Analysis and Stability of Deferoxamine and Hydrocortisone Admixtures

P. Yuan, N. U. Aigbogun1, C. Chamberlain, R. DeChristoforo, G. J. Grimes, G. K. Potti
National Institutes of Health

Purpose: Deferoxamine (DEF) is a chelating agent used to remove excess iron load from patients with sickle cell disease due to frequent blood transfusion to alleviate anemia. Common complaints with DEF infusions are redness, swelling, tenderness and pain at the site of the subcutaneous catheter. Hydrocortisone (HYD) is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema or topically for allergic rashes. The admixture of DEF and HYD has been given to patients as one of the alternatives for reducing the inflammations. This combination has been in clinical use, however, no published studies indicate that the combination is stable. The purpose of this study is to see if the combinations are stable for up to seven days.

Methods: The admixtures of DEF/HYD were prepared at concentration of 250 mg/ml DEF/1 mg/ml HYD (A) and 100 mg/ml DEF/1 mg/ml HYD (B) (all base drug equivalent) and stored in 60 cc monoject syringes at room temperature. Stability of the drug
admixtures was followed by visual observation, pH testing, USP chelating UV assay on DEF and Optical Rotation analysis on HYD. In addition, a stability-indicating HPLC assay has been developed to test DEF and HYD together.

Results: Both (A) and (B) solutions are visually clear, no precipitation over the 7 days period. The pH values of the solution are 5.1 +/- 0.1 for (A) and 5.46 +/- 0.08 for (B), contents of DEF and HYD are above 98% relative to initial testing over the seven days period from our preliminary analysis using UV and OR. Both DEF and HYD would degrade when subject to high temperature, acidic and alkali conditions and with the presence of hydrogen peroxide. The degradation products were well
resolved from DEF and HYD in the chromatograms. Stability-indicating HPLC analysis of the drug admixtures is in progress.

Conclusion: The admixtures of DEF and HYD are stable at controlled room temperature for at least seven days

Reference: . Referência: Yuan P, Aigbogun NU, Chamberlain C, DeChristoforo R, Grimes GJ, Potti GK. Analysis and Stability of Deferoxamine and Hydrocortisone Admixtures. Disponível em: http://www.aaps.org/abstracts Acesso em: 04 de agosto de 2010

Livro de Oncohematologia

Cada monografia foi organizada em categoria pelo tipo de informação: reconstituição; compatibilidade com frascos e equipos; diluente, volume final e tempo de infusão; compatibilidade; incompatibilidade; sinonímia e outras denominações e finalmente, os estudos sobre a estabilidade da solução diluída.

O perfil de cada medicamento segue um esquema consistente e lógico, onde informamos a referência bibliográfica específica do estudo, incluindo informações sobre alguns parâmetros de estabilidade, como uma tabela de pH, critérios de armazenamento e estocagem de cada preparação realizada, temperatura de armazenagem, sinonímias do fármaco, tabela de compatibilidade e incompatibilidade dos medicamentos, glossário de termos técnicos aplicados na área, legislação farmacêutica específica e referências bibliográficas por medicamento.

Espero sinceramente que médicos, enfermeiros, farmacêuticos, veterinários, professores e estudantes da área da saúde considerem o livro como um recurso valioso de informações.

Este livro apresenta 256 páginas, com 132 monografias de princípios ativos e mais de 300 preparações extemporâneas de medicamentos injetáveis ou não de uso em oncologia, cuidados paliativos e em hematologia, assim como os medicamentos de suporte de uso em oncohematologia, com a respectiva estabilidade do produto reconstituído ou manipulado que foram preparados a partir de cápsulas, comprimidos, ampolas ou de outras formas farmacêuticas existentes, também descrevemos a estabilidade de líquidos orais fracionados e estocados em seringa dosadora oral âmbar, estabilidade de preparações dermatológicas, estabilidade de preparações oftálmicas, assim como o preparo, compatibilidade, reconstituição e estabilidade de medicamentos citostáticos injetáveis.

O livro Oncohematologia: Manual de Diluição, Administração e Estabilidade de Medicamentos Citostáticos é um livro que desejamos que funcione como um livro prático, de leitura fácil, simples e que seja objetivo para acompanhar a equipe multiprofissional dos serviços de terapia antineoplásica.

