Preface

This will be published per chapters: part 1/8.

During my final year of my bachelor of pharmacy, I had the joy of doing a project in pharmaceutics on topical corticosteroids. My colleague and I achieved a distinction for this project but we do admit that we can see some mistakes in our project. This project took us 6 months to accomplish and it mainly taught us about research, reading the literature and to attempt at making a pharmaceutics project. This was more of an introduction to a masters degree path and also taught us to work on our own and be supervised with an allocated supervisor. All in all, we learned a great deal and we were thankful for it.

Authors: Andréas L.P. Astier, Priyanka Naidoo

Supervisors: Professor R. Walker, Dr S.M. Khamanga

Location: Pharmaceutics Department, Rhodes University, Grahamstown, 6140, South Africa.

Abstract

Topical semi-solid dosage forms are usually presented in the form of creams, gels, ointments and pastes (1). These present many challenges relating to bioavailability, stability, the release of active pharmaceutical ingredient (API), sterility and the method of manufacturing the product (2). In South Africa, corticosteroid creams are widely used in eczema, chronic discoid lupus, lichen planus, psoriasis, popular urticarial and photosensitive reactions (3,4). Clobetasol propionate (CBP) is the propionate salt form of clobetasol, a topical synthetic corticosteroid with anti-inflammatory, anti-pruritic, and vasoconstrictive properties (14). CBP is a corticosteroid used topically for its glucocorticoid activity in the treatment of various skin disorders (14). It is usually used as a cream, ointment, gel, scalp application, shampoo, or foam containing 0.05%.

At a laboratory scale, 0.05% of CBP aqueous cream was formulated using various excipients which included sodium lauryl sulphate, cetrimide, cetomacrogol, chlorocresol, dovate® and aqueous cream. This was done to mimic potential formulation that would be used in the pharmacy and demonstrate the danger of dilution and the usage of the wrong excipients. The formulations were assessed on their ability to release the percentage of CBP at a significant therapeutic level, on their spreadability, and their textural profiles all on day 0, 7, 14 and 28. A degradation study was made to approach a potential method which could predict the release percentage of CBP. These were compared on day 60. An accumulation study was also conducted to demonstrate the actual amount of aqueous cream patients would use during the time of usage of their creams.

The T-test and Chi-test were used statistically for the spreadability and the textural profiles of the formulations. Formulation 2 on day 0 and 28 compared to the standard was the only formulation to not have significantly changed on its spreadability. Formulation 2 and 3 statistically did not change at the textural profiling. The results of the study showed that the rate of drug release, over 180 minutes on day 0, from formulation 1, 2, 3 and 4 respectively was 60,77 %, 68,86 %, 46,25 % and 27,17 % mean percentage of API per cm2. On day 28, the release of CBP from formulation 1, 2, 3 and 4 respectively was 6,14 %, 3,99 %, 3,10 % and 2,17 %.

It was found that diluting and homogenizing the formulation at a pharmacy setting caused the restricting of the release of CBP which in terms would not cause the wanted pharmacological effect.

Acknowledgements

We would like to thank our supervisors Dr. S.M. Khamanga and Prof. R.B. Walker for their guidance in this project.

A special thanks to Mr. C. Nontyi for the laboratory support and the pharmaceutic masters’ students who stayed with us late at night.

To Fiona Drummond who helped me with language editing and her support, and to my Band Dalon who are always here for me and their occasional “koi fai ti pilon”. To my colleague, Priyanka, who managed to survive my presence.
Andréas L.P. Astier

To my family who is always there for me with their support and love. My friends who were kind and supporting me through the challenging times during this research endeavour. To my colleague where we had a few laughs during the experiments.
Priyanka Naidoo

CHAPTER ONE

Clobetasol (CB)

1.1. Introduction

Topical semi-solid dosage forms are normally presented in the form of creams, gels, ointments and pastes (1). Topical formulations present many challenges related to bioavailability, stability, the release of active pharmaceutical ingredient (API), sterility and the method of manufacturing the product (2). In South Africa, corticosteroid creams are widely used in eczema, chronic discoid lupus, lichen planus, psoriasis, popular urticarial and photosensitive reactions (3,4). Corticosteroids in dermatological preparations suppress the symptoms of inflammation and cause immune suppression (4,5). Clobetasol (CB) is a molecule part of the corticosteroid groups and is a restricted schedule four that is widely used. CB contains a potent pharmacological effect and is generally sold at a concentration of 0,05% in aqueous cream, ointment or fatty alcohol propylene glycol (FAPG) vehicle.

