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.
- Full Text:
- Date Issued: 2011
- 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.
- Full Text:
- Date Issued: 2011
Creating a new underclass : labour flexibility and the temporary employment services industry
- Authors: Van Der Merwe, Christine
- Date: 2010
- Subjects: Temporary employment , Unfair labor practices -- South Africa , Temporary help services , Temporary help services -- South Africa
- Language: English
- Type: Thesis , Masters , MSocSc
- Identifier: vital:3291 , http://hdl.handle.net/10962/d1003079 , Temporary employment , Unfair labor practices -- South Africa , Temporary help services , Temporary help services -- South Africa
- Description: The core of the research focuses on the Temporary Employment Services (TES) Industry and its ability to provide labour flexibility for a number of client firms. The underlying notion that work is changing and becoming more flexible creates an exploratory realm for the concept of non-standard employment. The thesis draws on the conceptual model of the „flexible firm‟ and argues that the rise in non-standard forms of employment, particularly temporary employment within the TES industry, is primarily a result of the demand for labour flexibility. The TES industry that offers „labour on demand‟ is found to be an extremely secretive industry that is diverse in both its structure and services. The thesis reveals that the clients within the triangular employment relationship (TER) are reaping the most benefits especially with regard to escaping their obligations as the employer. The thesis explores human resource practices, unfair labour practices and the extensive loopholes exploited by the TES industry because of poor regulation. Consequently, the industry creates an „underclass‟ that is unprotected, insecure and easily exploitable. Qualitative research techniques were used in the form of semi-structured interviews. The thesis provides insights into the demand and supply of temporary workers in Port Elizabeth and addresses the problems associated with a TER and the TES industry as a whole.
- Full Text:
- Date Issued: 2010
- Authors: Van Der Merwe, Christine
- Date: 2010
- Subjects: Temporary employment , Unfair labor practices -- South Africa , Temporary help services , Temporary help services -- South Africa
- Language: English
- Type: Thesis , Masters , MSocSc
- Identifier: vital:3291 , http://hdl.handle.net/10962/d1003079 , Temporary employment , Unfair labor practices -- South Africa , Temporary help services , Temporary help services -- South Africa
- Description: The core of the research focuses on the Temporary Employment Services (TES) Industry and its ability to provide labour flexibility for a number of client firms. The underlying notion that work is changing and becoming more flexible creates an exploratory realm for the concept of non-standard employment. The thesis draws on the conceptual model of the „flexible firm‟ and argues that the rise in non-standard forms of employment, particularly temporary employment within the TES industry, is primarily a result of the demand for labour flexibility. The TES industry that offers „labour on demand‟ is found to be an extremely secretive industry that is diverse in both its structure and services. The thesis reveals that the clients within the triangular employment relationship (TER) are reaping the most benefits especially with regard to escaping their obligations as the employer. The thesis explores human resource practices, unfair labour practices and the extensive loopholes exploited by the TES industry because of poor regulation. Consequently, the industry creates an „underclass‟ that is unprotected, insecure and easily exploitable. Qualitative research techniques were used in the form of semi-structured interviews. The thesis provides insights into the demand and supply of temporary workers in Port Elizabeth and addresses the problems associated with a TER and the TES industry as a whole.
- Full Text:
- Date Issued: 2010
Laboratory and occupation-simulating isokinetic and psychophysical responses of military personnel
- Authors: James, Jonathan Peter
- Date: 2001
- Subjects: Isokinetic exercise , Soldiers -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:5126 , http://hdl.handle.net/10962/d1005204 , Isokinetic exercise , Soldiers -- South Africa
- Description: The present study assessed the isokinetic responses of male military personnel(N=42). The study aimed to evaluate the strength capabilities of South African infantrymen and establish benchmark data on a population not previously tested. “Work-simulation” packages have not been widely exploited and this study further aimed to approximate how effectively occupation simulating tasks could identify the capabilities of soldiers. Testing was carried out using a CYBEX 6000 isokinetic dynamometer and involved six laboratory tests (LTs) and four occupation-simulating tests (OSTs). Subjects were required to complete two testing sessions with the order of tests randomized. The LTs consisted of ankle, elbow, hip, knee, shoulder and trunk. In the OSTs, gripping, valve-tightening, wrench-turning and pulling/pushing responses were collected. Slow, medium and fast test speeds were used for each bout. Cardiac responses were measured using heart rate monitoring and perceptual measures assessed using Borg’s (1971) RPE scale. The results of the testing showed significant differences in agonist and antagonist responses at all three testing speeds, the only exception being slow speed trunk values (peak torque). Upper- to lower-extremity ratios highlighted a possible weakness in the elbow flexors group, while correlations between LTs and OSTs highlighted the specificity of strength principle, as poor relationships were observed.