Abciximabe,Ácido Folínico, Ácido Zoledrônico, Aclarrubicina, Actinomicina D, Alemtuzumabe, Alopurinol, Amifostina, Amsacrina, Asparaginase, Azacitidina, Azatioprina, BCG, Bevacizumabe, Bleomicina, Bortezomibe, Bussulfano, Carboplatino, Carmustina, Cetamina, Cetuximabe, Ciclofosfamida, Cidofovir, Cisplatino, Citarabina, Citarabina Lipossomal, Cladribina, Clodronato, Clofarabina, Clorambucila, Codeína, Dacarbazina, Daclizumabe, Darbepoetina Alfa, Daunorrubicina, Daunorrubicina Lipossomal, Decitabina, Dexametasona, Dexrazoxano, Diamorfina, Dimetilsulfóxido, Docetaxel, Dolasetrona, Doxorrubicina, Doxorrubicina Lipossomal, Droperidol, Eculizumabe, Edrecolomabe, Epirrubicina, Eritropoetina Alfa-Recombinante, Estramustina, Estreptozocina, Etoposido, Fentanila, Filgrastima, Floxuridina, Fludarabina, Fluoruracila, Folinato de Cálcio, Folinato Dissódico, Fotemustina, Ganciclovir, Gemcitabina, Gemtuzumabe, Gemtuzumabe Ozogamicina, Granisetrona, Haloperidol, Hidromorfona, Hidroxiuréia, Idarrubicina, Idoxuridina, Ifosfamida, Infliximabe, Interferon Alfa-2b Recombinate, Interferon Alfa-2a, Interleucina, Irinotecano, Lenograstima, Mecloretamina, Melfalano, Mercaptopurina, Mesna, Metadona, Metilprednisolona, Metotrexato, Metronidazol, Mitomicina, Mitoxantrona, Mitramicina, Molgrastima, Morfina, Naloxona, Naltrexona, Nelarabina, Octreotida, Ondansetrona, Oxaliplatino, Oxicodona, Paclitaxel, Palonosetrona, Pamidronato, Panitumumabe, Pegaspargase, Pegfilgrastima, Pemetrexede, Pentostatina, Petidina, Procarbazina, Raltitrexede, Rasburicasa, Rituximabe, Saliva Artificial, Saliva Artificial com Lidocaína, Sargramostima, Solução Sedativa Oral, Sucralfato, Sunitibe, Temozolomida, Teniposido, Tintura de Ópio, Tioguanina, Tiotepa, Topotecano, Tositumomabe, Tramadol, Trastuzumabe, Treossulfano, Tropisetrona, Valrrubicina, Vidarabina, Vimblastina, Vincristina, Vindesina, Vinorelbina

Consequências dos erros de medicação em unidades de terapia intensiva e semi-intensiva

***

Maria Cecília Toffoletto (1); Kátia Grillo Padilha (2)

(1) Enfermeira. Mestranda do Programa de Pós-Graduação na Saúde do Adulto da Escola de Enfermagem da Universidade de São Paulo (EEUSP) mariacel@usp.br

(2) Professora Doutora do Departamento de Enfermagem Médico-Cirúrgica da EEUSP kgpadilha@usp.br

RESUMO

O estudo objetivou caracterizar erros de medicação e avaliar consequências na gravidade dos pacientes e carga de trabalho de enfermagem em duas Unidades de Terapia Intensiva (UTI) e duas Semi-Intensiva (USI) de duas instituições hospitalares do município de São Paulo. A amostra foi constituída por 50 pacientes e os dados obtidos por meio do registro de ocorrências e prontuários, retrospectivamente. A gravidade e carga de trabalho de enfermagem foram avaliadas antes e após o erro. Do total de 52 erros, 12 (23,08%) ocorreram por omissão de dose, 11 (21,15%) e 9 (17,31%) por medicamento e dose erradas, respectivamente. Não houve mudança na gravidade dos pacientes (p=0,316), porém houve aumento na carga de trabalho de enfermagem (p=0,009). Quanto ao grupo de medicamentos envolvidos, potencialmente perigosos e não potencialmente perigosos, não houve diferenças estatisticamente significantes na gravidade (p=0,456) e na carga de trabalho de enfermagem (p=0,264), após o erro de medicação.

Referência: Revista da Escola de Enfermagem da USP 2006;40(2):247-52

Topical cidofovir for the treatment of plantar warts: case report

***

Topical cidofovir for the treatment of plantar warts: case report

Amelia Troncoso, Ramon Cuiña, Juliana Alvarez, Cristina Vazquez, Maria Teresa Inaraja, Francisco Allegue

Pharmacy, Hospital Meixoerio, Dermatology, Hospital Meixoeiro, Vigo, Spain

Background and Objective: Plantar warts are hyperkeratotic lesions on the plantar surface caused by infection with Human papillomavirus. Lesions caused by warts are commonly refractory to therapy and may become large and painful in immunodeficient patients. Cidofovir is a cytidine analogue with activity against a broad spectrum of DNA viruses. It is indicated for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome and without renal dysfunction. We describe a case of plantar warts that was treated with topical cidofovir in a highly immunodeficient patient.

Results: A 29 years old woman, who received kidney transplant in 1996, presenting plantar warts refractory to conventional therapy since last four years. She was treated with topical 3% cidofovir cream twice daily. The treatment was authorised as compassionate use by the national regulatory agency on drugs. The glomerular filtration rate (GFR) was monitored in order to detect nephrotoxicity due to cidofovir.

The 3% cidofovir ointment was compounded as follows:

– Cidofovir 75 mg/ml 5 ml vial .…….. 20 ml
– Anhydrous Lanolin ……………………….. 5 g
– Beeler base …..sufficient to produce 50 g

It was packaged and labelled in a light-resistant containers and we assumed an expiration date of 3 months based on the duration of treatment and published studies. The quality controls of organoléptics properties were made according to the Good Manufacturing Practice (GMP)

After 10 weeks of therapy the patient did not show any improvement and developed severe local erosion, so treatment with cidofovir was withdrawn. Two weeks later this local erosion disappeared spontaneously. No systemic side effects were observed. The colour, texture and smell organoleptics characters were complied with GMPs.

Conclusions: There are not formal studies of optimal formulations or treatment regimens and further studies are needed to elucidate the role of cidofovir in treatment of plantar warts. The immunodeficiency of the patient and the large wart area could be related with the failure to the treatment.

