Acne is a very common disease affecting approximately 85% of people in some stage of their life (Wolff et al., 2005:2). The systemic drug isotretinoin is the only acne drug which has an influence on all the pathophysiological factors of this highly prevalent disease and is considered as the most effective treatment for acne, although it should be limited to the treatment of severe acne. Isotretinoin prescribing is under the largest risk-minimisation programme (called iPLEDGE) ever implemented for a drug in the United States of America, due to concerns with pregnancies during isotretinoin treatment (Honein et al., 2007:11). In comparison South Africa has no equal managing programme to regulate isotretinoin prescribing and the need to identify certain prescribing patterns is deemed necessary. The general objective of this study was to analyse the prescribing patterns of isotretinoin, including aspects of cost, in a section of the private healthcare sector of South Africa. A quantitative, retrospective drug utilisation review was performed to evaluate the prescribing patterns and cost of isotretinoin containing products claimed through a pharmacy benefit management organisation, over the study period of 2005 and 2006. Data were analysed by using the Statistical Analysis System, 9.1 (SAS). The information of prescriber, age, gender, and cost of isotretinoin usage were considered and evaluated. A total number of 6 427 and 6 927 patients claimed 18 589 and 20 232 isotretinoin prescriptions respectively during 2005 and 2006. Isotretinoin total costs contributed to 34.4% (n = R6 810 090) and 36.3% (n = R6 533 241) of the total identified acne medicine costs for 2005 and 2006 respectively. Isotretinoin represented the highest percentage of total costs in relation to any other acne product identified in both study years. Average costs of R314.82 ± 205.92 per prescribed isotretinoin item in 2005 and R277.63 ± 192.63 in 2006 were recorded in comparison to the total database medicine item cost of R95.33 ± 192.21 in 2005 and R95.33± 227.99 in 2006. The generic products of isotretinoin were claimed at a lower ratio (generic vs. innovator product ratio of 1.8:1 in 2005 and 2.2:1 in 2006) in relation to the total database (generic ratio of 3:1 in both years). Dermatologists prescribed 68.2% and 65.7% of isotretinoin prescriptions and general practitioners 27.5% and 29.7%. General practitioners were more likely to prescribe the generic equivalents of isotretinoin (68.9% in 2005 and 72.1% in 2006) in comparison to dermatologists (59.7% in 2005 and 63.4% in 2006). The teenage group 12 to 19 years received 48.4% (n = 8 989) and 47.7% (n = 9 656) of isotretinoin prescriptions claimed respectively at an estimated cost of R275 000 and R260 000 per 10 000 beneficiaries in this age group respectively for 2005 and 2006. There were 71 patients identified over both study years in the age group younger than 12 years, in which isotretinoin use is not recommended. Female patients received 56.2% (n = 10 450) and 57.4% (n = 11 610) of the total number of isotretinoin prescriptions claimed respectively for 2005 and 2006. The average cost per isotretinoin prescription claimed for male patients was higher (R406.36 ± 233.76 and R358.69 ± 218.29 respectively for 2005 and 2006) in relation to female patients (R335.15 ± 209.98 and R296.36 ± 197.74 respectively for 2005 and 2006). The median ages for female and male patients were 21 years and 18 years respectively. The concern, however, was the high number of female patients of child-bearing potential identified (2 892 and 3 201 female patients respectively for 2005 and 2006), claiming their isotretinoin prescriptions. Systemic isotretinoin occurred alone in 70.8% and 69.3% of prescriptions claimed respectively for 2005 and 2006. Oral contraceptives occurred in combination with isotretinoin in only 8.6% and 9.2% of isotretinoin prescriptions claimed. The contra-indicated use of a systemic tetracycline in combination with systemic isotretinoin occurred in 139 (0.75%) and 130 (0.64%) prescriptions. It can be concluded that the use of isotretinoin increased. Dermatologists played the major role in prescribing isotretinoin. The number of female isotretinoin users (especially of child-bearing potential) could be a concern, although pregnancy prevalence should be identified in South Africa. It is recommended that further studies be conducted in South Africa regarding the usage and control of isotretinoin, including the extension of regulating programmes, with special reference to age and gender. Effective management of the increasing popularity of this ultimately successful acne treatment is of utmost importance to ensure the effective and safe usage of isotretinoin. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.

