PT1864660E - Composições médicas para o tratamento intravesical do cancro da bexiga - Google Patents

Composições médicas para o tratamento intravesical do cancro da bexiga Download PDF

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PT1864660E
PT1864660E PT06077149T PT06077149T PT1864660E PT 1864660 E PT1864660 E PT 1864660E PT 06077149 T PT06077149 T PT 06077149T PT 06077149 T PT06077149 T PT 06077149T PT 1864660 E PT1864660 E PT 1864660E
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cancer
bladder cancer
formulation
bladder
intravesical
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PT06077149T
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Bastiaan Nuijen
Ernie Pfadenhauer
Jos F Beijen
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Spectrum Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Description

ΕΡ 1 864 660/ΡΤ DESCRIÇÃO "Composições médicas para o tratamento intravesical do cancro da bexiga"
ANTECEDENTES DO INVENTO 0 cancro da bexiga representa aproximadamente 2% de todos os cancros malignos e é o quinto e o décimo cancro mais comum nos homens e nas mulheres, respectivamente. A Sociedade Americana de Cancro estimou que, em 1997, teriam ocorrido 54 500 novos casos e 11 700 mortes. Os cancros da bexiga superficiais (pTa, pTl e CIS) representam 70-80% dos cancros na apresentação inicial. O controlo do cancro da bexiga superficial poderá ser obtido por ressecção cirúrgica endoscópica, frequentemente seguida por um ciclo de imunoterapia ou de quimioterapia intravesical adjuvante com o objectivo de erradicar as células tumorais remanescentes e evitar a recorrência do tumor (Herr HW (1987) Intravesical therapy-a criticai review. Urol Clin N Am 14:399-404). Tanto os antineoplásicos (mitomicina C [MMC], epirrubicina e tioTEPA) como a imunoterapia (BCG) administrados por via intravesical são eficazes na redução das taxas de recorrência tumoral, embora não seja claro se a progressão da doença para tumores invasivos musculares é evitada (Newling D (1990) Intravesical therapy in the management of superficial transitional cell carcinoma of the bladder: the experience of the EORTC GU group, Br J Câncer 61:497-499; Oosterlink et al. (1993) A prospective European Organization for Research and Treatment of Câncer Genitourinary Group randomized trial comparing transurethral resection followed by a single instillation of epirubicin or water in single stage Ta, Tl papillary carcinoma of the bladder. J Urol 149:749-752). Esta observação, juntamente com o facto da mortalidade devido ao cancro da bexiga ainda ser elevada, sublinha a necessidade de desenvolver agentes terapêuticos mais eficazes (Oosterlink et al., 1993).
Um destes agentes terapêuticos é a MMC, que pertence a uma classe de compostos conhecida por fármacos biorredutores (Workman, 1994). A MMC representa um dos agentes 2 ΕΡ 1 864 660/ΡΤ antineoplásicos utilizados para tratar os cancros da bexiga superficiais (Maffezzini et al., 1996; Tolley et al.r 1996). A MMC é activada numa espécie citotóxica por redutases celulares, embora o papel das enzimas redutases especificas que estão envolvidas na activação biorredutora permaneça mal definido e controverso (Cummings et al., 1998a). Isto é particularmente verdadeiro para a enzima NQ01 (NAD(P)H:quinona oxidorredutase, EC 1.6.99.2), a qual é uma flavoproteina citosólica que catalisa a redução com dois electrões de vários compostos baseados em quinonas, utilizando quer NADH quer NADPH como dadores de electrões (Schlager & Powis, 1988; Siegel et al., 1990). O composto estruturalmente relacionado E09 [5-(1-aziridinil)-3-(hidroximetil)-2-[(E)-3-hidroxiprop-l-enil]-l-metil-lH-indolo-4,7-diona] é, no entanto, um substrato muito melhor que a MMC para NQOl (Walton et al., 1991), e há uma boa correlação entre a actividade de NQOl e a quimiossensibilidade in vitro sob condições aeróbias (Robertson et al., 1994; Fitzsimmons et al., 1996; Smitkamp-Wilms et al., 1994). Sob condições hipóxicas, contudo, as propriedades de E09 são marcadamente diferentes, havendo pouca ou nenhuma potenciação da toxicidade de E09 observada