Development, manufacture and assessment of Clobetasol 17-propionate cream formulations
- Authors: Fauzee, Ayeshah Fateemah Beebee
- Date: 2011
- Subjects: Adrenocortical hormones , Adrenocortical hormones -- Physiological effect , Adrenocortical hormones -- Testing , Drugs -- Testing , Drugs -- Development , Dermatopharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3856 , http://hdl.handle.net/10962/d1013324
- Description: Eczema or dermatitis is the most common dermatological condition accounting for one-third of all diagnoses in the total population surveyed in South Africa. The prevalence of seborrhoeic dermatitis, extreme photodermatitis and severe psoriasis has increased markedly over the last decade and this increase may be ascribed to the HIV epidemic, first diagnosed in South Africa in 1982. Potent innovator corticosteroids, such as clobetasol 17-propionate (CP) that are used to treat skin disorders, are expensive and there is therefore a need for the production of generic topical corticosteroid products. Formulation and manufacturing processes can be challenging aspects for formulation scientists to produce a robust product that will elicit an appropriate and desirable pharmacokinetic-pharmacodynamic profile. Laboratory scale CP creams were manufactured using different concentrations of Gelot® 64 and propylene glycol in order to establish a composition that would produce a formulation, with similar physical and chemical characteristics and in vitro release profile as an innovator product, Dermovate®. These formulations were assessed in terms of their viscosity, spreadability, pH, content uniformity and in vitro release characteristics using a Franz diffusion cell apparatus. A formulation containing 3% w/w Gelot® 64 and 46% v/v propylene glycol (CPLS-02) was found to exhibit similar viscosity and spreadability characteristics and released CP in a manner similar to Dermovate®. The mechanism of drug release was evaluated using mathematical models such as zero order, first order and Higuchi models. In addition, the in vitro release profiles were characterised by use of difference (f1) and similarity (f2 and Sd) factors. A scale-up formulation with the same % w/w composition as the laboratory scale was also investigated following manufacture using a Wintech® cream/ointment mixer. A Central Composite Design approach was used to investigate the effect of process variables on the performance of the scale-up cream formulations. The homogenisation speed, anchor speed, homogenisation time and cooling time were the process variables investigated. Thirty scale-up batches were manufactured and analysed in terms of their viscosity, spreadability, pH, % drug content and cumulative % drug released per unit area over 72 hours. Model fitting using Design-Expert® software was undertaken and revealed that a correlation between the process variables and the cream responses was most suitably described by quadratic polynomial relationships. The homogenisation speed had the most significant effect on the quality of the scale-up formulations, whereas the anchor speed had a secondary effect on the measured responses, for the formulations investigated. The qualitative interpretation and statistical analysis of the in vitro release data from the scale-up formulations using ANOVA and the f1, f2 and Sd factors revealed that one scale-up batch (CPSU-04), for which the process variables were a homogenisation speed of 1900 rpm, an anchor speed of 35 rpm, a homogenisation time of 100 minutes and a cooling time of 100 minutes, released CP at a similar rate and extent to Dermovate®. A diffusion-controlled mechanism appeared to be predominant in these formulations. A human skin blanching study, using both visual and chromameter assessments, was performed to establish whether batch CPSU-04 was bioequivalent to Dermovate®. The bioequivalence of the selected scale-up formulation to Dermovate® was confirmed, following the calculation of a 90% CI.
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- Date Issued: 2011
Investigations of the assessment of bioequivalence of topical clotrimazole products using a dermatopharmacokinetic approach
- Authors: Parfitt, Natalie Rae
- Date: 2011 , 2010-07-05
- Subjects: Dermatopharmacology , Drugs -- Therapeutic equivalency , Antifungal agents , Therapeutics, Cutaneous and external
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3840 , http://hdl.handle.net/10962/d1007659 , Dermatopharmacology , Drugs -- Therapeutic equivalency , Antifungal agents , Therapeutics, Cutaneous and external
- Description: The specialised nature of the stratum corneum makes it an efficient barrier to foreign substances, including drug molecules. Therefore, cutaneous drug absorption is a slow and complex process of which stratum corneum penetration is the rate limiting step. The rate and extent of stratum corneum penetration by a drug compound depends greatly on the presence of penetration enhancing/retarding excipients and therefore the clinical outcomes of a product rely greatly on the components and quality of the formulation. Hence, establishing bioequivalence between topical products is crucial to ensure that patients receiving multisource drug products are assured of the same efficacy and safety as the brand product. Since locally acting topical formulations do not target the systemic circulation, conventional methods of assessing bioequivalence using plasma levels are not appropriate. Consequently, the current regulatory guidelines require comparative clinical trials to be carried out to show bioequivalence between topical products. As these studies are very expensive and time consuming, the development of a more direct and relatively rapid and inexpensive method for determining bioequivalence between topical products is required. Clotrimazole is an anti-fungal agent where the target site of action is in the stratum corneum. In this work, tape stripping, which involves the sampling of stratum corneum, was investigated as a tool for the determination of bioequivalence between topical clotrimazole products. The tape stripping method involved the analysis of each tape strip individually and standardization of stratum corneum thickness between subjects was carried out using TEWL measurements. This approach provided detailed information regarding the amount of clotrimazole present in the stratum corneum as well as the extent of drug penetration. Prior to the tape stripping studies an HPLC method was developed for the quantitative analysis of clotrimazole from the tape strip samples. This method was shown to be accurate and reproducible across the required range. It was also shown to be selective for clotrimazole in the presence of possible interfering substances such as those present in the tape adhesive and also skin components. The bioequivalence studies were conducted using a single “uptake” time point. In order to determine an appropriate dose duration for these studies a novel approach was employed, involving a preliminary dose duration study. For the bioequivalence investigations, Canesten® Topical cream was used as both test and reference products to determine if the method was capable of showing bioequivalence. Subsequently, Canesten® Topical cream was also compared to a 1% gel formulation to determine if the method could detect formulation differences. The conventional BE limits of 0.8 – 1.25 were used for the assessment of BE, however, the clinical relevance of using these limits for dermal studies is debatable since they are derived from oral pharmacokinetic studies. Therefore, the data from the tape stripping investigations were also assessed using more realistic limits of 0.75 – 1.33 and even 0.7 – 1.44. In addition to the tape stripping studies a novel method of determining the amount of drug present in the stratum corneum, the “Residual Method”, was investigated. This method involved assaying the amount of clotrimazole found in the residual formulation after a specified dose duration had elapsed and subtracting that amount from the amount of clotrimazole initially applied. The results of tape stripping investigations showed that, if the study is sufficiently powered, tape stripping may be used to determine bioequivalence according to the conventional limits, as well as possibly detect formulation differences between different clotrimazole products. Bioequivalence assessment using the widened intervals showed that fewer subjects were required to achieve a sufficient statistical power. The variability associated with this method was acceptable and tape stripping may therefore have the potential to be used as a BE tool in a regulatory setting for clotrimazole or other antifungal topical formulations. The “Residual Method” also showed promising results as a bioequivalence tool, but further investigation and extensive validation of this method is required before it can be suggested as a regulatory method. The results of these studies have clearly indicated that tape stripping has the potential to be used as an alternative to comparative clinical trails for the assessment of bioequivalence between clotrimazole formulations and also to assess bioequivalence between other antifungal products.