Acne is a very common disease affecting approximately 85% of people in some stage of their life (Wolff et al., 2005:2). The systemic drug isotretinoin is the only acne drug which has an influence on all the pathophysiological factors of this highly prevalent disease and is considered as the most effective treatment for acne, although it should be limited to the treatment of severe acne. Isotretinoin prescribing is under the largest risk-minimisation programme (called iPLEDGE) ever implemented for a drug in the United States of America, due to concerns with pregnancies during isotretinoin treatment (Honein et al., 2007:11). In comparison South Africa has no equal managing programme to regulate isotretinoin prescribing and the need to identify certain prescribing patterns is deemed necessary. The general objective of this study was to analyse the prescribing patterns of isotretinoin, including aspects of cost, in a section of the private healthcare sector of South Africa. A quantitative, retrospective drug utilisation review was performed to evaluate the prescribing patterns and cost of isotretinoin containing products claimed through a pharmacy benefit management organisation, over the study period of 2005 and 2006. Data were analysed by using the Statistical Analysis System, 9.1 (SAS). The information of prescriber, age, gender, and cost of isotretinoin usage were considered and evaluated. A total number of 6 427 and 6 927 patients claimed 18 589 and 20 232 isotretinoin prescriptions respectively during 2005 and 2006. Isotretinoin total costs contributed to 34.4% (n = R6 810 090) and 36.3% (n = R6 533 241) of the total identified acne medicine costs for 2005 and 2006 respectively. Isotretinoin represented the highest percentage of total costs in relation to any other acne product identified in both study years. Average costs of R314.82 ± 205.92 per prescribed isotretinoin item in 2005 and R277.63 ± 192.63 in 2006 were recorded in comparison to the total database medicine item cost of R95.33 ± 192.21 in 2005 and R95.33± 227.99 in 2006. The generic products of isotretinoin were claimed at a lower ratio (generic vs. innovator product ratio of 1.8:1 in 2005 and 2.2:1 in 2006) in relation to the total database (generic ratio of 3:1 in both years). Dermatologists prescribed 68.2% and 65.7% of isotretinoin prescriptions and general practitioners 27.5% and 29.7%. General practitioners were more likely to prescribe the generic equivalents of isotretinoin (68.9% in 2005 and 72.1% in 2006) in comparison to dermatologists (59.7% in 2005 and 63.4% in 2006). The teenage group 12 to 19 years received 48.4% (n = 8 989) and 47.7% (n = 9 656) of isotretinoin prescriptions claimed respectively at an estimated cost of R275 000 and R260 000 per 10 000 beneficiaries in this age group respectively for 2005 and 2006. There were 71 patients identified over both study years in the age group younger than 12 years, in which isotretinoin use is not recommended. Female patients received 56.2% (n = 10 450) and 57.4% (n = 11 610) of the total number of isotretinoin prescriptions claimed respectively for 2005 and 2006. The average cost per isotretinoin prescription claimed for male patients was higher (R406.36 ± 233.76 and R358.69 ± 218.29 respectively for 2005 and 2006) in relation to female patients (R335.15 ± 209.98 and R296.36 ± 197.74 respectively for 2005 and 2006). The median ages for female and male patients were 21 years and 18 years respectively. The concern, however, was the high number of female patients of child-bearing potential identified (2 892 and 3 201 female patients respectively for 2005 and 2006), claiming their isotretinoin prescriptions. Systemic isotretinoin occurred alone in 70.8% and 69.3% of prescriptions claimed respectively for 2005 and 2006. Oral contraceptives occurred in combination with isotretinoin in only 8.6% and 9.2% of isotretinoin prescriptions claimed. The contra-indicated use of a systemic tetracycline in combination with systemic isotretinoin occurred in 139 (0.75%) and 130 (0.64%) prescriptions. It can be concluded that the use of isotretinoin increased. Dermatologists played the major role in prescribing isotretinoin. The number of female isotretinoin users (especially of child-bearing potential) could be a concern, although pregnancy prevalence should be identified in South Africa. It is recommended that further studies be conducted in South Africa regarding the usage and control of isotretinoin, including the extension of regulating programmes, with special reference to age and gender. Effective management of the increasing popularity of this ultimately successful acne treatment is of utmost importance to ensure the effective and safe usage of isotretinoin. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.

