOOM and xanthan gum had the greatest retardant effect on drug release, interactions between the polymers used in the study were also important determinants of the measureable responses. An ANN model was trained for optimisation using the data generated from a central composite study. The efficiency of the network was optimised by assessing the impact of the number of nodes in the hidden layer using a three layer Multi Layer Perceptron (MLP). The results revealed that a network with nine nodes in the hidden layer had the best predictive ability, suitable for application to formulation optimisation studies. Pharmaceutical optimisation was conducted using both the RSM and the trained ANN models. The results from the two optimisation procedures yielded two different formulation compositions that were subjected to in vitro dissolution testing using USP Apparatus 3. The results revealed that, although the formulation compositions that were derived from the optimisation procedures were different, both solutions gave reproducible results for which the dissolution profiles were indeed similar to that of the reference formulation. RSM and ANN were further investigated as possible means of establishing a design space for formulation compositions that would result in dosage forms that have similar in vitro release test profiles comparable to the reference product. Constraint plots were used to determine the bounds of the formulation variables that would result in the manufacture of dosage forms with the desired release profile. ANN simulations with hypothetical formulations that were generated within a small region of the experimental domain were investigated as a means of understanding the impact of varying the composition of the formulation on resultant dissolution profiles. Although both methods were suitable for the establishment of a design space, the use of ANN may be better suited for this purpose because of the manner in which ANN handles data. As more information about the behaviour of a formulation and its processes is generated during the product Iifecycle, ANN may be used to evaluate the impact of formulation and process variables on measureable responses. It is recommended that ANN may be suitable for the optimisation of pharmaceutical formulations and establishment of a design space in line with ICH Pharmaceutical Development [1], Quality Risk Management [2] and Pharmaceutical Quality Systems [3]

L’étude des caractéristiques physico-chimiques du Compritol® (béhénate de glycérol) et du Précirol® (palmito-stéarate de glycérol) a été effectuée. Les méthodes d’évaluation consistaient en la calorimétrie différentielle à balayage, la microscopie sur platine chauffante et la rhéologie dans un rhéomètre capillaire à pression variable. Cette étude a montré une évolution de la structure cristalline de ces deux corps gras en fonction du temps et de la température de stockage. En effet, ces composés, après fusion et refroidissement, « recristallisent » sous une structure partiellement amorphe, qui évolue avec le temps en structure cristalline. Il est également ressorti de cette évaluation que ces deux excipients lipidiques présentent des plages de fusion bien distinctes. Cette caractéristique est conservée lorsqu’ils sont en mélanges binaires. Enfin, ces corps gras se déforment sous l’action de fortes forces de cisaillement à des températures inférieures à leurs plages de fusion. <p>L’utilisation du Compritol® et du Précirol® comme corps gras lipophiles pour former des microbilles à libération prolongée a alors été envisagée. Nous avons procédé moyennant une technique de fabrication simple et rapide appelée « la pelletisation thermoplastique ». Il s’agit d’un procédé en une étape qui met à profit le pouvoir liant des corps gras facilement fusibles et se passe ainsi de l’usage de l’eau ou de solvants organiques. L’appareillage utilisé est de type mélangeur granulateur à haute vitesse. <p>Nous nous sommes basés sur les renseignements fournis par l’étude de préformulation afin d’optimaliser les conditions de fabrication des microbilles. Le contrôle de la température du mélange est très important pour la réussite du procédé de pelletisation thermoplastique. La vitesse du bras du mélangeur, la température de la double paroi et le temps de sphéronisation constituent les paramètres clés pour réussir la pelletisation du mélange. Nous avons mis au point des formulations contenant 15% (m/m) de Précirol® et une quantité croissante de Compritol® variant de 3 à 65 % (m/m). La libération du chlorhydrate de phényléphrine, employé comme agent traceur, a déjà été ralentie pour les formulations contenant 25 % (m/m) de corps gras. Face à ces résultats encourageants, nous avons mis au point des formulations contenant 75 % (m/m) de différents principes actifs (chlorhydrate de ciprofloxacine, théophylline et kétoprofène) et 25 % (m/m) de corps gras. Ces formulations ont abouti à la fabrication de microbilles à libération prolongée. Une étude de stabilité menée sur certaines des formes finies a montré la stabilité des microbilles lipidiques pour autant que le principe actif incorporé dedans ne soit par lui-même facilement dégradable. <p>Afin d’élargir le champ d’application du procédé de fabrication, nous avons mis au point des microbilles flottantes à libération prolongée. Les formulations proposées contiennent comme excipients :les deux corps gras, un mélange effervescent (bicarbonate sodique/ acide tartrique) et du Methocel K100. Leur flottabilité a été prouvée in vitro sur une période de plus de huit heures et In vivo par administration de microbilles de riboflavine flottantes versus non flottantes à des volontaires humains sains.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished