Lipid nanocarriers : a novel approach to delivering ophthalmic clarithromycin
- Authors: Makoni, Pedzisai Anotida
- Date: 2021
- Subjects: Clarithromycin , Nanomedicine , Nanostructures , Antibiotics , Eye -- Diseases -- Treatment , Ocular pharmacology , Ophthalmic drugs , Karatitis -- Chemotherapy
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/171678 , vital:42109 , 10.21504/10962/171678
- Description: The feasibility of incorporating clarithromycin (CLA) into innovative solid lipid nanoparticles (SLN) and nanostructured lipi d carriers (NLC) using hot emulsification ultrasonication (HEUS) was investigated. This approach was investigated in an attempt to address the shortcomings associated with the use of lyophilized parenteral formulations administered via the ocular route suc h as toxic reactions, intolerance and patient discomfort due to frequent insti llation of topical solutions of CLA. In particular, sustained release approaches to delivery may enhance precorneal retention, increase ocular availability and permit dose reduction or use of a longer dosing frequency when treating ocular non - tuberculous m ycobacterial (NTM) keratitis infections. This approach may potentially improve the delivery of CLA to the eye, thereby addressing some or all of the unmet clinical needs described vide infra . Prior to initiating pre - formulation, formulation development a nd optimization studies of CLA - loaded SLN and/or NLC, Design of Experiments (DoE), specifically a Central Composite Design (CCD) was used in conjunction with Response Surface Methodology (RSM) to develop and optimize a suitable method for the quantitative determination of CLA in pharmaceutical formulations and for monitoring CLA release from SLN and/or NLC in vitro . A simple, accurate, precise, sensitive and stability - indicating reversed phase - high performance liquid chromatography (RP - HPLC) method with ele ctrochemical (EC) detection was developed, validated and optimized for the in vitro analysis of CLA loaded SLN and/or NLC formulations. Pre - formulation studies were undertaken to investigate the thermal stability of CLA and bulk lipids to facilitate the s election of lipid excipients for the manufacture of nanocarriers in addition to establishing compatibility of CLA with the excipients. It was established that CLA was thermostable up to a temperature of approximately 300 °C thereby indicating that HEUS cou ld be used for the manufacture of CLA - loaded SLN and/or NLC. Lipid screening revealed that CLA i s, in general, poorly soluble in solid and liquid lipids however a combination of stearic acid (SA) and Transcutol ® HP (THP) exhibited the best dissolution pote ntial for CLA of all lipids tested . Stearic acid appears to exist as polymorphic form B prior to exposure to heat however occurs as the form C polymorph following heating at 85 °C for one hour. The best ratio for the mixture of SA and THP for the manufactu re of CLA - NLC ii was an 80:20 ( w/w ) ratio of SA: THP as the two lipids are miscible in this ratio and exhibited the greatest dissolution potential for CLA. Furthermore, an investigation of binary mixtures of CLA/SA and SA/Transcutol ® HP, in addition to eutect ic mixtures of CLA, SA and Transcutol ® HP, revealed no obvious interaction between CLA and the lipids selected for the production of the nanocarriers. Due to the relatively high solubility of CLA in THP in comparison to SA, NLC are likely to exhibit a hig her loading capacity (LC) and encapsulation efficiency (EE) for CLA than SLN. Consequently the feasibility of incorporating CLA (10% w/w ) into NLC was investigated and evaluation of the production of SLN was not undertaken as the production of these might not result in the manufacture of a delivery technology with a high EE and LC for CLA. Tween ® 20 was used as the surfactant as it is readily available, exhibits little or no cytotoxicity and is relatively cheap. Polyethylene glycol (PEG) was used as a coati ng polymer to impart muco - adhesive properties the formulated CLA - NLC. Response surface methodology (RSM) in conjunction with DoE, specifically a Box - Behnken Design (BBD) used as a screening design was used to identify a formulation composition which would produce a product that would meet the pre - defined target critical quality attributes (CQA) for the nanoparticles viz. particle size (PS) in the nano - range, polydispersity index (PDI) < 0.5, Zeta Potential (ZP) ≥ ± 30 mV, and EE > 80%. The formulation composition identified was subsequently used for the optimization of the manufacturing parameters viz. sonication time and amplitude, using a Central Composite Design (CCD) . The LC and EE, in vitro CLA release, cytotoxicity, osmolarity, pH, degree of crystallinity and lipid modification, elemental analysis and surface morphology of the optimized batch was investigated and mon itored to ensure that CLA - loaded NLC, of the desirable quality, had been produced. On the day of manufacture the mean PS and PDI of the optimized CLA - loaded NLC formulation adjusted to physiological osmolarity (250 – 450 mOsm/kg) was 461.9 ± 40.16 nm and 0. 523 ± 0.104, respectively. The ZP for the optimized NLC generated on the day of manufacture using HPLC grade water as the dispersion medium was - 20.5 ± 4.82 mV. The pH and osmolarity of the optimized CLA - loaded NLC formulation was 7.76 ± 0.01 and 316 ± iii 2 m Osm/Kg, respectively and the EE was 88.62 ± 0.23 %. The optimized NLC exhibited a decreased crystallinity in comparison to the bulk lipid materials. DSC, WAXS and FT - IR revealed that CLA was molecularly dispersed in the nanocarriers. The optimized CLA - load ed NLC exhibited muco - adhesive properties, when tested under stationary conditions using laser doppler anemometry (LDA). The optimized formulation also exhibited sustained release of CLA over 24 hours during in vitro release testing and CLA release was bes t described using the Baker - Lonsdale model . The cumulative % CLA released over 24 hours was 56.13 ± 0.23% and mass balance analysis revealed 41.38 ± 0.02% CLA had been retained in the NLC. In vitro cytotoxicity testing revealed that the optimized CLA - NLC w ere less cytotoxic to HeLa cells when compared to CLA alone and further confirmed that the lipids and excipients used in these studies were of GRAS status . Stability studies revealed that the EE reduced over 28 days by 14.42% and 5.14% when stored at 4 °C and 22 °C , respectively. In addition, the particle size increased from the nm to μm range for samples stored at 22 °C. The findings are a good starting point but require further optimization to ensure prolongation of stability. In addition , the technology requires additional developmental studies and a powder for reconstitution for use as a single - dose considered as single dose packaging may be a solution to the compromised formulation stability observed in these studies. The CLA - NLC produced in these stu dies exhibit sound product attributes which serve as a useful foundation for the novel delivery of antibiotics to the eye. The results suggest that the optimized NLC have the potential to enhance precorneal retention and increase ocular availability of CLA , which in turn may be useful to reduce the required dose and dosing frequency when administering CLA as a reconstituted solution to treat susceptible organisms that infect ocular tissues.
- Full Text:
- Date Issued: 2021
- Authors: Makoni, Pedzisai Anotida
- Date: 2021
- Subjects: Clarithromycin , Nanomedicine , Nanostructures , Antibiotics , Eye -- Diseases -- Treatment , Ocular pharmacology , Ophthalmic drugs , Karatitis -- Chemotherapy
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/171678 , vital:42109 , 10.21504/10962/171678
- Description: The feasibility of incorporating clarithromycin (CLA) into innovative solid lipid nanoparticles (SLN) and nanostructured lipi d carriers (NLC) using hot emulsification ultrasonication (HEUS) was investigated. This approach was investigated in an attempt to address the shortcomings associated with the use of lyophilized parenteral formulations administered via the ocular route suc h as toxic reactions, intolerance and patient discomfort due to frequent insti llation of topical solutions of CLA. In particular, sustained release approaches to delivery may enhance precorneal retention, increase ocular availability and permit dose reduction or use of a longer dosing frequency when treating ocular non - tuberculous m ycobacterial (NTM) keratitis infections. This approach may potentially improve the delivery of CLA to the eye, thereby addressing some or all of the unmet clinical needs described vide infra . Prior to initiating pre - formulation, formulation development a nd optimization studies of CLA - loaded SLN and/or NLC, Design of Experiments (DoE), specifically a Central Composite Design (CCD) was used in conjunction with Response Surface Methodology (RSM) to develop and optimize a suitable method for the quantitative determination of CLA in pharmaceutical formulations and for monitoring CLA release from SLN and/or NLC in vitro . A simple, accurate, precise, sensitive and stability - indicating reversed phase - high performance liquid chromatography (RP - HPLC) method with ele ctrochemical (EC) detection was developed, validated and optimized for the in vitro analysis of CLA loaded SLN and/or NLC formulations. Pre - formulation studies were undertaken to investigate the thermal stability of CLA and bulk lipids to facilitate the s election of lipid excipients for the manufacture of nanocarriers in addition to establishing compatibility of CLA with the excipients. It was established that CLA was thermostable up to a temperature of approximately 300 °C thereby indicating that HEUS cou ld be used for the manufacture of CLA - loaded SLN and/or NLC. Lipid screening revealed that CLA i s, in general, poorly soluble in solid and liquid lipids however a combination of stearic acid (SA) and Transcutol ® HP (THP) exhibited the best dissolution pote ntial for CLA of all lipids tested . Stearic acid appears to exist as polymorphic form B prior to exposure to heat however occurs as the form C polymorph following heating at 85 °C for one hour. The best ratio for the mixture of SA and THP for the manufactu re of CLA - NLC ii was an 80:20 ( w/w ) ratio of SA: THP as the two lipids are miscible in this ratio and exhibited the greatest dissolution potential for CLA. Furthermore, an investigation of binary mixtures of CLA/SA and SA/Transcutol ® HP, in addition to eutect ic mixtures of CLA, SA and Transcutol ® HP, revealed no obvious interaction between CLA and the lipids selected for the production of the nanocarriers. Due to the relatively high solubility of CLA in THP in comparison to SA, NLC are likely to exhibit a hig her loading capacity (LC) and encapsulation efficiency (EE) for CLA than SLN. Consequently the feasibility of incorporating CLA (10% w/w ) into NLC was investigated and evaluation of the production of SLN was not undertaken as the production of these might not result in the manufacture of a delivery technology with a high EE and LC for CLA. Tween ® 20 was used as the surfactant as it is readily available, exhibits little or no cytotoxicity and is relatively cheap. Polyethylene glycol (PEG) was used as a coati ng polymer to impart muco - adhesive properties the formulated CLA - NLC. Response surface methodology (RSM) in conjunction with DoE, specifically a Box - Behnken Design (BBD) used as a screening design was used to identify a formulation composition which would produce a product that would meet the pre - defined target critical quality attributes (CQA) for the nanoparticles viz. particle size (PS) in the nano - range, polydispersity index (PDI) < 0.5, Zeta Potential (ZP) ≥ ± 30 mV, and EE > 80%. The formulation composition identified was subsequently used for the optimization of the manufacturing parameters viz. sonication time and amplitude, using a Central Composite Design (CCD) . The LC and EE, in vitro CLA release, cytotoxicity, osmolarity, pH, degree of crystallinity and lipid modification, elemental analysis and surface morphology of the optimized batch was investigated and mon itored to ensure that CLA - loaded NLC, of the desirable quality, had been produced. On the day of manufacture the mean PS and PDI of the optimized CLA - loaded NLC formulation adjusted to physiological osmolarity (250 – 450 mOsm/kg) was 461.9 ± 40.16 nm and 0. 523 ± 0.104, respectively. The ZP for the optimized NLC generated on the day of manufacture using HPLC grade water as the dispersion medium was - 20.5 ± 4.82 mV. The pH and osmolarity of the optimized CLA - loaded NLC formulation was 7.76 ± 0.01 and 316 ± iii 2 m Osm/Kg, respectively and the EE was 88.62 ± 0.23 %. The optimized NLC exhibited a decreased crystallinity in comparison to the bulk lipid materials. DSC, WAXS and FT - IR revealed that CLA was molecularly dispersed in the nanocarriers. The optimized CLA - load ed NLC exhibited muco - adhesive properties, when tested under stationary conditions using laser doppler anemometry (LDA). The optimized formulation also exhibited sustained release of CLA over 24 hours during in vitro release testing and CLA release was bes t described using the Baker - Lonsdale model . The cumulative % CLA released over 24 hours was 56.13 ± 0.23% and mass balance analysis revealed 41.38 ± 0.02% CLA had been retained in the NLC. In vitro cytotoxicity testing revealed that the optimized CLA - NLC w ere less cytotoxic to HeLa cells when compared to CLA alone and further confirmed that the lipids and excipients used in these studies were of GRAS status . Stability studies revealed that the EE reduced over 28 days by 14.42% and 5.14% when stored at 4 °C and 22 °C , respectively. In addition, the particle size increased from the nm to μm range for samples stored at 22 °C. The findings are a good starting point but require further optimization to ensure prolongation of stability. In addition , the technology requires additional developmental studies and a powder for reconstitution for use as a single - dose considered as single dose packaging may be a solution to the compromised formulation stability observed in these studies. The CLA - NLC produced in these stu dies exhibit sound product attributes which serve as a useful foundation for the novel delivery of antibiotics to the eye. The results suggest that the optimized NLC have the potential to enhance precorneal retention and increase ocular availability of CLA , which in turn may be useful to reduce the required dose and dosing frequency when administering CLA as a reconstituted solution to treat susceptible organisms that infect ocular tissues.
- Full Text:
- Date Issued: 2021
Preparation, characterization and optimization of carbamazepine based pellets prepared by extrusion-spheronization technique
- Authors: Makoni, Kudzai Gabriella
- Date: 2020-04
- Subjects: Carbamazepine , Pharmacokinetics , Anticonvulsants , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Drugs -- Administration , High performance liquid chromatography , International Conference on Harmonisation , Experimental design
- Language: English
- Type: Thesis , Masters , MSc (Pharmacy)
- Identifier: http://hdl.handle.net/10962/140478 , vital:37893
- Description: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) that is prescribed as a first-line treatment for partial seizures. CBZ is a class II compound according to the Biopharmaceutical Classification System (BCS), hence it exhibits low aqueous solubility and high gastrointestinal tract (GIT) permeability...
- Full Text:
- Date Issued: 2020-04
- Authors: Makoni, Kudzai Gabriella
- Date: 2020-04
- Subjects: Carbamazepine , Pharmacokinetics , Anticonvulsants , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Drugs -- Administration , High performance liquid chromatography , International Conference on Harmonisation , Experimental design
- Language: English
- Type: Thesis , Masters , MSc (Pharmacy)
- Identifier: http://hdl.handle.net/10962/140478 , vital:37893
- Description: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) that is prescribed as a first-line treatment for partial seizures. CBZ is a class II compound according to the Biopharmaceutical Classification System (BCS), hence it exhibits low aqueous solubility and high gastrointestinal tract (GIT) permeability...
- Full Text:
- Date Issued: 2020-04
Establishing a formulation design space for a generic clobetasol 17- propionate cream using the principles of quality by design
- Fauzee, Ayeshah Fateemah Beebee
- Authors: Fauzee, Ayeshah Fateemah Beebee
- Date: 2014
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:20983 , http://hdl.handle.net/10962/5868
- Description: The pharmaceutical industry is global, is highly regulated and is able to achieve reasonable product quality but at high cost with maximum effort. Numerous challenges face the pharmaceutical industry and include a shrinking research pipeline, less innovation, outsourcing, investments, increasing research and development costs, long approval times, growth of the generic industry, failure to understand or analyze manufacturing failure and wastage as high at fifty percent for some pharmaceutical products. An efficient and flexible pharmaceutical sector should be able to consistently produce high quality pharmaceutical products at a reduced cost with minimal waste. As a result, Food and Drug Administration (FDA) and other agencies such as the International Conference on Harmonization (ICH) have embraced a “Quality by Design” (QbD) paradigm and this has become the “desired state” so as to shift manufacturing from being empirical to a science, engineering, and risk based approach. QbD is a systematic approach for the development of high quality pharmaceutical dosage forms that begins with predefined objectives based on the premise that quality must be built into and not tested into a product. QbD together with the establishment of a design space for dosage forms is a fairly new concept and there is limited published data on QbD concepts that report the entire process of identifying Critical Quality Attributes (CQA), design of a formulation and manufacturing process to meet product CQA, understanding the impact of material attributes and process parameters on product CQA, identification and controlling sources of variability in materials and processes that affect the CQA of a product and finally establishing, evaluating and testing a design space using both in vitro and in vivo approaches to assure that a product of consistent quality can always be produced. The objective of these studies was to implement a QbD approach to establish a design space for the development and manufacture of a safe, effective, stable generic formulation containing 0.05% w/w clobetasol 17-propionate (CP) that had similar in vitro and in vivo characteristics to an innovator product, Dermovate® (Sekpharma® Pty Ltd, Sandton, Gauteng, RSA). Such a product would pose a minimal risk of failure when treating severe skin disorders such as seborrhoeic dermatitis, extreme photodermatitis and/or severe psoriasis in HIV/AIDS patients in Southern Africa.