När isotretinoin introducerades på marknaden i början av 1980-talet revolutionerade det behandlingen av svår akne och är än idag det effektivaste läkemedlet. Dock har läkemedlet tyvärr många biverkningar, bland annat har det en fosterskadande effekt och får därmed absolut inte användas vid graviditet. Läkemedlet får enbart förskrivas av specialiserade hudläkare och förskrivs endast till patienter som inte blivit hjälpta av andra aknebehandlingar. De konventionella doserna av isotretinoin är 0,5-1,0 mg/kg dagligen, men dessa kan ibland ge svåra biverkningar. Syftet med det här litteraturarbetet är att undersöka om behandling med låg-dos isotretinoin är lika effektivt som konventionell behandling vid svår akne och om låg-dosbehandling resulterar i färre och mildare biverkningar. Vidare undersöks om låg-dosbehandling är ett möjligt alternativ för patienter med mild och måttlig akne. För att hitta relevanta artiklar till det här arbetet gjordes en sökning i databasen Pubmed via Linnéuniversitetets bibliotek och det resulterade i fem studier. Slutsatsen av litteraturarbetet är att behandling med isotretinoin i lägre doser (< 0,5 mg/kg/dag) ger ett bra och effektivt resultat vid svår akne. En fördel med de lägre doserna är att de ger färre och mildare biverkningar jämfört med konventionell behandling (0,5-1,0 mg/kg/dag). Behandling med låg-dos isotretinoin ger ett mycket bra resultat på mild och måttlig akne, och kan med fördel även ges som behandling vid de lindrigare formerna av akne. / When isotretinoin was introduced in the early 1980s, the treatment of severe acne was revolutionized and isotretinoin is today the most effective drug. Isotretinoin has been shown to be the only drug that can delay the skin disease and can also cause healing. The drug acts on all four factors that contribute to the pathogenic mechanism of acne and that makes the drug a unique effective monotherapy. However, isotretinoin has many side effects such as dry skin and dry, chapped lips. It also has a teratogen effect and is prohibited for pregnant women. The drug can only be prescribed by dermatologists and is only prescribed to patients who have not been helped by other acne treatments, such as systemic treatment with antibiotics. The conventional doses of isotretinoin are 0,5-1,0 mg/kg daily, but these doses may sometimes cause severe side effects. The aim of this literature study was to investigate whether treatment with low-dose isotretinoin is as effective as the conventional treatment (0,5-1,0 mg/kg/day) against severe acne, and if low-dose treatment results in fewer and milder side effects. This literature study will also investigate if low-dose isotretinoin is a possible treatment option for patients with mild and moderate acne. The method used in this study was a literature search in Pubmed database via Linnaeus University Library and it resulted in five studies.   Low-dose isotretinoin (< 0,5 mg/kg/day) showed good effect against severe acne and it resulted in fewer and milder side effects than the conventional treatment. However, conventional doses gave earlier effect the first eight weeks of the treatment. In order to get the fastest results, patients with severe acne and who tolerate the high doses can start with conventional treatment and after eight weeks switch to low-dose treatment, thus mitigating the side effects but still gaining therapeutic effect. Treatment with low-dose isotretinoin gave a very good result on mild and moderate acne, and can be used to treat the milder forms of the disease. The conclusion that can be drawn from this literature study is that isotretinoin at lower doses (<0,5 mg/kg/day) provides a good and effective result in severe acne. An advantage of the lower doses is that they yield fewer and milder side effects compared to conventional treatment (0,5-1,0 mg/kg/day). Low-dose isotretinoin is a good alternative for patients with mild or moderate acne, who have not responded by other acne treatments.