Reference Alonso Diez M, de Miguel Cascón M, Sánchez Moreno H, González Mielgo FJ. Cidofovir tópico para tratamiento de lesiones cutáneas por Molluscum contagiosum y Papilomavirus humano. XLIV SEFH Congress.1999; 156–57

Voriconazol colírio: estabilidade após a manipulação

***

Stability of extemporaneously prepared voriconazole ophthalmic solution

AL-BADRIYEH, DAOUD; LI, JIAN; STEWART, KAY; KONG, DAVID C. M.; LEUNG, LOK; DAVIES, GEOFFREY E.; FULLINFAW, ROBERT

Methods: Voriconazole solutions (2% and 1%) were reconstituted from the i.v. formulation. After thorough mixing, 3-mL samples of each of the resulting 2% and 1% solutions were filtered into eyedroppers. Three samples for both solutions were analyzed in triplicate at each time point. The 2% voriconazole ophthalmic solutions were stored at 2–8 °C, 25 °C, and 40 °C. The 1% voriconazole eye drops were stored at 2–8 °C. The 2% voriconazole solution samples were analyzed at time 0 and at weeks 1, 2, 4, 8, 16, and 32. The 1% solution samples were analyzed at time 0 and at weeks 6 and 14. Stability was measured using high-performance liquid chromatographic analysis.

Results: The 2% voriconazole ophthalmic solution demonstrated excellent stability at 2–8 °C and 25 °C for up to 16 weeks. The voriconazole solution displayed no significant change in pH at all time intervals. No change in visual appearance or clarity was observed in the 2% voriconazole eye drops at any point of the study for all study temperatures. Voriconazole 1% solution was stable at 2–8 °C for up to 14 weeks.

Conclusion: Voriconazole 2% (20 mg/mL) solution preserved with 0.01% benzalkonium chloride prepared as alternative antifungal eye drops was stable for 16 weeks when stored at 2–8 °C and 25 °C and for 8 weeks when stored at 40 °C, while voriconazole 1% solution was stable at 2–8 °C for up to 14 weeks.

Reference: American Journal of Health-System Pharmacy
Issue: Volume 66(16), 15 August 2009, p 1478–1483

Poor preservation efficacy versus quality and safety of pediatric extemporaneous liquids.

***

Ghulam A, Keen K, Tuleu C, Wong IC, Long PF.

The School of Pharmacy, University of London, London, England.

Background: Most medicines are available only as solid, adult-strength dosage forms from which oral extemporaneous liquids are often prepared for children. There are few comprehensive reference lists for the preparation of pediatric extemporaneous formulations. Some pediatric reformulations are made by diluting the suspending vehicle, and a shelf life of up to 3 months can be used without documented microbial stability. Although most commercially available ready-to-use vehicles are supplied as preserved formulations, it is still common practice in many European dispensaries to prepare and dilute these vehicles as required for specific prescriptions.

Objective: To determine what influence dilution of vehicles has on the preservation efficiency of extemporaneous formulations.

Methods: Suspending vehicles were made by diluting methylcellulose 1% and simple syrup, BP (British Pharmacopoeia) in ratios of 1:1 and 1:4. The efficacy of antimicrobial preservation was tested according to the 2007 standards required by the BP.

Results: Dilution in ratios greater than 1:1 failed the BP 2007 criteria. Such dilution represents a potential biohazard, especially to premature, newborn, or immunocompromised children, exposing them not only to possible organoleptic changes of the preparation, but also to ingestion of either dangerous numbers of microorganisms or medicines that may have undergone biotransformation, rendering them inactive or toxic.

Conclusions: Significant concerns have been raised regarding the quality of extemporaneous preparations. We call for further research in this neglected area to address issues of antimicrobial preservation, including revision of existing quality assurance monographs. Moreover, these monographs should take into account testing that simulates multiple dosing from a single storage container during the intended in-use shelf life of multidose extemporaneous preparations.

Reference: Ann Pharmacother. 2007 May;41(5):857-60. Epub 2007 Apr 17.

Stability of morphine sulphate and diamorphine hydrochloride in Intrasite gel

***

Stability of morphine sulphate and diamorphine hydrochloride in Intrasite gel

Giovambattista Zeppetella G; Joel SP; Ribeiro MDC.
St. Clare Hospice, Hastingwood, Essex; Medical Oncology Department, St. Bartholomew's Hospital, London; Peace Hospice, Watford

Several studies have reported that opioids applied topically to painful ulcers produce an analgesic effect. It is unknown whether these opioids (usually mixed with hydrogels) are stable and, if so, for how long. We investigated the stability of morphine sulphate and diamorphine hydrochloride, each mixed with intrasite gel at a concentration of 1.25 mg/mL. Samples were prepared in the laboratory and then stored in plastic containers in the dark, at room temperature, in conditions of normal day/night at room temperature, and at 48C. Aliquots were collected from each container over a 28-day period and analysed using HPLC. No known degradation products were measured in the morphine–intrasite gel mixture stored for up to 28 days, irrespective of the temperature and whether or not samples were exposed to light, suggesting that morphine remains stable. Diamorphine, breaks down to morphine and no other degradation products are measurable.