- Full Text:
- Date Issued: 2014
- Authors: Fauzee, Ayeshah Fateemah Beebee
- Date: 2014
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:20983 , http://hdl.handle.net/10962/5868
- Description: The pharmaceutical industry is global, is highly regulated and is able to achieve reasonable product quality but at high cost with maximum effort. Numerous challenges face the pharmaceutical industry and include a shrinking research pipeline, less innovation, outsourcing, investments, increasing research and development costs, long approval times, growth of the generic industry, failure to understand or analyze manufacturing failure and wastage as high at fifty percent for some pharmaceutical products. An efficient and flexible pharmaceutical sector should be able to consistently produce high quality pharmaceutical products at a reduced cost with minimal waste. As a result, Food and Drug Administration (FDA) and other agencies such as the International Conference on Harmonization (ICH) have embraced a “Quality by Design” (QbD) paradigm and this has become the “desired state” so as to shift manufacturing from being empirical to a science, engineering, and risk based approach. QbD is a systematic approach for the development of high quality pharmaceutical dosage forms that begins with predefined objectives based on the premise that quality must be built into and not tested into a product. QbD together with the establishment of a design space for dosage forms is a fairly new concept and there is limited published data on QbD concepts that report the entire process of identifying Critical Quality Attributes (CQA), design of a formulation and manufacturing process to meet product CQA, understanding the impact of material attributes and process parameters on product CQA, identification and controlling sources of variability in materials and processes that affect the CQA of a product and finally establishing, evaluating and testing a design space using both in vitro and in vivo approaches to assure that a product of consistent quality can always be produced. The objective of these studies was to implement a QbD approach to establish a design space for the development and manufacture of a safe, effective, stable generic formulation containing 0.05% w/w clobetasol 17-propionate (CP) that had similar in vitro and in vivo characteristics to an innovator product, Dermovate® (Sekpharma® Pty Ltd, Sandton, Gauteng, RSA). Such a product would pose a minimal risk of failure when treating severe skin disorders such as seborrhoeic dermatitis, extreme photodermatitis and/or severe psoriasis in HIV/AIDS patients in Southern Africa.
- Full Text:
- Date Issued: 2014
The development of an orodispersible sildenafil citrate tablet intended for paediatric use
- Authors: Dagnolo, Bianca
- Date: 2012
- Subjects: Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3751 , http://hdl.handle.net/10962/d1003229 , Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Description: Sildenafil citrate (SC) is a phosphodiesterase-5 inhibitor that is used to treat pulmonary hypertension (PH) in paediatric patients. The purpose of these studies was to develop a formulation and manufacture an orodispersible tablet (ODT) that can be easily administered to neonates and children with PH. The advantages of ODT dosage forms include ease of administration, rapid dissolution of the API, SC. Furthermore the dosage form can be taken without water which is beneficial to patients without immediate access to potable fluids. A simple, rapid, accurate, precise and selective reversed-phase HPLC method was developed and validated in accordance with International Conference on Harmonization (ICH) guidelines and was successfully used for the analysis of SC as raw material and in SC containing pharmaceutical dosage forms. Preformulation studies were performed on SC, alone and in combination with potential excipients that could be used to make tablets. Investigations into potential interactions between SC and the excipients were performed using Differential Scanning Calorimetry (DSC) and Infrared Spectroscopy (IR). DSC results revealed that SC was compatible with all potential excipients except mannitol and magnesium stearate. However these interactions were not observed with IR and therefore it was concluded that the interactions were induced by the high temperatures that DSC operates at. Particle size and shape was also established by use of Scanning Electron Microscopy (SEM) and flow properties were monitored by calculating Carr’s Index (CI) and the Hausner Ratio (HR). Direct compression was used as the method of manufacture for SC tablets as this approach is simple and the most economic production approach. The powder blends were assessed for bulk and tapped density and the CI and HR were used to determine the flowability of the blends. The quality attributes of the resultant tablets that were monitored included uniformity of weight, friability, crushing strength, tensile strength, disintegration, wetting and in vitro dispersion times. Design of Experiments is an efficient statistical approach that has become a popular tool used in the pharmaceutical industry to optimize formulation compositions, as it allows for the investigation of several input factors at the same time whilst not using the tedious and traditional “ modification of one variable at a time” approach. A Central composite experimental design was chosen as the most appropriate means to optimize the formulation as it produces more accurate results as opposed to other experimental designs approaches as input factors are investigated at five different levels. Through the use of mathematical modelling, optimum concentrations of disintegrant(s) and an appropriate blending time were established. Analysis of the data from the experimental design and mathematical modelling studies reveal that no changes in disintegrant concentration or blending time altered the disintegration time of the formulation to any significant extent. This result is most likely due to the fact that the critical disintegrant concentration has been reached and increasing the disintegrant concentration further has no effect on disintegration time. It was also established that a change in the concentration of CMS and CRP altered the wetting time of the tablet significantly. Finally it was noted that there was a linear relationship between blending time and the uniformity of content of the tablets produced in these studies. The optimized product was a white tablet with a diameter of 7.31 mm with a thickness of 2.80mm.The dosage form had no visible cracks or evidence of picking or sticking. The tablet exhibits suitable friability and tensile strength while exhibiting a disintegration time of only 8s. Therefore an orodispersible tablet containing SC intended for paediatric use has been successfully developed, manufactured and optimized through the use of preformulation studies, appropriate quality control monitoring and mathematical modelling. These formulations require further optimization in respect of addition of flavours and or additional sweetening agents.
