WO1989010122A1 - Procedes et compositions de traitement de troubles hyperproliferatifs cutanes - Google Patents

Procedes et compositions de traitement de troubles hyperproliferatifs cutanes Download PDF

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Publication number
WO1989010122A1
WO1989010122A1 PCT/US1989/001767 US8901767W WO8910122A1 WO 1989010122 A1 WO1989010122 A1 WO 1989010122A1 US 8901767 W US8901767 W US 8901767W WO 8910122 A1 WO8910122 A1 WO 8910122A1
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WO
WIPO (PCT)
Prior art keywords
inhibitor
dna synthesis
inhibitors
novo
methotrexate
Prior art date
Application number
PCT/US1989/001767
Other languages
English (en)
Inventor
Leonard M. Milstone
Pauline M. Schwartz
Original Assignee
Yale University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yale University filed Critical Yale University
Publication of WO1989010122A1 publication Critical patent/WO1989010122A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to compositions and methods for the treatment of cutaneous diseases such as psoriasis and actinic eratosis in which there is abnormal proliferation or growth of cells of the skin, particularly keratinocytes, and hyperplastic and neoplastic conditions of other epithelial organ systems which are accessible to direct application of a pharmaceutical agent.
  • cutaneous diseases such as psoriasis and actinic eratosis in which there is abnormal proliferation or growth of cells of the skin, particularly keratinocytes, and hyperplastic and neoplastic conditions of other epithelial organ systems which are accessible to direct application of a pharmaceutical agent.
  • Normal skin epidermis is a complex epithelial tissue containing keratinocytes that are proliferating, differentiating and desquamating, and is stratified such that morphological and functional changes in the keratinocytes occur in an orderly progression. More specifically, the basal layer of the epidermis contains proliferating keratinocytes which synthesize DNA, while the superbasal layers of the epidermis contain highly differentiated keratinocytes which degrade DNA. Thus, the normal epidermis is maintained in a dynamic steady state as proliferation of keratinocytes continually compensates for the loss of cells which are shed from the surface of the skin.
  • psoriasis squamous cell carcinoma, keratoacanthoma, actinic keratosis and warts
  • psoriasis which is characterized by scaly, red, elevated plaques on the skin
  • the keratinocytes are known to proliferate much more rapidly than normal and to differentiate less completely.
  • Topical 5-fluorouracil may be an effective treatment for psoriasis, but is usually considered to be unacceptably irritating. Goette, J. Am Acad Dermatol 4.:633-649 (1981).
  • che otherapeutic agents which have been used to treat the hyperproliferative diseases of the epidermis have been inhibitors that block de. novo synthesis of nucleotide precursors of DNA.
  • These chemotherapeutic agents have sought to block the de novo synthesis of thymidine monophosphate, which, in the cell, is converted in several steps to thymidine triphosphate, one of the four deoxynucleoside phosphates needed by the cell to synthesize DNA.
  • Another means by which the cell obtains thymidine for DNA synthesis is by the so-called "salvage" mechanism, whereby thymidine is transported into the cell by cell transport mechanisms, e.g., facilitated diffusion.
  • methods for the treatment of hyperproliferative diseases of the skin and other epithelial tissue which comprise the concurrent adminstration to a patient of at least one inhibitor of the de novo pathway in DNA synthesis and at least one inhibitor of the salvage pathway in DNA synthesis.
  • at least one type of these inhibitors is administered topically at the site of the hyperproliferative disease.
  • Fig. 1 depicts the effect of dipyrida ole (DP) and 5- fluorouracil (5-FU) on the growth of human keratinocytes.
  • Fig. 2 depicts the effect of dypyridamole (DP) and methotrexate (MTX) on the growth of human keratinocytes.
  • the present invention relates to novel methods of use of pharmaceutical compositions for the treatment of psoriasis and other hyperproliferative and neoplastic diseases of the skin and other topically accessible lining epithelia. More specifically, the methods of use of the invention comprise the combined use of inhibitors of de. novo and "transport” or “salvage” pathways in DNA synthesis for the treatment of a variety of hyperproliferative disorders of the skin, such as psoriasis, actinic keratosis, squamous cell carcinoma, keratocanthoma, etc.
  • the "transport" inhibitors have a synergistic effect on the antiproliferative action of de novo inhibitors when used together to inhibit DNA synthesis in cells of the skin. Both types of these inhibitors of DNA synthesis need to be available to the proliferating cell to exhibit this synergistic effect.
  • the methods according to the invention should be particularly effective when the affected areas are directly contacted with at least one inhibitor.