Reference: Palliative Medicine, Vol. 19, No. 2, 131-136 (2005)

Efectividad y seguridad de diltiazem 2 % tópico

***
Efectividad y seguridad de diltiazem 2 % tópico en fisura anal

M.I. Fernández García*, R. Albornoz López, I. Pérez Rodrigo y J. Abellón Ruiz

Servicio de Farmacia, Hospital Universitario Reina Sofía, Córdoba, España

Objetivo: Evaluar la efectividad y la seguridad de la pomada de diltiazem al 2 % en el tratamiento de la fi sura anal. Analizar la relación entre la cicatrización de la fi sura y diagnóstico, duración del tratamiento y número de aplicaciones.

Métodos: Estudio prospectivo observacional de todos los pacientes diagnosticados de fi sura anal que comenzaron tratamiento con diltiazem tópico entre enero y junio de 2007. La pomada de diltiazem al 2 % se preparó como fórmula magistral en el servicio de farmacia. La efectividad y la seguridad se evaluó mediante encuesta telefónica a cada paciente tras 8 semanas de tratamiento, completándose con la historia clínica del paciente. Las variables analizadas fueron cicatrización, efectos adversos, diagnóstico, duración del tratamiento y número de aplicaciones, entre otras. Se realizó seguimiento hasta resolución de la fi sura hasta un período de 1 año. El análisis de los datos se realizó mediante estadística descriptiva y frecuencia, tablas de contingencia y  2.

Resultados: Se incluyó a un total de 70 pacientes y se produjo cicatrización en el 48,6 % de éstos. Cicatrizó en el 54,5 % de los pacientes con fi sura anal y en el 33,3 % con fi sura anal y hemorroides. El 30 % experimentó efectos adversos. El 5,7 % abandonó el tratamiento por reacción adversa. La fi sura cicatrizó en el 60 % de los pacientes que estuvieron más de 1 mes en tratamiento. No hubo más cicatrización con más de 2 aplicaciones diarias. En ninguno de estos resultados hubo diferencias estadísticamente signifi cativas.

Conclusiones: A pesar de no encontrarse diferencias signifi cativas entre las variables estudiadas, el tratamiento de la fi sura anal con la pomada de diltiazem al 2 % ha evitado la intervención quirúrgica casi en un 50 % de los pacientes, con efectos adversos poco frecuentes.

Reference: Farm Hosp. 2009;33(2):80-8

Vancomycin: stability in syringes

***

Chemical stability and microbiological potency of intravenous
vancomycin hydrochloride in polypropylene syringes for use in
the neonatal intensive care unit

Study objectives : To determine the chemical stability and microbiological potency of “almost” ready-to-use vancomycin solutions in polypropylene syringes at a concentration of 5 mg/mL in both 5% glucose and 0.9% sodium chloride at 4°C and 25°C, for use in the neonatal intensive care unit.

Methods: Ten-millilitre syringes were filled using aseptic techniques with a solution of vancomycin, covering body weights of 500 g to 3 kg at a dosage of 15mg/kg, prepared by reconstitution and dilution of commercially available vancomycin hydrochloride powder (Vancocin) and kept at 4°C and 25°C, respectively. At various storage times, the chemical stability was determined using a high-performance liquid chromatography method and the microbiological potency was assayed according to the European Pharmacopoeia 2002. Arbitrarily, 56 day samples at 4°C were brought to 25°C and analyzed after 48 hours to simulate ward conditions. The standards were the T0 solution kept at -70°C and the International Vancomycin Reference Standard.

Results: The vancomycin was found to be chemically and microbiologically stable at 4°C for 6 months. Losses were important after 14 days at 25°C in both cases. The samples subjected to simulated ward conditions were stable for 48 hours at 25°C. A shelf life of 6 months was proposed.

Conclusions: Syringes of low dose vancomycin manufactured and supplied by the pharmacy can be stored in the neonatal intensive care unit refrigerator for use in emergency situations thus avoiding calculation and dilution errors and reducing the risk of bacterial contamination. The solution brought to 25°C must be used within 48 hours.

References: This work was presented as a poster at the 8th congress of the European
Association of Hospital Pharmacists, Florence, Italy, 2003.

Dr Pascal Bonnabry, Head of pharmacy, Pharmacy Department University Hospitals of Geneva (HUG). William Griffiths, PharmD, Jocelyne Favet, PhD, Ho Ing, PharmD, Farshid Sadeghipour, PhD, Pascal Bonnabry, PhD

Elaboración de mezclas intravenosas individualizadas

***

Elaboración de mezclas intravenosas individualizadas
como mejora de la seguridad del paciente

Gimeno MJ, Fernández J, Pinto C, Acosta P

Servicio de Farmacia. Hospital de Poniente. Almeria

Objetivo: Los errores relacionados con medicamentos constituyen la principal causa de eventos adversos en los hospitales. La elaboración de mezclas intravenosas individualizadas por parte del Área de Farmacia permite evitar errores de dosifi cación que puedan producirse durante la preparación de éstas en el área de hospitalización. El objetivo del presente trabajo es describir la actividad asistencial que se ha llevado a cabo desde la unidad de mezclas intravenosas durante el 2006.

Material y métodos: A partir de los datos de dispensación en dosis unitarias la unidad de mezclas intravenosas elabora de forma individualizada aquellos antibióticos cuya estabilidad sea mayor de 48 h. Se consideran mezclas intravenosas individualizadas aquellas cuya dosifi cación es diferente a la de las mezclas protocolizadas que se elaboran a modo de reposición de stock.