In our experiment aqueous cream BP was utilized. Aqueous Cream BP, a non-ionic cream (6), is the most widely prescribed emollient for the treatment of dry skin conditions. It is inexpensive, effective in some individuals and often represents the first line of treatment for patients with dermatological disorders (7). Emollient therapy provides moisture to the dehydrated barrier allowing improved flexibility of the skin which would otherwise be taut and more prone to develop cracks. Fissures in the protective outer layer of the skin barrier, the stratum corneum (SC), increase the permeability of xenobiotics and allergens contributing to irritation and the eventual development of eczematous flares (7). An emollient regimen has therefore been perceived as a great benefit to patients with eczema and the use of this approach has therefore increased markedly. Creams are white, semi-solid preparations often medicated and are generally manufactured as o/w (oil in water phase) emulsion and can also be w/o (water in oil phase) which are less greasy than ointments (8,9).

Many studies had been done on the understanding of extemporaneous cream in term of its active pharmaceutical ingredients (API) release, absorption of the API and penetration of the API into the integumentary system. However, there is a need for studies in the field of manufacturing creams at the pharmacy practice level and its stability effect of the semi-solid preparations. The dilution of a commercially available topical corticosteroid formulation is a common practice prescribed by a dermatologist and other practitioners in South Africa (3).

However, there is a risk from the physicians from the lack of knowledge and awareness in pharmaceutics studies, where the prescription of a semi-solid preparation must be diluted with another semi-solid preparation. Furthermore, the pharmacist would then mix the semi-solid preparation by using a homogenizer, if available, influencing the final semi-solid preparation by the usage of a non-standard approach in the manufacturing.

J.F. Smith (10) and Hanan R. et al (11) studies have mentioned that these assumptions of dilution and mixing semi-solids could reduce the activity of the corticosteroid formulation. The risk of accelerating the chemical and physical decomposition and the facilitating degradation by micro-organisms could well interfere with the interactions within the formulation (11). Other studies such as A.D. Magnus et al (12) have mentioned that the release of API is unaffected by the dilution if diluted by an acceptable semi-solid formulation. Hanan R. et al, shows that the biopharmaceutical incompatibilities arise from the inappropriate selection of the vehicle used in dilution (11) which may imply that any changes in concentration or component of the base may affect the rate release of the corticosteroid from the final preparation. Hanan R. et al, also found that the release of the drug was greatly affected by the composition and rheology properties of the vehicle used in the dilution as well as the solubility of the drug in the preparation (11). The study concluded that it is difficult for physicians and pharmacist to predict the effect of dilution on the activity on the API (11).

Interestingly, The Pharmaceutical Codex (13), have mentioned that it is allowed to dilute creams with a suitable diluent. However, particular care should be taken in the dilution of steroids preparation, which is normally manufacture under sterile or ‘near sterile’ conditions. This is important as the presence of Pseudomonas aeruginosa, for instance, in corticosteroids cream could present a risk to patients due to the reduced resistance to local infection caused by the immune suppressant effects of the steroids (13). Hence, any creams used as a diluent and the dilutions should be prepared under hygienic conditions, which is not always present is some pharmacies or if good manufacturing practise is not done properly. The Pharmaceutical Codex further mentions that an unsuitable diluent may yield a product of limited bactericidal efficiency due to the diluent not containing a preservative or containing one that is either inactive or incompatible. The diluent, if not containing a preservative, may further dilute the cream which had the right amount of preservative, and hence causing the preservative to be ineffective as there is more cream to cover. A diluent that differs in pH from the original cream may promote chemical breakdown or the inactivation of the active substance (13). The physical breakdown may also occur when a system formed by an anionic emulsifier mixed with a cationic based emulsion or a system containing a cationic active substance (13).

The Pharmaceutical Codex specifically mentions that it is inadvisable to make dilutions in the absence of information on the suitability of the diluent. Diluted creams must, therefore, be freshly prepared without the application of heat and must have an expiry period of two weeks from the date of issue (13). As such, why do we observe, in the pharmacy practice settings, corticosteroids creams being prepared for more than two weeks’ usage? Hence a good understanding of pharmaceutics is crucial.