  • at least one type of these inhibitors is applied topically at the site of the hyperproliferative cell growth so as to increase local efficacy without increasing toxicity in the subject, while the other type of inhibitor may be administered syste ically, e.g., orally.
  • both of these types of inhibitors of DNA synthesis are applied topically to the site of the proliferative disease.
  • the invention also contemplates the systemic, e.g., oral, administration of both of these types of inhibitors.
  • the method according to the invention is directed to the use of at least one "transport” inhibitor together with at least one "de novo” inhibitor to block DNA synthesis in cells of the skin and other lining epithelia in which abnormally high DNA synthesis, and consequently abnormal cell production, is occurring.
  • the cell is prevented from compensating for the disruption of de. novo DNA synthesis caused by the concurrently administered de novo inhibitor by transporting the nucleoside, e.g., thymidine, into the cell by means of the "salvage" pathway.
  • the cell In attacking the hyperproliferative cell growth through both the "de novo" and “salvage” mechanisms, the cell is hindered or precluded from producing dTTP, and consequently, DNA. Since no mechanism other than the salvage mechanism is known to exist in the cell whereby the cell can compensate for the loss of de. novo nucleoside producing ability, the invention contemplates the simultaneous blocking or hindering of all pathways which permit DNA synthesis in such hyperproliferative cells.
  • De novo inhibitors are those compositions which inhibit DNA synthesis by preventing the synthesis of nucleotides in the cell from a ino acids, ATP and CO-.
  • these compositions can generally be classified into three groups: antifolates such as methotrexate and trimetrexate; antimetabolites, such as 5-fluorouracil, 5-fluorouridine, 5-fluorodeoxyuridine, phosphon-L-aspartate (PALA) and acivicin; and inhibitors of nucleic acid synthesis which act by other mechanisms, such as adriamycin.
  • the "transport” inhibitors generally act to block nucleosides, including thymidine, from entering or leaving the cell, thereby preventing the cell from utilizing outside sources of nucleosides to synthesize DNA. These inhibitors of nucleoside transport thus block the "salvage" of extracellular pyrimidine nucleosides and potentiate the inhibitory action of de. novo inhibitors of DNA synthesis. By inhibiting the uptake of nucleosides, i.e., thymidine, the nucleoside cannot be converted to dTTP.
  • the nucleoside "transport” inhibitors include compounds such as dipyridamole, dilazep and nitrobenzylthioinosine.
  • a preferred embodiment of the present invention comprises the use of methotrexate as the de novo inhibitor and dipyridamole as the "transport” inhibitor. This combination has been found to be particularly effective in inhibiting DNA synthesis in skin cells.
  • methotrexate be administered orally in an amount less than about 5-50 mg/week, together with the topical administration of dipyridamole in a concentration of about .5-5 wt.%.
  • Oral methotrexate treatment for the treatment of psoriasis is already known, and toxicity can be controlled by those skilled in the art.
  • 5-fluorouracil as the de .
  • novo inhibitor may be efficaciously combined with dipyridamole.
  • An exemplary mode of administration would be to administer both inhibitors topically, e.g., 1-5 wt.% 5-fluorouracil and 0.5-5 wt.% dyridamole.
  • each type of inhibitor may be used in the methods according to the invention.
  • more than one of the "transport” or de . novo inhibitors may be utilized in the treatment of a patient, provided toxic levels are taken into consideration by the physician supervising the regimen.
  • Toxic thresholds vary widely, even between members of each group of inhibitors, and may be easily assessed by those skilled in the art. Since there is minimal concern over toxicity to a subject when one of the inhibitors r either de novo or "transport", is applied topically to an isolated skin site in need of treatment, a wide range of amounts of such inhibitors may be utilized in the invention.
  • pharmaceutical compositions of "de novo" and "transport” inhibitors in the range of about 0.1-5 wt.% should generally be effective and non-toxic when coupled with topical or systemic administration of the other inhibitor.
  • amounts of an inhibitor equal to or less than the known toxic value for that compound should be utilized when administered together with the topical use of the other inhibitor(s) .
  • the concentration ranges set forth herein are provided by way of description and not by way of limitation since it is recognized that the concentration may be adjusted over a wide range depending on a number of factors.
  • the efficacious amount and concentration of the inhibitors are those which result in the composition exhibiting the property or properties required in the treatment for which the composition is being used, e.g., psoriasis or actinic keratosis.
  • the preferred amounts depend upon the particular condition being treated, the severity of the condition, the method of delivery to the treatment site, e.g., topical or systemic, the rate of delivery of the active ingredients to the treatment site, the number of applications of the formulation which can be used, the other inhibitor used, the carrier material, etc. Preferred amounts for any specific application may be determined by normal pharmacological screening methods used in the art.