- Full Text:
- Date Issued: 2001
- Authors: James, Jonathan Peter
- Date: 2001
- Subjects: Isokinetic exercise , Soldiers -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:5126 , http://hdl.handle.net/10962/d1005204 , Isokinetic exercise , Soldiers -- South Africa
- Description: The present study assessed the isokinetic responses of male military personnel(N=42). The study aimed to evaluate the strength capabilities of South African infantrymen and establish benchmark data on a population not previously tested. “Work-simulation” packages have not been widely exploited and this study further aimed to approximate how effectively occupation simulating tasks could identify the capabilities of soldiers. Testing was carried out using a CYBEX 6000 isokinetic dynamometer and involved six laboratory tests (LTs) and four occupation-simulating tests (OSTs). Subjects were required to complete two testing sessions with the order of tests randomized. The LTs consisted of ankle, elbow, hip, knee, shoulder and trunk. In the OSTs, gripping, valve-tightening, wrench-turning and pulling/pushing responses were collected. Slow, medium and fast test speeds were used for each bout. Cardiac responses were measured using heart rate monitoring and perceptual measures assessed using Borg’s (1971) RPE scale. The results of the testing showed significant differences in agonist and antagonist responses at all three testing speeds, the only exception being slow speed trunk values (peak torque). Upper- to lower-extremity ratios highlighted a possible weakness in the elbow flexors group, while correlations between LTs and OSTs highlighted the specificity of strength principle, as poor relationships were observed.
- Full Text:
- Date Issued: 2001
Physiological, perceptual and other performance decrements in combat related tasks following prolonged heavy-load marching
- Authors: Clark, Lisa Anne
- Date: 2000
- Subjects: Performance -- Psychological aspects , Performance standards -- Case studies , Exercise -- Physiological aspects , Exercise -- Psychological aspects , Marching -- Physiological aspects , Soldiers -- Job stress
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:5130 , http://hdl.handle.net/10962/d1005209 , Performance -- Psychological aspects , Performance standards -- Case studies , Exercise -- Physiological aspects , Exercise -- Psychological aspects , Marching -- Physiological aspects , Soldiers -- Job stress
- Description: In response to challenging situations physiological and psychological adaptations result in elevated levels of arousal and when these levels are 'optimal' performance is enhanced. There are however, limitations to the amount of physiological and mental stimulation one can tolerate, with cumulative fatigue effects being the outcome when stressful conditions are imposed on the individual over an extended period of time. As a result of the extreme physical and cognitive demands placed on military forces while in combat, with soldiers being thrust into battle and required to make critical life-or-death determining decisions followed by appropriate motor responses, the physical and psychological capabilities of the troops are pushed to maximal limits, often resulting in undesirable decrements in physical and mental performance, with consequential human and materiel losses. Thirty-two soldiers participated in a battery of combat-related field and laboratory tests, first under 'normal' conditions with no prior physical activity and then immediately after the participation of an intensive bout of exercise. Physiological and perceptual responses plus standard of performance were measured at various stages of testing. Results of the Rating of Perceived Exertion (RPE), Body Discomfort Scale and heart rate responses revealed significantly higher levels of psychophysical strai,n in response to the strenuous physical activity. Despite these findings, the electromyographic (EMG) activity and efficiency of the combat-related skills were not negatively affected. Rather, nominal improvements in post-activity performance were noted, specifically response time, and this was attributed to elevated arousal and activation as a result of the exercise that was of sufficient duration to enhance arousal without imposing long term cumulative fatigue effects.