nas células ricas em NQOl (Plumb & Workman, 1994) . Porém, em linhas celulares deficientes em NQOl, têm sido referidas razões elevadas de citotoxicidade hipóxica (Workman, 1994) . Por conseguinte, E09 dispõe do potencial para explorar a fracção aeróbia dos tumores ricos em NQOl ou a fracção hipóxica dos tumores deficientes em NQOl (Workman, 1994). O composto E09 tem sido clinicamente avaliado. Contudo, apesar da comunicação de três remissões parciais em ensaios clínicos de fase I, não se observou qualquer actividade contra o NSCLC (cancro do pulmão de células não pequenas), o cancro gástrico, o cancro da mama, o cancro pancreático e o cancro do cólon em ensaios subsequentes de fase II (Schellens et al., 1994; Dirix et al., 1996). Estas constatações são particularmente decepcionantes em face não só dos estudos pré-clínicos (Hendriks et al., 1993), como também das referências de que vários tipos de tumores possuem níveis elevados de NQOl (Malkinson et al., 1992; Smitkamp-Wilms et al., 1995; Siegel et al., 1998). Foram propostas várias explicações possíveis para a ausência de eficácia clínica de E09 (Connors, 1996; Phillips et al., 1998). Estudos recentes demonstraram que o 3 ΕΡ 1 864 660/ΡΤ fracasso de Ε09 no aspecto clínico poderá não se dever a interacções farmacodinâmicas fracas, mas sim ser o resultado de uma fraca entrega do fármaco nos tumores (Phillips et al., 1998). A rápida eliminação plasmática de E09 (11/2 = 10 min nos seres humanos), em conjugação com uma fraca penetração através das camadas multicelulares, sugere que o composto E09 não penetrará mais de alguns mícrones a partir de um vaso sanguíneo durante o seu período de vida farmacocinético (Schellens et al., 1994; Phillips et al., 1998). A administração intratumoral de E09 a tumores ricos e a tumores deficientes em NQOl produziu atrasos de crescimento significativos (embora não tenha sido feita uma distinção entre os danos na fracção aeróbia ou na fracção hipóxica), sugerindo que se o composto E09 puder ser entregue nos tumores, será possível obter efeitos terapêuticos (Cummings et al., 1998b). Embora estas características indesejáveis sejam uma contrariedade importante para o tratamento da doença sistémica, paradoxalmente elas poderão ser vantajosas para o tratamento dos cancros que ocorrem num terceiro compartimento, como seja o cancro da bexiga superficial. Neste cenário, a entrega do fármaco não é problemática por meio da via intravesical, e a penetração de E09 no tecido avascular pode ser aumentada através da manutenção de concentrações terapeuticamente relevantes do fármaco no interior da bexiga (utilizando, por exemplo, um período de instilação de uma hora). Embora este método de instilar o composto E09 no interior da bexiga possa ser útil, continua a existir a necessidade de dispor de veículos de entrega de fármacos que sejam capazes de entregar uma quantidade eficaz de E09 no interior da bexiga. J D de Vries et al. (Int J Pharmaceutics, 100 (1993) 181— 188) investigaram a estabilidade química de E09, utilizando um ensaio de HPLC de fase inversa indicador da estabilidade, com detecções no UV e espectrofotometria no UV. A cinética de degradação de E09 foi estudada em função do pH, da composição do tampão, da força iónica e da temperatura. J D Jonkman-de Vries et al. (Câncer Chemother Pharmacol (1994) 34:416-422) referiram um estudo efectuado para criar uma forma farmacêutica parentérica estável de E09. O estudo investigou a liofilização de soluções aquosas de E09. 4 ΕΡ 1 864 660/ΡΤ
Choudry et al. (Br J Câncer (2001) 85(8), 1137-1146) divulgam composições para tratar o cancro da bexiga, em que estas composições incluem E09. Este documento estuda a relação entre a actividade de NQOl no tecido tumoral e a selectividade de E09. Adicionalmente, Choudry et ai. ensinam que a entrega de E09 num veiculo ácido resulta em maior actividade no interior da bexiga, com qualquer fármaco absorvido na corrente sanguinea tornando-se relativamente inactivo devido à subida do pH. Contudo, este documento não discute métodos para a estabilização de uma composição de E09 reconstituída.