Orientador: Francisco Benedito Teixeira Pessine / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-22T06:49:33Z (GMT). No. of bitstreams: 1 Martins_MileneHeloisa_D.pdf: 5657297 bytes, checksum: 0591f1d89a55f401bdc492136908b11b (MD5) Previous issue date: 2007 / Resumo: Este trabalho teve como objetivos preparar, caracterizar, verificar a estabilidade e avaliar a permeação na pele e a irritação cutânea de formulações lipossomais contendo isotretinoína (ISOTN), destinadas ao tratamento dermatológico de casos severos de acne, com a finalidade de reduzir os efeitos adversos e a degradação do fármaco. As formulações lipossomais foram obtidas através da técnica de hidratação do filme lipídico seco. Foi observado que nos lipossomas constituídos apenas de fosfatidilcolinas saturadas (HPC) houve vazamento do fármaco inicialmente encapsulado. O máximo de encapsulação (> 98%), com aumento da fluidez das bicamadas lipídicas, foi obtido com as seguintes suspensões lipossomais: (a) mistura de HPC com 40% mol de surfatante insaturado Lipopeg 4DO (DO) - Lipo_HPC/DO; (b) mistura de HPC com 40% mol de fosfatidilcolinas insaturadas (PC) - Lipo_HPC/PC; (c) lipossomas contendo apenas PC - Lipo_PC; (d) mistura de PC com 20% mol de colesterol (Col) - Lipo_PC/Col e (e) mistura de PC com 10% mol de fosfatidilserina (PS) - Lipo_PC/PS. Devido ao elevado teor de encapsulação da ISOTN nestes lipossomas, foi desnecessário separar o fármaco não encapsulado. A razão molar ISOTN/lipídios foi ~0,026:1. Análises usando microscopia eletrônica de transmissão e de varredura das suspensões lipossomais confirmaram a estrutura lamelar e a geometria esférica dos lipossomas, respectivamente. A encapsulação da ISOTN nas bicamadas lipossomais foi monitorada por microscopia óptica, avaliando a presença de cristais do fármaco na suspensão. A comprovação da encapsulação da ISOTN nas bicamadas lipídicas foi verificada através da fluorescência de pireno (aumento do grau de anisotropia e diminuição da intensidade de fluorescência da sonda). As suspensões lipossomais mantiveram-se estáveis durante 3 meses de armazenamento a 8 oC, em relação ao diâmetro médio (~300 nm) e à porcentagem de ISOTN encapsulada. A encapsulação lipossomal de ISOTN diminuiu sua fotodegradação em comparação com este fármaco dissolvido em etanol. Géis aquosos contendo ISOTN lipossomal apresentaram maior estabilidade fotoquímica que o gel alcoólico convencional contendo ISOTN. Os géis lipossomais apresentaram menor fluxo através da pele de orelha de porco, indicando menor absorção sistêmica in vivo. Géis contendo Lipo_PC/PS e Lipo_HPC/DO retiveram mais fármaco na pele em comparação ao fármaco permeado. Com exceção do gel contendo Lipo_HPC/DO, todos os demais géis lipossomais foram menos irritantes à pele de coelho em relação aos géis alcoólicos convencionais. Portanto, a encapsulação da ISOTN em lipossomas aumentou sua estabilidade e diminuiu efeitos adversos em relação aos produtos comerciais / Abstract: The mail goals of this work were the preparation, characterization, verification of the stability, skin permeation and cutaneous irritation of isotretinoína (ISOTN) liposomal formulations used in dermatological treatment and designed to reduce adverse effects and drug degradation. The liposomal formulations were obtained by the technique of dry film hydration. Liposomes made of only saturated phosphatidylcholine (HPC) caused leakage of the encapsulated drug. The maximum encapsulation was obtained (> 98%) by increasing the fluidity of the lipidic bilayers, with the following liposomal suspensions: (a) a mixture of HPC with 40% mol of the unsaturated surfactant Lipopeg4DO (DO) - Lipo_HPC/DO; (b) a mixture of HPC with 40% mol of unsaturated phosphatidylcholine (PC) - Lipo_HPC/PC; (c) liposomes with only PC - Lipo_PC; (d) a mixture of PC with 20% mol of cholesterol (Col) - Lipo_PC/Col, and (e) a mixture of PC with 10% mol of phosphatidylserine (PS) - Lipo_PC/PS. Due to the high yield of encapsulation of ISOTN in these liposomes, the suspensions didn't require separation of non encapsulated drug. The molar ratio ISOTN/lipids was approximately 0,026: 1. Transmission and scanning electron microscopy of the liposomal suspensions showed the lamellar structure and spherical geometry of the vesicles. ISOTN encapsulation in the lipid bilayers was monitored by optical microscopy, since this drug crystallizes outside the vesicles. This encapsulation was also confirmed by increase of the degree of anisotropy of the fluorescent probe pyrene and the decrease of its fluorescence intensity due to quenching processes. The liposomal suspensions were stable for 3 months at 8 oC, maintaining the diameter and the percentage of encapsulated drug. The encapsulation in liposomes decreased ISOTN photodegradation in comparison to the drug dissolved in ethanol. Aqueous gels containing