1.2. Clobetasol pre-formulation studies

Clobetasol propionate (CBP) is the propionate salt form of clobetasol, a topical synthetic corticosteroid with anti-inflammatory, anti-pruritic, and vasoconstrictive properties (14). CB on its own is extremely non-soluble in water, hence the addition of propionate aids in its general solubility. CBP is a corticosteroid used topically for its glucocorticoid activity in the treatment of various skin disorders (14). It is usually used as a cream, ointment, gel, scalp application, shampoo, or foam containing 0.05%. When applied topically, particularly to large areas, when the skin is broken, or under occlusive dressings, corticosteroids may be absorbed in sufficient amounts to cause systemic effects (14).

Figure 1.1. The chemical structure of CBP (15)

CB is available on the market and has been used mainly as creams and ointment as CBP 0,05% (16). Other corticosteroids such as hydrocortisone, betamethasone, beclometasone, diflucortolone, fluocinolone acetonide, fluticasone, hydrocortisone butyrate, methylprednisolone aceponate and mometasone, include creams, ointment, fatty ointment, scalp solution and lotion, where all the products range from 1% to 0,025% w/w (16). Cream products that are available in South Africa are sold as Dermovate® Sekpharma, Dovate®Aspen Pharmacare, and Xenovate® Aspen Pharmacare (16).

1.2.1. Description

CBP is 21-Chloro-9-fluoro-11β-hydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-17-yl propanoate (15).

CBP appears as a white or almost white, crystalline powder (15).

The empirical formula of CBP is C25H32ClFO5 with a molecular weight of 467.0 g/mol (15).

CBP contains not less than 97.0 per cent to 102.0 per cent (dried substance) (15).

International coding (14):

BAN: Clobetasol Propionate [BANM]
USAN: Clobetasol Propionate
CAS: 25122-41-2 (clobetasol); 25122-46-7 (clobetasol propionate) ATC code: D07AD01
ATC code (veterinary): QD07AD01
UNII code: 779619577M

1.2.2. Dissociation constant (pKa)

CBP has a pKa of 12.88 (17).

1.2.3. Solubility studies

The solubility of clobetasol is demonstrated in various solvents in Table 1.1.

Table 1.1. Solubility of clobetasol in various solvents

Approximate quantity of solvent by volume for one part of soluble by weight. For example, 1g of a very soluble substance dissolves in less than 1ml of solvent (18).

1.2.4. Melting point, Boiling point and Density

CBP approximately melts at 226° degrees Celsius (20).

Boiling Point: 569.0° C at 760 mmHg (17).

Density: ~1.3 g/cm3 (Predicted) (17).

1.2.5. Impurities

Specified and detectable impurities A, B, C, D, E, L, M (15).

The other detectable impurities, if the following substances would be detected by one or other of the tests in the monograph at a sufficient level, are not necessarily needed to be identified: F, G, H, I, J, K (15).

Figure 1.2. Schematic diagram of CBP main impurities (15, 21)

A. R1 = CO-C2H5, R2 = OH: 9-fluoro-11β,21-dihydroxy-16β-methyl-3,20-dioxopregna-dien-17-yl propanoate (betamethasone 17-propionate) (15, 21).

B. 21-chloro-9-fluoro-11β-hydroxy-16-methylpregna-1,4,16-triene-3,20-dione (15, 21).

C. 21-chloro-9-fluoro-11β-hydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-17-yl propanoate (15, 21).

D. 21-chloro-9-fluoro-11β-hydroxy-16β-methyl-3,20-dioxopregn-4-en-17-yl (1,2-dihydroclobetasol 17-propionate) (15, 21).

E. 21-chloro-16β-methyl-3,20-dioxopregna-1,4-dien-17-yl propanoate (15, 21).

L. unknown structure (15, 21).

M. unknown structure (15, 21).

1.2.6. Optical rotation

Optical rotation is the property displayed by chiral substances of rotating the plane of polarization of polarised light (22). Optical rotation is considered to be positive (+) for dextrorotatory substances (those that would rotate the plane of polarisation in a clockwise direction) and negative (-) for laevorotatory substances (22).

CBP displays an optical rotation of: + 112 to + 118 (dried substance), this is done by dissolving 0.500 g in acetone R and dilute to 50.0 mL with the same solvent (15).