Resultados: En el 2006 se han elaborado 230868 mezclas intravenosas de las que 2217 fueron individualizadas (0,96% total). De éstas el 87,1% (1931) pertenecen al Área de Pediatría.

Conclusiones: La elaboración centralizada en el Área de Farmacia de los antibióticos descritos evita que el personal de enfermería de hospitalización tenga que realizar cálculos de dosifi cación a los que puede no estar habituado (p.e. no tener en
cuenta el aumento de volumen que se produce al reconstituir algunos antibióticos); facilita la administración del tratamiento ya que va correctamente identifi cado; y se asegura una elaboración en condiciones estériles al ser preparados en cabina
de fl ujo laminar horizontal.

Referência: IV Congreso de la Sociedad Andaluza de Farmacéuticos de Hospitales. Spaña. 2007

Aripiprazol, eficaz a largo plazo en el tratamiento del trastorno bipolar

***

El trastorno bipolar es una enfermedad mental grave que provoca cambios extremos en el estado de ánimo, la energía y las habilidades de los afectados (se calcula que aproximadamente 2,4 millones de ciudadanos europeos padecen este tratorno).

Por ello, es especialmente importante que los tratamientos "sean eficaces y bien tolerados a largo plazo", según señala a CF Eduard Vieta, profesor de Psiquiatría de la Universidad de Barcelona y director del Programa de Trastornos Bipolares del Hospital Clínico de Barcelona.

Este experto ha dirigido un ensayo clínico presentado en el último congreso de la World Psychiatric Association (WPA), celebrado en Florencia, que ha demostrado que aripiprazol, un moderno antipsicótico, en combinación con los estabilizadores del ánimo (litio o valproato) es un tratamiento bien tolerado a largo plazo en pacientes con trastorno bipolar de tipo I y con respuesta inadecuada a la monoterapia con litio o valproato, terapias habituales en esta patología.

Según comenta Vieta, "ya se tenían datos previos positivos de aripiprazol en monoterapia, pero el nuevo estudio aporta valor añadido, al describir el comportamiento del fármaco en condiciones clínicas mucho más habituales en la clínica, como es el caso de la terapia combinada".

En este trastorno, explica, el fármaco proporciona un control rápido de los episodios maníacos, evita que aparezcan nuevos episodios y aporta un control continuado de la manía.

La eficacia y seguridad de aripiprazol, en combinación con litio o valproato, fueron investigadas en un estudio multicéntrico, doble ciego, randomizado y controlado con placebo de 6 semanas de duración, en el que participaron 348 pacientes.

Una vez finalizado, se ofreció a los participantes la posibilidad de continuar en una fase de extensión abierta de 46 semanas.

Referência: Correo Farmaceutico. Madrid: Apr 13, 2009.

Ketamina: estabilidade em seringas

***

Development of ready-to-use ketamine hydrochloride syringes for safe use in post-operative pain

M Cyril Stucki, PharmD; Sandrine Fleury-Souverain, PhD; Anna-Maria Sautter, PhD; Farshid Sadeghipour, PhD; Pascal Bonnabry, PhD

ABSTRACT: Study objectives: To increase safety in use of ketamine. This would be achieved by introducing a ready-to-use (RTU) intravenous syringe of ketamine hydrochloride, which would be prepared under aseptic conditions in the hospital pharmacy, for post-operative pain.

Methods: The chemical stability of ketamine hydrochloride solution (1 mg/mL) in 0.9% sodium chloride was determined at 4°C, 25°C and 40°C by means of a stability-indicating capillary electrophoresis method. Changes in pH and the presence
of non-visible particulate matter were measured throughout the study. Sterility testing was performed to check the integrity of the syringes.

Results: The loss in potency was less than 8% after 12 months at the three temperatures, and no degradation products were detected. The pH values did not change appreciably and the syringe contents remained sterile throughout the study. Each syringe fulfilled all US Pharmacopeia criteria in terms of non-visible particles.

Conclusion: RTU syringes of ketamine hydrochloride with a shelf life of one year can be manufactured and supplied by the hospital pharmacy for use in post-operative pain. This product will help reduce the risk of dilution errors and lead to
significant economic advantages.

M Cyril Stucki, PharmD
Pharmacy Department
University Hospitals of Geneva
24 Rue Micheli du Crest
CH-1211 Geneva 14, Switzerland
Tel: +41 22 382 39 74
Fax: +41 22 382 39 40
cyril.stucki@hcuge.ch
www.hcuge.ch/Pharmacie

Reference: EJHP Science • Volume 14 • 2008 • Issue 1 • P. 14-18

Bupivacaína + sufentanila: estabilidade em seringas

***

Chemical stability of a solution of bupivacaine hydrochloride 0.125% and sufentanil citrate 0.5 μg/mL for filling syringes using a repeater pump.

Karin Janssen, PharmD; René Wisselo, B App Sci; Charles Geerlings, PharmD; Jan Pieter Schouten, PharmD, MBM

ABSTRACT: Study objective: In Sint Franciscus Gasthuis, Rotterdam, The Netherlands, syringes filled with bupivacaine hydrochloride 0.125% and sufentanil citrate 0.5 μg/mL are administered epidurally during post-operative analgesia. These syringes are filled in the pharmacy using a Baxa Repeater pump. The suitability of the filling method and the shelf-life of the solution in the syringes were investigated.