liposomal ISOTN were more protect after photolysis than ISOTN in the conventional alcoholic gel. The liposomal gels presented a slower rate of permeation through the skin of a piglet ear, indicating a tendency of present a lower systemic absorption in vivo. Gels containing Lipo_PC/PS and Lipo_HPC/DO were able to retain more drug at the skin than the free drug. With the exception of the gel containing Lipo_HPC/DO, the other liposomal gels were less irritating to the rabbit skin in relation to the conventional alcoholic gels. Therefore, the encapsulation of ISOTN in liposomes increased its stability and diminished its adverse effects in comparison to the commercial products / Doutorado / Físico-Química / Doutor em Ciências

Akne är en inflammatorisk sjukdom. Det innebär att den är en typ av utslag som orsakas av inflammerade talgkörtlar. Akne förekommer vanligast hos tonåringar. Ungefär var tredje tonåring får besvär men även vuxna kan få akne. Isotretinoin (13-cis vitamin A-syra) är ett peroralt läkemedel för behandling av svår akne till exempel nodulocystisk- och konglobat akne samt ärrbildande akne, som inte kan kontrolleras med andra systemiska antibiotika och lokalterapi.  Isotretinoin ger en hel del biverkningar. Bland de sällsynta, men allvarliga, biverkningar, som kan inträffa vid (≥1/10 000, <1/1 000) behandlingar, finns depression. Det har också registrerats många rapporter angående depression, humörförändringar, ångest, och förvärrande av befintlig depression hos människor som genomgått en systemisk behandling med isotretinoin. År 1998 utfärdade FDA en varning till läkarna om att det kan föreligga en koppling mellan användningen av isotretinoin och depression, självmordstankar samt psykos.  Syftet med denna litteraturstudie är att undersöka om behandling med läkemedlet isotretinoin vid akne kan orsaka negativa psykiska besvär såsom depression, ångest och nedsatt livskvalitet. Sökningarna till detta litteraturarbete genomfördes i PubMed via Linnéuniversitetets bibliotek. Det var fem studier som inkluderades. Studierna använde olika självskattningsformulär för att utvärdera symtom på depression, ångest och livskvalitet hos deltagarna. Resultaten av detta arbete visade att behandlingen med isotretinoin inte orsakade psykiska störningar såsom depression, ångest och nedsatt livskvalitet. Tvärtom fann studierna signifikant förbättring i patienternas psykiatriska tillstånd. Det finns emellertid fortfarande inte tillräckliga underlag för att kunna bekräfta eller helt utesluta uppkomsten av psykiska störningar under isotretinoinbehandling. / Background  Acne is an inflammatory disease, i.e. it is a kind of rash that is caused by inflammatory sebaceous gland. Acne is most prevalent in teenagers, it is estimated that1/3rd of all teenagers suffer from acne but adults can also develop the disease. Isotretinoin is a peroral prescription drug used to treat severe acne, for example: nodulocystic- acne conglobata and scarring acne that cannot be controlled with other systemic treatments such as antibiotics and/or local therapy. Isotretinoin gives the best and most effective results in the treatment of severe acne and improves the condition and reduces acne in the long term. Isotretinoin is teratogenic and has several and serious side effects and is therefore only used in severe cases of acne and the treatment is performed by a dermatologist. Among the rare (≥1/10 000, <1/1 000) but serious side effects which can occur upon treatment with Isotretinoin, is depression. There have been many reports regarding depression, mood swings, anxiety and worsening of already existing mental conditions in patients with depression, from individuals who have received systemic Isotretinoin treatments. In 1998 the FDA issued a warning to doctors that there could be a link between Isotretinoin treatment and depression, suicidal thoughts and possibly even psychosis.  Purpose  The purpose of this literature study is to investigate if acne treatments with the drug isotretinoin can cause mental disorders such as depression, anxiety, and an overall impaired quality of life.  Method  The literature searches were conducted in PubMed through the library of Linnaéus University. There are five studies referenced. The studies used different forms of self-assessment to evaluate symptoms of depression, anxiety, and overall quality of life in the participants.  Results and Conclusions The results of this work showed that there is no indication of a connection between isotretinoin treatments and mental negative effects in patients with acne. On the contrary, the studies found signs of improvement in the mental condition of the patients by the end of the treatment. There is, however, still not enough data to be able to confirm or rule out the origins of mental disturbance when a patient is treated with isotretinoin.