- Full Text:
- Date Issued: 2000
- Authors: Clark, Lisa Anne
- Date: 2000
- Subjects: Performance -- Psychological aspects , Performance standards -- Case studies , Exercise -- Physiological aspects , Exercise -- Psychological aspects , Marching -- Physiological aspects , Soldiers -- Job stress
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:5130 , http://hdl.handle.net/10962/d1005209 , Performance -- Psychological aspects , Performance standards -- Case studies , Exercise -- Physiological aspects , Exercise -- Psychological aspects , Marching -- Physiological aspects , Soldiers -- Job stress
- Description: In response to challenging situations physiological and psychological adaptations result in elevated levels of arousal and when these levels are 'optimal' performance is enhanced. There are however, limitations to the amount of physiological and mental stimulation one can tolerate, with cumulative fatigue effects being the outcome when stressful conditions are imposed on the individual over an extended period of time. As a result of the extreme physical and cognitive demands placed on military forces while in combat, with soldiers being thrust into battle and required to make critical life-or-death determining decisions followed by appropriate motor responses, the physical and psychological capabilities of the troops are pushed to maximal limits, often resulting in undesirable decrements in physical and mental performance, with consequential human and materiel losses. Thirty-two soldiers participated in a battery of combat-related field and laboratory tests, first under 'normal' conditions with no prior physical activity and then immediately after the participation of an intensive bout of exercise. Physiological and perceptual responses plus standard of performance were measured at various stages of testing. Results of the Rating of Perceived Exertion (RPE), Body Discomfort Scale and heart rate responses revealed significantly higher levels of psychophysical strai,n in response to the strenuous physical activity. Despite these findings, the electromyographic (EMG) activity and efficiency of the combat-related skills were not negatively affected. Rather, nominal improvements in post-activity performance were noted, specifically response time, and this was attributed to elevated arousal and activation as a result of the exercise that was of sufficient duration to enhance arousal without imposing long term cumulative fatigue effects.
- Full Text:
- Date Issued: 2000
Population dynamics and growth rates of the brown mussel (Perna perna) on wave exposed and wave sheltered shores of South Africa
- Authors: Lindsay, Tracy Lynn
- Date: 1999
- Subjects: Perna -- South Africa , Mussels -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:5741 , http://hdl.handle.net/10962/d1005427 , Perna -- South Africa , Mussels -- South Africa
- Description:
Population dynamics of Perna perna in low shore mussel beds were investigated over a 15 month period at six sites along the south coast of South Africa, with particular reference to the effects of wave exposure. The degree of exposure was first quantitatively ascertained using the dissolution of cement blocks to measure average wave force and dynamometers to measure maximum wave force. The mean mass loss of the cement blocks was higher at Diaz Cross and Kwaai Hoek than at Mgwalana, Rufanes and Riet River. No data were available for Fish River. The mean maximum wave force encountered at Diaz Cross, Kwaai Hoek and Fish River was significantly higher (p
- Full Text:
- Date Issued: 1999
- Authors: Lindsay, Tracy Lynn
- Date: 1999
- Subjects: Perna -- South Africa , Mussels -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:5741 , http://hdl.handle.net/10962/d1005427 , Perna -- South Africa , Mussels -- South Africa
- Description:
Population dynamics of Perna perna in low shore mussel beds were investigated over a 15 month period at six sites along the south coast of South Africa, with particular reference to the effects of wave exposure. The degree of exposure was first quantitatively ascertained using the dissolution of cement blocks to measure average wave force and dynamometers to measure maximum wave force. The mean mass loss of the cement blocks was higher at Diaz Cross and Kwaai Hoek than at Mgwalana, Rufanes and Riet River. No data were available for Fish River. The mean maximum wave force encountered at Diaz Cross, Kwaai Hoek and Fish River was significantly higher (p
- Full Text:
- Date Issued: 1999
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
Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
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