BREVE SUMÁRIO DO INVENTO
De acordo com o presente invento, é proporcionada uma formulação anticancerosa tal como definida na reivindicação 1, compreendendo E09 e propilenoglicol.
De acordo com o presente invento, a composição do presente invento compreende E09 e um agente de revestimento que é propilenoglicol. O agente de revestimento permite uma melhor adesão da composição à parede da bexiga. Consequentemente, a composição e, em particular, ο E09, contactam e podem ser capazes de penetrar no tecido avascular que a constitui durante um periodo de tempo suficiente para tratar o cancro da bexiga.
DESCRIÇÃO DETALHADA DO INVENTO
As concretizações do presente invento referem-se a composições destinadas ao tratamento do cancro da bexiga por via de instilação intravesical. É aqui divulgada uma composição compreende 5-(1-aziridinil)-3-(hidroximetil)-2-[(E)-3-hidroxiprop-l-enil]-l-metil-lH-indolo-4, 7-diona (E09) e um veiculo de formulação. Os veículos de formulação são solventes que melhoram a solubilidade e a estabilidade de E09.
De acordo com uma concretização exemplificativa, a formulação anticancerosa pode ser preparada utilizando um veículo de reconstituição que compreende 2% de bicarbonato de sódio, 0,02% de edetato dissódico e propilenoglicol: água (60:40 V/V). Este veículo de reconstituição dissolve a composição liofilizada e produz uma solução estável para 5 ΕΡ 1 864 660/ΡΤ administração durante até 24 horas. Adicionalmente, o veículo de reconstituição proporciona uma ampola possuindo um volume extractável de 5 mL de E09 reconstituído compreendendo propilenoglicol/água/bicarbonato de sódio/edetato de sódio 60/40/2/0,02% v/v/p/p.
Choudry GA, Hamilton Stewart PA, Double JA, Krul mrl, Naylor B, Flannigan GM, Shah TK, Brun JE e Phillips RM (2001); A novel strategy for NQOl (NAD(P)H: quinine oxidoreductase, EC 1.6.99.2) mediated therapy of bladder câncer based on the pharmacological properties of E09. Br J Câncer 85(8) 1137-1146 .
Connors TA (1996) Bioreductive agents, hypoxic cells and therapy. Eur J Câncer 32A: 1833-1834.
Cummings J, Spanswick VJ, Tomaz M e Smyth JF (1998a) Enzymology of MMC metabolic activation in tumor tissue. Implications for enzyme directed bioreductive drug development. Biochem Pharmacol 56: 405-414.
Cummings J, Spanswick VJ, Gardiner J, Ritchie A e Smyth, IF (1998b) Pharmacological and biochemical determinants of the antitumour activity of the indoloquinone E09. Biochem Pharmacol 55: 253-260.
Dirix LY, Tonnesen F, Cassidy J, Epelbaum R, Huinink WWT, Pavlidis N, Sorio R, Gamucci T, Wolff I, Tevelde A, Lan j, e Verweij J (1996) E09 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the early clinicai studies group. Eur J Câncer 32A: 2019-2022.
Fitzsimmons S A, Workman P, Grever M, Paull K, Camalier R e Lewis AD (1996) Reductase enzyme expression across the National Câncer Institute tumor cell line panei: Correlation with sensitivity to MMC and E09. J Natl Câncer Inst 88: 259-269
Gutierrez PL (1989) Mechanism of bioreductive alkylation. The example of diazaquinone (AZQ. Free Radical Bio Med 6: 405-445.
Hendriks HR, Piazo PE, Berger DP, Kooistra KL, Bibby MC, Boven E, Dreef-Van Der Meulen HC, Henrar-REC, Fiebig HH, Double JA, Homstra HW, Pinedo HM, Workman P e Swartsmann G 6 ΕΡ 1 864 660/ΡΤ (1993) Ε09: A novel bioreductive alkylating indoloquinone with preferential solid tumor activity and lack of bone marrow toxicity in preclinical models. Eur J Câncer 29A: 897-906.
Herr HW (1987) Intravesical therapy - a criticai review. Urology Clinics of N America 14: 399-404.
Maffezzini M, Simonata A, Zanon M, Raber M e Carmig ani G (1996) Up-front chemotherapy for low stage low grade recurrent bladder câncer. J Urol 155; 91-93 .