- Full Text:
- Date Issued: 2012
- Authors: Dagnolo, Bianca
- Date: 2012
- Subjects: Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3751 , http://hdl.handle.net/10962/d1003229 , Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Description: Sildenafil citrate (SC) is a phosphodiesterase-5 inhibitor that is used to treat pulmonary hypertension (PH) in paediatric patients. The purpose of these studies was to develop a formulation and manufacture an orodispersible tablet (ODT) that can be easily administered to neonates and children with PH. The advantages of ODT dosage forms include ease of administration, rapid dissolution of the API, SC. Furthermore the dosage form can be taken without water which is beneficial to patients without immediate access to potable fluids. A simple, rapid, accurate, precise and selective reversed-phase HPLC method was developed and validated in accordance with International Conference on Harmonization (ICH) guidelines and was successfully used for the analysis of SC as raw material and in SC containing pharmaceutical dosage forms. Preformulation studies were performed on SC, alone and in combination with potential excipients that could be used to make tablets. Investigations into potential interactions between SC and the excipients were performed using Differential Scanning Calorimetry (DSC) and Infrared Spectroscopy (IR). DSC results revealed that SC was compatible with all potential excipients except mannitol and magnesium stearate. However these interactions were not observed with IR and therefore it was concluded that the interactions were induced by the high temperatures that DSC operates at. Particle size and shape was also established by use of Scanning Electron Microscopy (SEM) and flow properties were monitored by calculating Carr’s Index (CI) and the Hausner Ratio (HR). Direct compression was used as the method of manufacture for SC tablets as this approach is simple and the most economic production approach. The powder blends were assessed for bulk and tapped density and the CI and HR were used to determine the flowability of the blends. The quality attributes of the resultant tablets that were monitored included uniformity of weight, friability, crushing strength, tensile strength, disintegration, wetting and in vitro dispersion times. Design of Experiments is an efficient statistical approach that has become a popular tool used in the pharmaceutical industry to optimize formulation compositions, as it allows for the investigation of several input factors at the same time whilst not using the tedious and traditional “ modification of one variable at a time” approach. A Central composite experimental design was chosen as the most appropriate means to optimize the formulation as it produces more accurate results as opposed to other experimental designs approaches as input factors are investigated at five different levels. Through the use of mathematical modelling, optimum concentrations of disintegrant(s) and an appropriate blending time were established. Analysis of the data from the experimental design and mathematical modelling studies reveal that no changes in disintegrant concentration or blending time altered the disintegration time of the formulation to any significant extent. This result is most likely due to the fact that the critical disintegrant concentration has been reached and increasing the disintegrant concentration further has no effect on disintegration time. It was also established that a change in the concentration of CMS and CRP altered the wetting time of the tablet significantly. Finally it was noted that there was a linear relationship between blending time and the uniformity of content of the tablets produced in these studies. The optimized product was a white tablet with a diameter of 7.31 mm with a thickness of 2.80mm.The dosage form had no visible cracks or evidence of picking or sticking. The tablet exhibits suitable friability and tensile strength while exhibiting a disintegration time of only 8s. Therefore an orodispersible tablet containing SC intended for paediatric use has been successfully developed, manufactured and optimized through the use of preformulation studies, appropriate quality control monitoring and mathematical modelling. These formulations require further optimization in respect of addition of flavours and or additional sweetening agents.
- Full Text:
- Date Issued: 2012
Development, manufacture and assessment of Clobetasol 17-propionate cream formulations
- Fauzee, Ayeshah Fateemah Beebee
- 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.