The British Pharmacopoeia describes that the specific optical rotation of a substance in solution is the angle of rotation α, expressed in degrees (°), of the plane of polarisation at the wavelength of the D-line of sodium (λ = 589.3 nm) measured at 20 °C in a solution of the substance to be examined and calculated with reference to a layer of 1 dm containing 1 g/mL of the substance (22). The specific optical rotation of a substance in solution is always expressed with reference to a given solvent and concentration (22).

1.2.7. Partition coefficient

An important feature in cream and ointment formulation is the ability for the API to be absorbed through the integumentary system and produce a local pharmacological effect, as creams and ointment are generally spread onto the skin. The skin is oily and fatty naturally, hence for the best results in permeation into the skin, the drug should naturally be lipophilic (23).

Lipophilicity is important in the role of solubility, absorption, membrane penetration, plasma protein binding, distribution, CNS penetration and partitioning into other tissues or organs such as the liver and has an impact on the routes of clearance (24, 25). It is important in ligand recognition, not only to the target protein but also CYP450 interactions, HERG binding, and PXR mediated enzyme induction (24). However, CBP will not be used systemically and will not influence these enzymes.

LogP is the measure of lipophilicity of a certain molecule, where it is the partition coefficient between an aqueous and lipophilic phase, usually octanol and water (24, 25). These measurements can be in different ways but most commonly the shake-flask method is utilized (24, 25). This consists of dissolving some of the solutes in a known volume of octanol and water, shaking for a known period of time, then measuring the concentration of the solute in each solvent (24). A faster method of log P determination is the utilization of high-performance liquid chromatography (24).

Thus a higher log P would indicate that a molecule has an affinity to be in a hydrophobic environment, hence demonstrate if the molecule would be absorbed through the skin. CBP has an octanol/water partition coefficient (log PO/W) of 3.5 (19, 20), which is optimal for a transdermal route since the range should be between 3 – 4 log PO/W (25). Above log PO/W of 5 would cause a build-up of toxicity in the adipose tissue (25).

1.3. Stability

1.3.1. Storage conditions

CBP Cream should be stored at a temperature not exceeding 30°, out of sunlight and airtight (14, 15).

1.3.2. Shelf-life and degradation

Stability studies provide evidence on how the quality of a drug varies over time under the influence of a variety of parameters such as temperature, humidity, and light (26). The physical and chemical degradation of a drug may result in altered therapeutic efficacy and even toxic effects (26). In the literature, CBP was subjected to different stress conditions such as acidic, basic, heat, oxidation, light, and neutral hydrolysis (26, 27). It was found that the greatest degradation occurred under a strong base and oxidative conditions (27). Mohammad S.A. et al demonstrated, in a nanoemulsion formulation of CBP, that the shelf-life was 2.18 years. Mohammad S.A. et al also stated that these results indicated the optimized formulation was stable, as there were no significant changes in the physical parameters (droplet size, viscosity, pH, conductivity, and RI) over a period of 3 months (27). The degradation of CBP was very slow at each temperature which indicated the chemical stability of CBP in the nanoemulsion formulation (27). Even though our formulation was not a nanoemulsion formulation but an aqueous cream formulation we can insinuate that CBP is a stable molecule at room temperature, on the skin and in the container for a period of a maximum of 14 days.

1.4. Clinical pharmacology

1.4.1. Taxonomy

This compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogens and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety (19, 20). Kingdom: Organic compounds, Super Class: Lipids and lipid-like molecules, Class: Steroids and steroid derivatives, Sub Class: Pregnane steroids, Direct parent: Gluco/mineralocorticoids, progestogens and derivatives (19, 20).

1.4.2. Mechanism of action

Like other topical corticosteroids, clobetasol has anti-inflammatory, antipruritic, and vasoconstrictive properties (4, 5, 16, 20). It is a very high potency topical corticosteroid that should not be used with occlusive dressings (20). The SAMF, 12th edition, classified CBP as a Group IV with a very potent pharmacological action (4, 16). It is recommended that treatment should be limited to 2 consecutive weeks and therapy should be discontinued when adequate results have been achieved (20).