Methods: During the filling process six samples were taken. Three syringes were stored at room temperature and three in the refrigerator. Samples were taken on days 4, 7, 14 and 28. High performance liquid chromatographic (HPLC) methods were used to measure the concentrations of both drugs in the samples.

Results: No loss of drugs was observed during the filling process. After 28 days at room temperature and in the refrigerator, the concentration of bupivacaine hydrochloride was 97.4 ± 0.9% and 97.9 ± 1.0% respectively, and that of sufentanil
citrate was 95.6 ± 4.2% and 99.2 ± 1.4%.

Conclusion: The filling method used with a Baxa Repeater pump is acceptable. Bupivacaine/sufentanil solution in syringes is chemically stable for at least 28 days in the refrigerator.

Contact: Karin Janssen, PharmD
Apotheek Zuwe Hofpoort Ziekenhuis
2 Polanerbaan
3447 GN Woerden, The Netherlands
Tel: +31 348 427385
Fax: +31 348 427489
kjanssen@zuwe.nl

Reference: EJHP Science • Volume 15 • 2009 • Issue 1 • P. 11-14

Osmolalidade e pH: metotrexato, citarabina e tiotepa.

Evaluation of osmolality and pH of various concentrations of methotrexate, cytarabine, and thiotepa prepared in normal saline, sterile water for injection, and lactated Ringer's solution for intrathecal administration.

Background: Neurotoxicity of intrathecal (IT) chemotherapy has been variously attributed to the preservatives, volume, osmolality, and pH of the preparations. There has been little evaluation of how different drug concentrations or diluents can affect the osmolality and pH of the final solution. We conducted a three-part study: survey of cancer centers regarding the drug concentrations and diluent used in preparing IT chemotherapy; review of the literature on common practice of preparing IT chemotherapy; evaluation of the pH and osmolality of commonly used chemotherapy preparations for IT.

Method: We surveyed selected cancer centers to provide information on their standard volume, drug concentrations, and choice of diluents. MEDLINE was searched for clinical reports using the MeSH terms of 'cytarabine,' 'methotrexate,' or 'thiotepa' with the subheading 'Cerebrospinal fluid' and combined with 'intrathecal' in all database fields. Data retrieved included the choice of diluent, volume, and/or drug concentration. We evaluated the pH and osmolality of methotrexate (1, 2, 5, and 10 mg/mL), cytarabine (2, 5, 10, and 25 mg/mL), and thiotepa (1, 2, and 5 mg/mL) in normal saline, sterile water for injection (SWFI), and lactated Ringer's solution.

Results: Nine centers were surveyed (seven in Canada, one in Australia, one in United Kingdom). Most centers used 5mL of preservative-free normal saline, irrespective of the drug or drug concentration used. Forty-four reports in the literature were reviewed. Most reported 5mL of preservative-free normal saline. Most information on drug concentrations was provided for methotrexate, with an average concentration of about 1-2.5 mg/ mL. Cytarabine 0.4-20 mg/mL and thiotepa 1 mg/mL were also reported. In our in vitro evaluation, there was a trend of increased pH associated with increasing concentration of methotrexate and cytarabine. There was no apparent impact of thiotepa concentration on the pH values of the final preparations, irrespective of the diluent used. Except for cytarabine 10 and 25 mg/mL, all the tested solutions have pH within 10% of the physiologic range of CSF. There was a concentration-dependent change in osmolality with methotrexate and cytarabine preparations. Osmolality was increased with increased concentrations in all except methotrexate mixed in SWFI and thiotepa mixed in normal saline and lactated Ringer's solution. Except for some thiotepa solutions, all the tested solutions have osmolality within 10% of the physiologic range of CSF.

Conclusions: There is limited published literature on the potential impact of diluent and drug concentration on the pH and osmolality of IT chemotherapy preparation. Most cancer centers conventionally prepare IT chemotherapy with 5mL of preservative diluent normal saline, irrespective of the specific drug or dose used. The conventional practice means that most methotrexate preparations are likely to have comparable pH and osmolality to CSF. In contrast, cytarabine preparations may show significantly higher pH than the CSF, while thiotepa preparations generally have lower osmolality than the CSF.

Reference: Lemos et al. Evaluation of osmolality and pH of various concentrations of methotrexate, cytarabine, and thiotepa prepared in normal saline, sterile water for injection, and lactated Ringer's solution for intrathecal administration. Journal of Oncology Pharmacy Practice; Mar 2009, Vol. 15 Issue 1, p 45-52

Chemical stability of a solution of bupivacaine hydrochloride 0.125% and sufentanil citrate 0.5 μg/mL

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Chemical stability of a solution of bupivacaine hydrochloride 0.125% and sufentanil citrate 0.5 μg/mL for filling syringes using a repeater pump

Karin Janssen, PharmD; René Wisselo, B App Sci; Charles Geerlings, PharmD; Jan Pieter Schouten, PharmD, MBM

ABSTRACT: Study objective: In Sint Franciscus Gasthuis, Rotterdam, The Netherlands, syringes filled with bupivacaine hydrochloride 0.125% and sufentanil citrate 0.5 μg/mL are administered epidurally during post-operative analgesia. These syringes are filled in the pharmacy using a Baxa Repeater pump. The suitability of the filling method and the shelf-life of the solution in the syringes were investigated.