- Full Text:
- Date Issued: 2011
- 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.
- Full Text:
- 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.
- Full Text:
- Date Issued: 2011
- 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.
- Full Text:
- Date Issued: 2011
Development and assessment of minocycline sustained release capsule formulations
- Sachikonye, Tinotenda Chipo Victoria
- Authors: Sachikonye, Tinotenda Chipo Victoria
- Date: 2010
- Subjects: Drugs -- Controlled release , Drugs -- Dosage forms , Capsules (Pharmacy) , Drugs -- Administration , Acne -- Treatment , Tetracyclines , Antibiotics -- Side effects
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3854 , http://hdl.handle.net/10962/d1013127
- Description: The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.
- Full Text:
- Date Issued: 2010
- Authors: Sachikonye, Tinotenda Chipo Victoria
- Date: 2010
- Subjects: Drugs -- Controlled release , Drugs -- Dosage forms , Capsules (Pharmacy) , Drugs -- Administration , Acne -- Treatment , Tetracyclines , Antibiotics -- Side effects
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3854 , http://hdl.handle.net/10962/d1013127
- Description: The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.
- Full Text:
- Date Issued: 2010
Development and assessment of azithromycin paediatric suppository formulations
- Authors: Mollel, Happiness
- Date: 2006
- Subjects: Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3774 , http://hdl.handle.net/10962/d1003252 , Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Description: The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.
- Full Text:
- Date Issued: 2006
- Authors: Mollel, Happiness
- Date: 2006
- Subjects: Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3774 , http://hdl.handle.net/10962/d1003252 , Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
- Description: The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.
- Full Text:
- Date Issued: 2006
Formulation and assessment of monolithic beta blocker sustained release tablets prepared by direct compression
- Authors: Kieser, Leith Faye
- Date: 2002
- Subjects: Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3764 , http://hdl.handle.net/10962/d1003242 , Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Description: Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.
- Full Text:
- Date Issued: 2002
- Authors: Kieser, Leith Faye
- Date: 2002
- Subjects: Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3764 , http://hdl.handle.net/10962/d1003242 , Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Description: Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.
- Full Text:
- Date Issued: 2002
Formulation and dissolution assessment of a novel repeat action tablet containing a decongestant and an antihistamine
- Authors: Verner, Jennifer Joan
- Date: 2001
- Subjects: Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3798 , http://hdl.handle.net/10962/d1003276 , Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Description: Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.
- Full Text:
- Date Issued: 2001
- Authors: Verner, Jennifer Joan
- Date: 2001
- Subjects: Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3798 , http://hdl.handle.net/10962/d1003276 , Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Description: Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.
- Full Text:
- Date Issued: 2001
Assessment of amoxycillin suppositories
- Authors: Webster, Jessica Angela
- Date: 1997
- Subjects: Solid dosage forms , Suppositories , Amoxicillin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3802 , http://hdl.handle.net/10962/d1003280 , Solid dosage forms , Suppositories , Amoxicillin
- Description: The investigations in this dissertation have been 'conducted to investigate the formulation and analysis of a paediatric amoxycillin suppository. The oral administration of antibiotics to young children can at times be roblematic. Compliance is sometimes poor because of a sore throat, nausea, vomiting, a high fever or a dislike for the taste or smell of the medicine:- In-such cases the rectal administration of an antibiotic could provide an alternative route of administration that avoids some of the problems that affect oral administration. Difficulties associated with rectal administration are bioavailability, local irritation, acceptability to patients and rejection of the dosage form. Few data, however, are available on the usefulness in children of suppositories in general, and antibiotic suppositories in particular. The areas of investigation have included the formulation of an amoxycillin suppository in various fatty bases, the quantitation of amoxycillin in both aqueous solution and human serum, assessment of stability of amoxycillin in stored aqueous and biological samples, in vitro drug release testing of suppositories, and bioavailability and pharmacokinetics following administration to human subjects of capsule, suppository, oral suspension and rectal suspension dosage forms. Suppositories containing 250 mg amoxycillin were prepared in theobroma oil and in the semisynthetic bases Witepso[ W35, Suppocire A32, Novata BD and Novata 299. The in vitro release characteristics of amoxycillin from these lipophilic suppository formulations were investigated using the USP rotating basket method. The dissolution of a drug from a solid dosage unit is an important parameter affecting drug bioavialability. High Performance Liquid Chromatography (HPLC) was used as the main analytical technique. An original HPLC method for analysis of amoxycillin in aqueous solution, using ultraviolet detection at 230 nm was develcfped. The validated method was a~plied to the determination of the stability of aqueous amoxycillin solutions, and was utilized to determine the amount of drug released during dissolution testing. Differential scanning calorimetry (DSC) is a technique commonly used in preformulation studies. Dissolution testing was used in conjunction with DSC to select a suppository base suitable for formulation with amoxycillin trihydrate. An HPLC method for analysis of amoxycillin in human serum using UV detection at 230 nm is presented. The method involves a solid phase extraction procedure followed by chromatography on a reversed phase column. The limit of sensitivity of 0.3 ILg/mL in serum is sufficiently sensitive to monitor serum concentrations of amoxycillin in humans after the administration of a single 250 mg oral dose. Pharmacokinetic parameters were calculated from data obtained following the administration of a capsule and oral suspension. These parameters were consistent with previously published results. Following administration of a lipophilic suppository and a rectal suspension, to human volunteers, it was concluded that amoxycillin trihydrate is not readily absorbed from the rectum. Further investigations into the modification of the suppository dosage form with absorption enhancers to improve rectal absorption of amoxycillin, as well as elucidation of the mechanism of absorption of the drug, could assist in improving this formulation so that it is suitable for paediatric use.