Acne is a skin condition which is caused when the sebaceous glands become inflamed. This disease can affect different people at different ages, but it appears most commonly in adolescence. Acne can have different degrees of severity, which should be taken into consideration while choosing the right treatment. Acne nodulocystic is characterized by deeper infiltrates and pus-filled cysts. This type of acne is severe and should be treated only with isotretinoin.  In the early 1980s, isotretinoin was developed to treat moderate to severe acne with a tendency to scarring. Currently, it has been reported that in Sweden about 6000-8000 patients are treated with isotretinoin annually. However, it is important to point out that isotretinoin is associated with high risks. Therefore, isotretinoin is only prescribed by a physician with a specialist qualification in dermatology or by personal exemption by the Medicines Agency. Regarding the dosage, 0.5 mg/kg/day is usually a suitable starting dose in normal cases. This dose can be further increased after tolerance to 1.0 mg/kg/day. However, a lower dose of 0.2 mg/kg/day may be a good option to reduce the risk of side effects such as: mucocutaneous dryness, muscle pain and others. The purpose of this literature survey was to examine which one of the new isotretinoin formulations would give better effect in acne treatment given that both are expected to be independent of food intake at the time of administration. The method used was a literature search in the Pubmed database to find and select relevant scientific articles. The results of the studies in this literature project suggest that both lidose and micronized isotretinoin exhibited similar bioequivalent results in comparison to isotretinoin in the fed state but an improved result in fasting. Moreover, it was noted that the micronized form showed a similarity in pharmacokinetics compared to Lidose in the fed state but better in fasting. However, there is insufficient evidence to determine that the micronized form was superior to Lidose-isotreitnoin.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2014-08-06T11:34:54Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Estudo_da_Encapsulacao_da_isotretinoina_nas_formas_livres_e_associada_a_ciclodextrinas_em_niossomas.pdf: 2030155 bytes, checksum: 19eecf0e1e4b0f42b01d0975d4634686 (MD5) / Made available in DSpace on 2014-08-06T11:34:54Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Estudo_da_Encapsulacao_da_isotretinoina_nas_formas_livres_e_associada_a_ciclodextrinas_em_niossomas.pdf: 2030155 bytes, checksum: 19eecf0e1e4b0f42b01d0975d4634686 (MD5) Previous issue date: 2009-12-15 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Fundação de Apoio à Pesquisa - FUNAPE / Non-ionic surfactant vesicles (niosomes) and cyclodextrins (CDs) are able to modify physical-chemical properties of incorporated drugs. One of the major challenges for the topical administration of retinoids, such as isotretinoin (31cisRA), is the stability of these compounds in formulations capable of reducing their toxicity during the treatment. The purpose of this research was to develop vesicular carries capable to transport and deliver isotretinoin for topical application during acne treatment. The niosomes were obtained from Bryj®30:Cholesterol:DCP (50:25:10) by the film hydration method. The HP CDs:isotretinoin complex was obtained by agitation for 8 days in phosphate buffer pH 7.4. The vesicles were characterized and it was possible to encounter a large amount of morphological varieties, flexible structures and fluid membrane, after inclusion of free isotretinoin. The fluidness of the membrane that contains isotretinoin allowed leaking of the drug when in concentration above 5 mM. The HP CDs:Isotretinoin (20:1) increased the vesicle size considerably, also allowing drug leaking. The systems developed presented themselves as potential carries of isotretinoin for topical application and played the roll of drug delivery system, / Os niossomas, vesículas formadas por tensoativos não-iônicos, e as ciclodextrinas (HP CDs) são sistemas capazes de alterar as características físico-químicas originais de diversos fármacos. O maior desafio da administração tópica de retinóides, como isotretinoína (ácido 13-cis-retinóico), é a manutenção de sua estabilidade em formulações capazes de reduzir a sua toxicidade durante o tratamento. A proposta deste trabalho foi desenvolver sistema para o transporte e liberação da isotretinoína com potencial para aplicação na terapêutica tópica da acne. Os niossomas foram formados a partir de Brij®30:Colesterol:DCP (50:25:10) pelo método de hidratação do filme lipídico. O complexo HP Ciclodextrinasisotretinoína foi obtido por agitação durante 8 dias em tampão fosfato pH 7,4. Os niossomas foram caracterizados sendo possível verificar grande variedade morfológica, estruturas flexíveis e membrana fluída após a inclusão da isotretinoína livre. A fluidez da membrana que contém isotretinoína permitiu o vazamento de fármaco quando em concentrações maiores que 5 mM. O complexo HP CDs:isotretinoína (20:1) aumentou consideravelmente o tamanho das vesículas, também permitindo vazamentos. Os sistemas desenvolvidos possuem potencial para uso como carreadores da isotretinoína na aplicação tópica demonstrando comportamento de “sistema de liberação modificado”.