Methods: During the filling process six samples were taken. Three syringes were stored at room temperature and three in the refrigerator. Samples were taken on days 4, 7, 14 and 28. High performance liquid chromatographic (HPLC) methods were used to measure the concentrations of both drugs in the samples.

Results: No loss of drugs was observed during the filling process. After 28 days at room temperature and in the refrigerator, the concentration of bupivacaine hydrochloride was 97.4 ± 0.9% and 97.9 ± 1.0% respectively, and that of sufentanil
citrate was 95.6 ± 4.2% and 99.2 ± 1.4%.

Conclusion: The filling method used with a Baxa Repeater pump is acceptable. Bupivacaine/sufentanil solution in syringes is chemically stable for at least 28 days in the refrigerator.

References: EJHP Science • Volume 15 • 2009 • Issue 1 • P. 11-14

Jarabe de Paracetamol

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Jarabe de Paracetamol

Fórmula:
Paracetamol ............................................................. 1 % p/v
Propilenglicol ......................................................... 25 % v/v
Agua purificada..........................................................35 % v/v
Esencia de fresa.................................................................c.s.
Colorante hidrosoluble........................................................c.s.
Conservante......................................................................c.s.
Jarabe simple c.s.p........................................................ 100 mL

Tecnica: En un vaso de precipitado, se disuelve el paracetamol en el agua. Se añade el propilenglicol y se homogeneiza. Esta mezcla se vierte en una probeta graduada y se completa hasta la cantidad a elaborar, con jarabe simple. Finalmente, se vierte el contenido de la probeta al vaso de precipitado, se añaden la esencia, el conservante y el colorante y se mezcla todo bien hasta obtener un sistema
homogéneo.

Envasado: El jarabe se envasa en un frasco de cristal topacio, de capacidad adecuada a la cantidad de fórmula a dispensar; acompañado de jeringa.

Usos y Aplicaciones: Se utiliza como analgésico y antipirético

Conservación y Estabilidad: Se conserva a temperatura ambiente y protegido de la luz.

Referência: UNIVERSIDAD DE SEVILLA, FACULTAD DE FARMACIA, DEPARTAMENTO DE FARMACIA Y
TECNOLOGÍA FARMACÉUTICA

Stability of high dose melphalan in saline solution.

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Stability of high dose melphalan in saline solution

M.T. Baylatry, D. Geay, C. Guntz, J.L. Prugnaud, A.C. Joly
Saint-Antoine Hospital, Pharmacy, Paris Cedex 12, France

Background: Melphalan is an effective anticancer drug used in high doses as preparative regimen for haematopoietic stem cell transplantation (off-label indication). In Saint-Antoine hospital, melphalan concentration for chemotherapy infusion bag, in this indication, is between 0.8 mg/mL and 1.6 mg/mL. In melphalan
summary of product characteristics, the recommended maximum concentration is 0.45 mg/mL and the stability at this concentration in infusion bag is reported to be 90 min at room temperature. A chemical stability assay of high dose melphalan has been developed firstly to validate the safety of this unlicensed preparation and then to make possible melphalan centralized preparation and storage.

Methods: A liquid chromatographic UV method was used. The evaluation of stability (International Conference on Harmonization guidelines) and the accelerated degradation (temperature) were performed. The stability was established as the 95% of initial concentration. Melphalan solution in saline (0.9% NaCl) infusion bags were assessed at room temperature (average: 28°C) for 0.3 mg/mL (n=3) and 1.6 mg/mL (n=3) concentrations and at + 4°C for 0.8 mg/mL (n=3) and 1.6 mg/mL (n=3). Samples were collected at different times from 0h to 24h. Visible particulate formation or colour change were also evaluated.

Results: Melphalan solutions were degraded at room temperature within 2 hours (76% and 78% of initial concentration respectively for 0.3 mg/mL and 1.6 mg/mL). At + 4°C, melphalan concentrations (0.8 mg/mL and 1.6 mg/mL) remained above 95% for 3 hours. No color change or visible particulate formation were observed.

Conclusions: High dose melphalan is not degraded rapidly in saline solution. This study allows to prepare high dose melphalan infusion bags without recurring to high volumes of saline solution which may expose patients to hydric overload. The 3 hour stability of melphalan at + 4°C is compatible with an anticancer drug centralized preparation in Pharmacy department in order to avoid an extemporaneous preparation by nurses in Haematology department and improve their safety.

References: 14th Congress of EAHP. Barcelona. 2009

Tamiflu (oseltamivir): preparation and stability of extemporaneous oral liquid formulations of oseltamivir using commercially available capsules.

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Preparation and stability of extemporaneous oral liquid formulations of oseltamivir using commercially available capsules.

Winiarski AP, Infeld MH, Tscherne R, Bachynsky M, Rucki R, Nagano-Mate K.

Professional Product Information, Roche Laboratories, Nutley, NJ 07110-1199, USA. aleksander.winiarski@roche.com

OBJECTIVES: To develop a simple, standardized method for the extemporaneous compounding of an oral liquid form of oseltamivir from commercially available Tamiflu 75 mg capsules (Roche Pharmaceuticals) and to determine the stability of oseltamivir in this preparation.