- Full Text:
- Date Issued: 1997
- Authors: Webster, Jessica Angela
- Date: 1997
- Subjects: Solid dosage forms , Suppositories , Amoxicillin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3802 , http://hdl.handle.net/10962/d1003280 , Solid dosage forms , Suppositories , Amoxicillin
- Description: The investigations in this dissertation have been 'conducted to investigate the formulation and analysis of a paediatric amoxycillin suppository. The oral administration of antibiotics to young children can at times be roblematic. Compliance is sometimes poor because of a sore throat, nausea, vomiting, a high fever or a dislike for the taste or smell of the medicine:- In-such cases the rectal administration of an antibiotic could provide an alternative route of administration that avoids some of the problems that affect oral administration. Difficulties associated with rectal administration are bioavailability, local irritation, acceptability to patients and rejection of the dosage form. Few data, however, are available on the usefulness in children of suppositories in general, and antibiotic suppositories in particular. The areas of investigation have included the formulation of an amoxycillin suppository in various fatty bases, the quantitation of amoxycillin in both aqueous solution and human serum, assessment of stability of amoxycillin in stored aqueous and biological samples, in vitro drug release testing of suppositories, and bioavailability and pharmacokinetics following administration to human subjects of capsule, suppository, oral suspension and rectal suspension dosage forms. Suppositories containing 250 mg amoxycillin were prepared in theobroma oil and in the semisynthetic bases Witepso[ W35, Suppocire A32, Novata BD and Novata 299. The in vitro release characteristics of amoxycillin from these lipophilic suppository formulations were investigated using the USP rotating basket method. The dissolution of a drug from a solid dosage unit is an important parameter affecting drug bioavialability. High Performance Liquid Chromatography (HPLC) was used as the main analytical technique. An original HPLC method for analysis of amoxycillin in aqueous solution, using ultraviolet detection at 230 nm was develcfped. The validated method was a~plied to the determination of the stability of aqueous amoxycillin solutions, and was utilized to determine the amount of drug released during dissolution testing. Differential scanning calorimetry (DSC) is a technique commonly used in preformulation studies. Dissolution testing was used in conjunction with DSC to select a suppository base suitable for formulation with amoxycillin trihydrate. An HPLC method for analysis of amoxycillin in human serum using UV detection at 230 nm is presented. The method involves a solid phase extraction procedure followed by chromatography on a reversed phase column. The limit of sensitivity of 0.3 ILg/mL in serum is sufficiently sensitive to monitor serum concentrations of amoxycillin in humans after the administration of a single 250 mg oral dose. Pharmacokinetic parameters were calculated from data obtained following the administration of a capsule and oral suspension. These parameters were consistent with previously published results. Following administration of a lipophilic suppository and a rectal suspension, to human volunteers, it was concluded that amoxycillin trihydrate is not readily absorbed from the rectum. Further investigations into the modification of the suppository dosage form with absorption enhancers to improve rectal absorption of amoxycillin, as well as elucidation of the mechanism of absorption of the drug, could assist in improving this formulation so that it is suitable for paediatric use.
- Full Text:
- Date Issued: 1997
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