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- Date Issued: 2011
The development and assessment of a fixed dose combination tablet of Ranitidine and Metronidazole
- Authors: King'ori, Loti David
- Date: 2011 , 2011-04-07
- Subjects: Ulcers -- Treatment , Ranitidine -- Evaluation , Metronidazole -- Evaluation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3858 , http://hdl.handle.net/10962/d1013359
- Description: The oral route of drug administration is convenient since it is acceptable to most patients and the manufacturing processes used to produce tablets and capsules are relatively simple when compared to those used to manufacture other types of dosage forms. Metronidazole (MTZ) and Ranitidine (RTD) have been used in combination, as part of triple therapy for the treatment of ulcers. However the use of large numbers of tablets and long duration of therapy makes adherence to drug treatment challenging for patients. Therefore the formulation of a fixed dose combination (FDC) of MTZ and RTD may improve patient adherence to therapy and consequently may reduce morbidity and mortality due to ulcers. A stability indicating HPLC method for the simultaneous analysis of MTZ and RTD was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method was sensitive, selective, precise, accurate and linear.Preformulation studies were performed on the active pharmaceutical ingredients (API) alone and in combination with potential excipients. Differential scanning calorimetry (DSC) studies revealed a potential interaction between MTZ and RTD, however the interaction was not apparent following IR analysis of the same samples. DSC analyses of the API in combination with potential excipients revealed that the compounds were compatible with most materials with the exception of a binary mixture of RTD and Dibasic calcium phosphate (DCP) that exhibited a potential interaction. Thermal gravimetric analysis (TGA) of MTZ and RTD revealed that both compounds exhibited thermal stability. The Carrs Index (CI) and Hausner Ratio (HR) values of MTZ and RTD indicated that both compounds exhibited poor flow and compressibility properties, whereas the CI and HR values for (Microcrystalline cellulose) MCC and DCP indicated better flowability and compressibility characteristics.Direct compression and wet granulation processes were assessed to identify a suitable method of manufacture of FDC tablets of MTZ and RTD. The blends were evaluated using bulk and tapped density and the resultant tablets were evaluated for weight uniformity, crushing strength, tensile strength and disintegration time. The wet granulation method of manufacture produced tablets that showed acceptable pharmacotechnical properties: this approach was therefore used as the method of manufacture of FDC tablets of MTZ and RTD. Tablet formulations comprised of API, viz. MTZ and RTD and different compositions of MCC, DCP, Sodium starch glycolate (SSG) and Croscarmellose sodium (CCS), were manufactured in order to screen for an appropriate diluent and disintegrant composition for use in response surface studies. Assays of tablet content and in vitro drug release were undertaken using the validated HPLC method. Tablets in which MCC and CCS were used appeared to produce better assay and dissolution results as compared to those manufactured using DCP and SSG. Consequently a formulation comprised of MCC and CCS was selected and used in studies in which the effect(s) of level two formulation and composition changes as described in the Scale and Post Approval Changes for Immediate Release (SUPAC-IR) Guidelines on tablet disintegration and in vitro release were assessed. A Box-Behnken statistical design was used for the investigation of the effect of input factors, viz. CCS, (Polyvinyl pyrollidone K30) PVP-K30 and magnesium stearate on measured responses, viz. disintegration time and percent drug release in 10 minutes (Q10). CCS appeared to have an inverse linear relationship on disintegration time and a linear relationship with the Q10 for MTZ and RTD, whereas PVP-K30 and magnesium stearate appeared to have an antagonistic effect on the measured responses. Furthermore CCS and magnesium stearate exhibited an interaction that had an agonistic effect on the Q10 value for RTD. A numerical optimization approach was used to predict a formulation composition that would produce tablets that exhibited a disintegration time and Q10 values for MTZ and RTD that fell within the constraints set in our laboratory. The resultant model was found to be accurate and had a percent prediction error of < 5% for all measured response variables.FDC tablets of MTZ and RTD have been successfully produced. The disintegration of the tablet and dissolution of the API were within compendial specifications and the tablets are of suitable quality and have the potential to be further investigated to reduce the pill burden in the treatment of ulcers.
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- Date Issued: 2011