Malkinson AM, Siegel D, Forrest GL, Gazdar AF, Oie HK, Chan DC, Bunn PA, Mabry M, Dykes DJ, Harrison SD e Ross D (1992) Elevated NQOl activity and messenger RNA content in human non small cell lung carcinoma - Relationship to the response of lung tumor xenografts to mmc. Câncer Res 52: 4752-4757 .
Newling D (1990) Intravesical therapy in the management of superficial transitional cell carcinoma of the bladder: the experience of the EORTC GU group. Br J Câncer 61: 497-499.
Oosterlink W, Kurth KH, Schrõder F, Bultinck J, Hammond B, Sylvester R, e membros da European Organisation for Research and Treatment of Câncer Genitourinary
Phillips RM, Loadman PM e Cronin BP (1998) Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumors. Br J Câncer 77: 2112-2119.
Plumb JA e Workman P (1994) Unusually marked hypoxic sensitisation to indoloquinone E09 and MMC in a human colon tumor cell line that lacks NQOI activity. Int J Câncer 56: 134-139.
Robertson N, Haigh A, Adams GE e Stratford U (1994) Factors affecting sensitivity to E09 in rodent and human tumor cells in vitro: NQOl activity and hypoxia. Eur J Câncer 30A: 1013-1019.
Schellens JHM, Planting AST, Van Acker BAC, Loos WJ, De Boer-Dennert M, Van Der Burg MEL, Koier I, Krediet RT, Stoter G e Verweij J (1994) Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09. J Natl Câncer Inst 86: 906-912. 7 ΕΡ 1 864 660/ΡΤ
Schlager JJ e Powis G (1988) MMC is not metabolised by but is an inhibitor of human kidney NAD(P)H:(quinone acceptor) oxidoreductase. Câncer Chemother Pharmacol 22: 126-130.
Siegel D, Beall HD, Kasai M, Gibson NW e Ross D (1993) PH dependent inactivation of NQOl by MMC and porfiromycin. Mol Pharmacol 44: 1128-1134 . Siegel D, Franklin WA and Ross D (1998) Immunohistochemical detection of NAD(P)H:Quinone oxidoreductase in human lung and lung tumors. Clin Câncer Res 4: 2065-2070.
Smitkamp-Wilms E, Peters GJ, Pinedo HM, Van Arkotte J e Giaccone G (1994) Chemosensitivity to the indoloquinone E09 is correlated with NQOl activity and gene expression. Biochem Pharmacol 47: 1325-1332.
Smitskamp-Wilms E, Giaccone G, Pinedo HM, Van Der Laan BFAM e Peters GJ (1995) NQOl activity in normal and neoplastic human tissues: An indicator of sensitivity to bioreductive agents?. Br J Câncer 72: 917-921.
Tolley da, Parmar mkb, Grigor KM, Lallemand G e o Medicai Research Council superficial bladder câncer working party (1996) The effect of intravesical MMC on recurrence of newly diagnosed superficial bladder câncer: A further report with 7 years of followup. J Urol 155: 1233-1238.
Walton MI, Smith PJ e Workman P (1991) The role of NAD(P)H:quinone reductase (EC 1.6.99.2, NQOl) in the reductive bioactivation of the novel indoloquinone antitumour agent E09. Câncer Commun 3: 199-206.
Workman P (1994) Enzyme directed bioreductive drug development revisited: A commentary on recent progress and future prospects with emphasis on quinone anticancer drugs and quinone metabolising enzymes, particularly NQOl. Oncol Res 6: 461-475.
Lisboa, 2011-03-24

Claims (2)

  1. EP 1 864 660/PT 1/1 REIVINDICAÇÕES 1. Formulação anticancerosa compreendendo: a) (5-(1-azaridinil)-3-(hidroximetil)-2-[(E)-3-hidroxiprop-l-enil]-l-metil-lH-indolo-4,7-diona (E09); e b) propilenoglicol.
  2. 2. Formulação anticancerosa de acordo com a reivindicação 1 compreendendo uma dose unitária de 8 mg de E09. Lisboa, 2011-03-24
PT06077149T 2001-11-01 2002-11-01 Composições médicas para o tratamento intravesical do cancro da bexiga PT1864660E (pt)

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CA2466148A1 (en) 2003-05-08
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