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Objetivos: objetivo geral deste trabalho foi avaliar a penetração cutânea da isotretinoína nanoencapsulada e livre utilizando técnicas de microdiálise e tape stripping in vitro. Métodos: A viabilidade da utilização da técnica de microdiálise para avaliar o perfil farmacocinético da isotretinoína após aplicação tópica foi investigada através da determinação da recuperação relativa (RR) in vitro por diálise e retrodiálise. A influência da concentração, do fluxo de perfusão e a ligação do fármaco à tubulação das sondas de microdiálise foram investigadas. A metodologia analítica para quantificação do fármaco em microdialisado foi validada. Em seguida, as penetrações cutâneas da isotretinoína livre e nanoencapsulada incorporada em géis hidrofílicos foram comparadas através da técnica de tape stripping in vitro em células de difusão de Franz utilizando pele humana e pele de porco. Para garantir a integridade das formulações, a estabilidade físico-química das mesmas foi avaliada. Os resultados de penetração cutânea foram comparados com os resultados in vivo obtidos em trabalho prévio do grupo de pesquisa. Resultados e Conclusões: Um método analítico simples e rápido para a determinação de isotretinoína em microdialisado foi validado de acordo com o FDA. A RR mostrou-se concentração independente e observou-se que há diferenças significativas entre as RR avaliadas pelos dois métodos utilizados, sendo a recuperação por retrodiálise 2,7 a 3,5 vezes superior que a obtida por diálise para os fluxos investigados. O fármaco aderiu às tubulações da sonda de microdiálise devido à sua lipofilicidade. Os hidrogéis de isotretinoína apresentaram estabilidade durante 2 meses de estocagem à 4 °C. Os experimentos de tape stripping in vitro mostraram que a isotretinoína não foi encontrada no compartimento receptor após 8 h, para ambas as formulações. A nanoencapsulação aumentou a penetração e prolongou a liberação da isotretinoína no estrato córneo de ambas as peles. A penetração cutânea em ambas as peles mostrou proporções similares para as duas formulações embora diferentes quantidades de fármaco tenham sido detectadas no estrato córneo. A pele de porco, mais permeável que a pele humana, é apropriada para prever a penetração cutânea da isotretinoína no estrato córneo humano in vitro (R = 0,79). O método in vitro não foi capaz de prever a penetração cutânea da isotretinoína in vivo. / Objectives: The aim of the present work was to assess the cutaneous penetration of isotretinoin free and loaded into polymeric nanocapsules using microdialysis and tape stripping in vitro. Methods: The feasibility of using microdialysis to determine the pharmacokinetic profile of isotretinoin after topical application was investigated through assessment of relative recovery (RR) in vitro by dialysis and retrodialysis. The influence of isotretinoin concentration, perfusion flow rate and drug binding to the probes were determined. The analytical method for quantification of microdialysate samples was validated. Furthermore the cutaneous penetration of isotretinoin free and loaded nanocapsules incorporated in hydrogel formulations were compared by tape stripping in vitro using Franz-type diffusion cells with excised human and pig skin. In order to ensure the integrity of the formulations used in this study, the chemical and physical stabilities were evaluated. The results of cutaneous penetration were compared with the results of tape stripping in vivo acquired in a previous study of our group. Results and Conclusions: A simple and rapid analytical method for quantification of isotretinoin in microdialysate samples was validated according to FDA. RR was concentration independent but method dependent under the conditions investigated being the retrodialysis recovery 3.5 to 2.7 times higher than the dialysis. Isotretinoin bound to the microdialysis tubing due to its high lipophilicity. The hydrogels showed storage stability for 2 months at 4 °C. In vitro tape stripping in human and pig skin showed that no isotretinoin reaches the receptor compartment for both formulations up to 8 h. Nanoencapsulation increased isotretinoin skin penetration for both stratum cornea and prolonged drug release. Similar proportion of cutaneous penetration for human and pig skin were observed although different amounts of drug were detected at the stratum corneum of both skin specimens. Pig skin, more permeable than human skin, is suitable for predicting cutaneous penetration of isotretinoin in humans in vitro (R = 0.79). The in vitro experiments were not suitable to reflect the in vivo results for percutaneous penetration of isotretinoin.