CBP exerts its effect by binding to cytoplasmic glucocorticoid receptors and subsequently activates glucocorticoid receptor-mediated gene expression (20). This results in the synthesis of certain anti-inflammatory proteins while inhibiting the synthesis of certain inflammatory mediators (20). CBP induce phospholipase A2 inhibitory proteins, thereby controlling the release of the inflammatory precursor arachidonic acid from membrane phospholipids by phospholipase A2 (20).

1.4.3. Indications

CBP is indicated for inflammatory dermatoses such as any eczema including seborrheic and atopic eczema, photosensitive reactions, psoriasis (not responding to simpler approaches), chronic discoid lupus, lichen planus and alopecia areata (3, 4, 14 -16).

Apply sparingly as a thin film, initially twice a day (4, 16). Reduce the frequency or strength of the application as soon as a positive result is obtained (4, 16). Do not use over 50 grams of cream per week (28, 29).

1.4.4. Contra-Indication

Rosacea, acne, peri-oral dermatitis, skin lesions caused by infection with viruses, fungi or bacteria (including tuberculosis); known hypersensitivity; ulcerative conditions – healing may be delayed (4, 16).

1.4.5. Drug-interaction

CBP is only utilized topically as other corticosteroids such as hydrocortisone, cortisone, prednisolone, prednisone, methylprednisolone, triamcinolone, dexamethasone, betamethasone and fludrocortisone would be used systemically for conditions such as steroid-responsive disorders (Cushing’s syndrome and Addison disease), management of inflammatory diseases, oedemas, asthma, chronic obstructive pulmonary disease and anaphylaxis (4, 16). Topically CBP has little to no drug interactions, as it is mainly localized pharmacological effects (4, 16).

Systemically corticosteroids interact with medications such as amphotericin B, potassium-depleting diuretics, e.g. furosemide, thiazides, digoxin, hepatic enzyme-inducing agents, e.g. phenobarbital, carbamazepine, phenytoin, alcohol and rifampicin, other agents with sodium- retaining properties, e.g. NSAIDs (4, 16).

1.4.6. Adverse reactions and toxicology

1.4.6.1. Adverse Reactions

CBP has various adverse effects. These are primarily cardiovascular, dermatologic, endocrine, immunologic, musculoskeletal, neurologic, ophthalmic, renal and a respirator (30). CBP may cause marked adrenocortical suppression. Hypothalamic-pituitary-adrenal axis (HPA) suppression occurs thus causing adrenal insufficiency which then leads to both local and systemic side effects (31).

1.4.6.2. Toxicology

CBP displays toxicology in the form of decreased calcium absorption, increased calcium excretion and inhibited osteoblast formation, thus to a decreased bone formation and increased bone resorption (32). This then results in the development of osteoporosis. If any corticosteroid, including that of CBP, is taken in overdose, acute toxicity is rare and the clinical effects of acute ingestion are also rare (32). Acute adrenal insufficiency is rarely reported after the event of an overdose but adverse effects can include cardiac dysrhythmias, seizures and anaphylaxis (32). In chronic exposure, Cushing appearance, muscle wasting and weakness, hypertension, hyperglycaemia, subcapsulary cataracts and glaucoma, osteoporosis and psychosis can occur (32). If a corticosteroid is abruptly withdrawn then dysphoria, irritability, emotional liability, depression, fatigue, anxiety, depersonalization, myalgia, and arthralgia are a possibility (32).

1.4.6.3. Local side effects

A vast array of skin conditions can be caused by CBP. These include acne, acneiform eruptions, dermatitis, allergic contact dermatitis, pigmentation to the site of application, hypersensitivity reaction to the application site, eczema, burning, dry skin, erythema, folliculitis, skin fissures, pruritus, skin irritation and pustules (32). Hypersensitivity reactions caused by CBP are also classified as immunological side effects (32).

CBP may also affect the scalp and hair follicles causing swollen hair follicles as well as alopecia which is temporary hair loss (32).

1.4.6.4. Systemic side effects

Oedema is commonly encountered as a cardiovascular effect of CBP (32).

1.4.6.5. Endocrine or metabolic side effects

Cushing’s syndrome, delayed growth and development and secondary hypercortisolism can be caused by the use of CBP (32). These endocrine side effects occur due to the systemic absorption of CBP which causes HPA axis suppression.

CBP can also cause the unmasking of latent diabetes mellitus and hyperglycemia which occurs from the inhibition of beta-cell function and decreased tissue sensitivity to insulin when is CBP systemically absorbed (32, 33).