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INTERVENTION: Extemporaneous oral liquid formulations of oseltamivir (15 mg/mL) were prepared in Cherry Syrup (Humco) and Ora-Sweet SF (Paddock Laboratories) using methods consistent with current compounding practice in a pharmacy setting. Preparations were stored in amber glass and amber polyethyleneterephthalate bottles at 5 degrees C +/- 2 degrees C (41 degrees F +/- 4 degrees F) and 25 degrees C +/- 2 degrees C (77 degrees F +/- 4 degrees F) at 60% +/- 5% relative humidity (RH) for 35 days and 30 degrees C +/- 2 degrees C (86 degrees F +/- 4 degrees F) at 65% +/- 5% RH for 13 days.

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RESULTS: The Cherry Syrup preparation, in either bottle type, was stable for up to 35 days under refrigeration (5 degrees C) and up to 5 days at room temperature (25 degrees C). It was not stable when stored at 30 degrees C for 5 days. The Ora-Sweet SF preparation was stable for up to 35 days at 5 degrees C or 25 degrees C and for up to 13 days at 30 degrees C in either bottle type. Both preparations maintained microbiologic stability for 35 days.

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CONCLUSION: Both preparations are stable under the described conditions and may provide an option in situations where the marketed suspension is unavailable.

Reference: J Am Pharm Assoc (2003). 2007 Nov-Dec;47(6):747-55.

Formulation and stability evaluation of bromhexine hydrochloride for veterinary use

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Formulation and stability evaluation of 1% w/v oral solution of Bromhexine hydrochloride for veterinary use

Purpose: The aim of this study is to develop bromhexine hydrochloride 1 %w/v oral solution for veterinary use and to evaluate its stability.

Methods: Solutions of Bromhexine hydrochloride (1%w/v) were prepared by dissolving bromhexine hydrochloride in benzyl alcohol at 50 °C then alcohol 96 % v/v; Tween 80 and purified water were added. The obtained solution was filled in amber glass bottles, and the solution was stored at 25 °C/60 % relative humidity (RH) and at 40 °C /75% RH. The strengths of bromhexine hydrochloride were determined by High performance liquid chromatographic assay at 0, 2, 4, 6, 8, 10, 12, 16, 20 and 24 months. The concentrations of the drug were directly related to the peak area. pH, odor, color and crystal formation was also monitored.

Results: The degradation of bromhexine hydrochloride 1% w/v oral solution was faster at 40 °C/75% RH than at 25 °C /60% RH. No significant differences were found between the initial and final pH value for the solution at the studied conditions. No detectable changes in color, odor or precipitations were observed for the solutions stored at the upper conditions.

Conclusions: Bromhexine hydrochloride 1% w/v oral solution could be formulated and remains stable for at least 2 years when is stored at 25°C /60% RH and for 16 months when stored at 40 °C /75% RH.

Reference: The Islamic University Journal (Series of Natural Studies and Engineering), Vol.15, No. 1, pp 13 -22 , 2007

GEL DE CLORIDRATO DE DILTIAZEM

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ESTABILIDADE QUÍMICA, FÍSICA E MICROBIOLÓGICA DE UM GEL DE CLORIDRATO DE DILTIAZEM

Ana C. Salgado, Marina Lobo Alves, Fátima Falcão, João F. Pinto.

Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade de Lisboa; Serviços Farmacêuticos Hospital São Francisco Xavier

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Resumo: A fissura anal é um problema comum que afecta ambos os sexos. A hipertonia do esfíncter anal é o principal factor fisiopatológico que condiciona a cicatrização. É mais frequente em doentes com obstipação crónica. É caracterizada por dor e hematoquezias. O índice de cicatrização não ultrapassa os 65 a 70%, independentemente da utilização dos tratamentos médicos disponíveis, obrigando frequentemente ao recurso a procedimento cirúrgico. A utilização do cloridrato de diltiazem por via tópica constitui uma nova abordagem terapêutica das fissuras anais. O objectivo deste trabalho é o desenvolvimento de um gel de cloridrato de diltiazem a 2% e o estudo da sua estabilidade química, física e microbiológica. O protocolo de estabilidade adoptado obedeceu, nos aspectos relevantes, às normas em vigor para estudos de estabilidade de especialidades farmacêuticas.Para o efeito, foram produzidos três lotes de gel de composição idêntica que foram armazenados durante 93 dias, em frascos de vidro incolor, a 22±3ºC e protegidos da luz. A intervalos de tempo apropriados foram colhidas amostras e analisados os seguintes parâmetros: aspecto, viscosidade, doseamento do cloridrato de diltiazem (HPLC) com pesquisa de produtos de degradação e controlo microbiológico (realizado segundo a FP VII para preparações líquidas para uso oral). O método de doseamento da substância activa foi devidamente validado quanto à sensibilidade, linearidade, exactidão e precisão. A estabilidade do gel foi definida como a retenção de um teor em cloridrato de diltiazem ³95% sem alterações significativas nos restantes parâmetros analisados. Os resultados indicam que o gel de cloridrato de diltiazem a 2% armazenado à temperatura ambiente (22±3ºC) é estável química, física e microbiologicamente durante todo o tempo do estudo (93 dias).

Referência: 5º Congresso Nacional da APFH. Lisboa. 2007