Objetivos: objetivo geral deste trabalho foi avaliar a penetração cutânea da isotretinoína nanoencapsulada e livre utilizando técnicas de microdiálise e tape stripping in vitro. Métodos: A viabilidade da utilização da técnica de microdiálise para avaliar o perfil farmacocinético da isotretinoína após aplicação tópica foi investigada através da determinação da recuperação relativa (RR) in vitro por diálise e retrodiálise. A influência da concentração, do fluxo de perfusão e a ligação do fármaco à tubulação das sondas de microdiálise foram investigadas. A metodologia analítica para quantificação do fármaco em microdialisado foi validada. Em seguida, as penetrações cutâneas da isotretinoína livre e nanoencapsulada incorporada em géis hidrofílicos foram comparadas através da técnica de tape stripping in vitro em células de difusão de Franz utilizando pele humana e pele de porco. Para garantir a integridade das formulações, a estabilidade físico-química das mesmas foi avaliada. Os resultados de penetração cutânea foram comparados com os resultados in vivo obtidos em trabalho prévio do grupo de pesquisa. Resultados e Conclusões: Um método analítico simples e rápido para a determinação de isotretinoína em microdialisado foi validado de acordo com o FDA. A RR mostrou-se concentração independente e observou-se que há diferenças significativas entre as RR avaliadas pelos dois métodos utilizados, sendo a recuperação por retrodiálise 2,7 a 3,5 vezes superior que a obtida por diálise para os fluxos investigados. O fármaco aderiu às tubulações da sonda de microdiálise devido à sua lipofilicidade. Os hidrogéis de isotretinoína apresentaram estabilidade durante 2 meses de estocagem à 4 °C. Os experimentos de tape stripping in vitro mostraram que a isotretinoína não foi encontrada no compartimento receptor após 8 h, para ambas as formulações. A nanoencapsulação aumentou a penetração e prolongou a liberação da isotretinoína no estrato córneo de ambas as peles. A penetração cutânea em ambas as peles mostrou proporções similares para as duas formulações embora diferentes quantidades de fármaco tenham sido detectadas no estrato córneo. A pele de porco, mais permeável que a pele humana, é apropriada para prever a penetração cutânea da isotretinoína no estrato córneo humano in vitro (R = 0,79). O método in vitro não foi capaz de prever a penetração cutânea da isotretinoína in vivo. / Objectives: The aim of the present work was to assess the cutaneous penetration of isotretinoin free and loaded into polymeric nanocapsules using microdialysis and tape stripping in vitro. Methods: The feasibility of using microdialysis to determine the pharmacokinetic profile of isotretinoin after topical application was investigated through assessment of relative recovery (RR) in vitro by dialysis and retrodialysis. The influence of isotretinoin concentration, perfusion flow rate and drug binding to the probes were determined. The analytical method for quantification of microdialysate samples was validated. Furthermore the cutaneous penetration of isotretinoin free and loaded nanocapsules incorporated in hydrogel formulations were compared by tape stripping in vitro using Franz-type diffusion cells with excised human and pig skin. In order to ensure the integrity of the formulations used in this study, the chemical and physical stabilities were evaluated. The results of cutaneous penetration were compared with the results of tape stripping in vivo acquired in a previous study of our group. Results and Conclusions: A simple and rapid analytical method for quantification of isotretinoin in microdialysate samples was validated according to FDA. RR was concentration independent but method dependent under the conditions investigated being the retrodialysis recovery 3.5 to 2.7 times higher than the dialysis. Isotretinoin bound to the microdialysis tubing due to its high lipophilicity. The hydrogels showed storage stability for 2 months at 4 °C. In vitro tape stripping in human and pig skin showed that no isotretinoin reaches the receptor compartment for both formulations up to 8 h. Nanoencapsulation increased isotretinoin skin penetration for both stratum cornea and prolonged drug release. Similar proportion of cutaneous penetration for human and pig skin were observed although different amounts of drug were detected at the stratum corneum of both skin specimens. Pig skin, more permeable than human skin, is suitable for predicting cutaneous penetration of isotretinoin in humans in vitro (R = 0.79). The in vitro experiments were not suitable to reflect the in vivo results for percutaneous penetration of isotretinoin.