1.4.6.6. Renal

Glycosuria may occur with the use of CBP due to HPA axis suppression (32).

1.4.6.7. Neurologic

Headaches, acute intracranial hypertension and numbness in the fingers may occur with the use of CBP (32).

1.4.6.8. Ophthalmic

Eye irritation and raised intraocular pressure are possible when using CBP (32).

1.4.6.9. Respiratory

Nasopharyngitis, streptococcal pharyngitis and upper respiratory infection are respiratory side effects that can occur (32).

1.4.6.10. Musculoskeletal

Osteonecrosis and osteoporosis may occur with long term use of CBP (32).

1.4.6.11. Other

Due to the immunosuppressive nature of CBP, there is an increased risk of secondary infections and infestations occurring (32).

1.4.7. Guidelines for use

For skin disorders, CBP (cream, emollient, foam, gel, lotion or ointment) is applied topically as a thin layer to the affected area, twice daily. A maximum of 50 g/week or 50 mL/week may be applied and the maximum duration of application is 2 consecutive weeks (4, 16, 20, 28, 29, 32).

1.4.8. Precautions

1.4.8.1. Topical corticosteroids

Application of CBP to the eyes, lips, face, groin, or axillae areas must be avoided, as must ophthalmic, oral, or intravaginal application (30, 33). It is not recommended that CBP be used for acne vulgaris, rosacea or perioral dermatitis. Allergic contact dermatitis may occur from the use of CBP which thus fails to heal (32, 33). If an uncontrolled skin infection is present, then the use of CBP must be discontinued. Refrain from using CBP on an altered skin barrier or large surface areas as this may increase the risk of systemic absorption which leads to an increased risk of systemic and metabolic side effects such as the unmasking of latent diabetes mellitus, hyperglycaemia, and Cushing syndrome from prolonged use and large doses (30, 33). The hypothalamic-pituitary-adrenal is at risk of suppression even with systemic absorption at low doses (33). Clobetasol propionate highly potent and has been shown HPA axis suppression at doses as low as 2 g/day (4, 30, 33).

Glucocorticosteroid insufficiency may result after treatment withdrawal therefore monitoring is recommended alongside the implementation dose adjustment (33). When dosing on a normal regimen, additional benefits of extending treatment for more than 2 weeks, should be weighed against the risk of HPA axis suppression and treatment extending for 4 or more consecutive weeks is not recommended due to HPA axis suppression (4,16, 20, 28-30, 33).

Note that in the presence of hepatic failure, systemic absorption may be enhanced. Occlusive dressings should be avoided as they may increase the risk of systemic absorption (30, 33).

If CBP is administered to paediatrics, then the use of foam, lotion, or shampoo is not recommended in patients younger than 18 years of age (4, 16, 30, 33). This is due to the increased risk of systemic toxicity from equivalent dose and the larger skin surface to body mass ratio of paediatric patients (30, 33). This places paediatric patients at an increased risk of systemic exposure which also leads to an increased risk of HPA axis suppression (30, 33).

As a last note, prolonged use of CBP increases the risk of systemic absorption.

1.5. Clinical pharmacokinetics

1.5.1. Bioavailability

CBP is absorbed through normal, intact skin but the percutaneous penetration of CBP varies amongst different individuals due to various factors (30). The extent of percutaneous absorption is affected by factors such as the vehicle, integrity of the epidermal barrier and the use of occlusive dressings (30). The absorption of CBP percutaneously, can be increased by the use of occlusive dressings and also by inflammation and disease processes that affect the epidermal barrier, for example, psoriasis and eczema (32).

1.5.2. Metabolism and Elimination

There is a lack of evidence to define the distribution of corticosteroids to various organs in the body but currently existing knowledge states that upon topical application CBP is absorbed through the skin and metabolized primarily by the liver (30, 33). The metabolites are then excreted by the kidneys and to a lesser extent, in the bile (30). Data for the degree of protein binding, the volume of distribution, half-life, the percentage in urine that is unchanged and clearance are not available (30, 33).

Hepatic injury or failure may enhance systemic absorption due to the decreased ability of the liver to metabolise CBP (33). This could potentially lead to systemic toxicity and HPA axis suppression which results in various adverse effects such as those stated in section 1.4.6.5. and 1.4.8.1.

Published 31st July 2019. Last reviewed 30th December 2021.

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