  • Psoriasis .1 to 5 5 to 50 Apply at least one wt.% mg/wk inhibitor topically inhibitor inhibitor at the desired (e.g. , (e.g. , metho ⁇ site, while at dypyamole) trexate) approximately the same time administer the other inhibitor orally, actinic 0.1 to 5 5 to 50 three times a keratosis wt.% mg. t.i.d. day.
  • Repeat inhibitor inhibitor application of e.g., 5- (e.g., dipy ⁇ topically fluorouracil) ridamole) administered inhibitor as needed, avoiding toxic blood levels.
  • Healing period may extend for several weeks.
  • the topically administered inhibitor(s) is usually formulated with a pharmaceutically-acceptable carrier.
  • Carrier materials are well known in the pharmaceutical formulation art and include those materials referred to as diluents or vehicles.
  • the carriers may include inorganic or organic materials and should have sufficient viscosity to allow spreading of the composition and provide good adherence to the skin. Examples of such carriers include polyols such as glycerol, propylene glycol, polyethylene glycol, and other materials well known to those skilled in this art.
  • the topical formulation can contain pharmacologically-acceptable additives or adjuvants such as antimicrobial agents, e.g., methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid as well as benzyl alcohol, chlorobutanol, phenol, ascorbic acid, etc.
  • the formulation can also contain thickening agents, coloring agents, buffers, stabilizers and preservatives including antioxidants such as butyl hydroxyanisole in accordance with the practice of the art.
  • the formulation can also contain penetration enhancers such as dimethyl sulfoxide, long-chain alcohols such as monoxynol, long- chain carboxylic acids, propylene glycol, N-(2- hydroxyethyl)pyrrolidone, l-dodecyl-azacycloheptan-2- one, and the like.
  • penetration enhancers such as dimethyl sulfoxide, long-chain alcohols such as monoxynol, long- chain carboxylic acids, propylene glycol, N-(2- hydroxyethyl)pyrrolidone, l-dodecyl-azacycloheptan-2- one, and the like.
  • absorption-delaying agents such as aluminum monostearate and gelatin.
  • compositions of the invention can be adjusted using components well-known in the formulation art to provide a pharmaceutical formulation which is a gel, cream, ointment, solid, liquid, semi-solid, etc.
  • a pharmaceutical formulation which is a gel, cream, ointment, solid, liquid, semi-solid, etc.
  • the particular physical form of the formulation depends on the desired method of treatment and the patient to be treated.
  • Typical pharmaceutical formulations according to the invention are set forth in Table II.
  • concentration of active ingredients in a particular formulation required to provide a particular effective dose may be determined by a person skilled in the pharmaceutical formulation art based upon the properties of the carrier and the particular additives introduced into the formulation. It is contemplated that formulations can be prepared that have significantly higher concentrations of one or more of the inhibitors depending upon the carrier and additives being used, as well as the amount of inhibitor being given orally, if any.
  • the concentrations of the inhibitor in the formulation can be substantially increased in order to provide an effective treatment.
  • a formulation contain the lowest concentrations of inhibitor which effectively acts together with the other inhibitor to treat the condition with the desired number of applications, i.e., a lower effective dose rate can be tolerated if multiple applications are used. This low concentration limit is dependent upon the delivery effectiveness of the carrier vehicle.
  • the inhibitor is normally mixed with a suitable solvent.
  • solvents which are effective for this purpose include ethanol, acetone, acetic acid, acidic solutions, dimethyl sulfoxide, glycerine, glycerol, propylene glycol, monoxynol, ethyl ether, polyethylene glycol, etc.
  • DMEM Dulbecco's Modified Eagle's Medium
  • Complete medium consisted of Dulbecco's Modified Eagle's Medium supplemented with 20% Fetal bovine serum, hydrocortisone (0.4 ug/ml), epidermal growth factor (10 ng/ml), cholera toxin (lOOpM), penicillin (100 u/ml) and streptomycin (100 ug/ml).
  • the Ca concentration was 1.8mM.
  • 3T3 cells (ATCC CCL #92) were grown in DMEM with 10% calf serum. Confluent cultures were x-irradiated (1000 rads) and subcultured with trypsin.
  • Complete MCDB-153 was basal MCDB 153 medium supplemented with epidermal growth factor (5ng/ml), insulin (5ug/ml), hydrocortisone (0.4ug/ml), ethanolamine (O.lmM), phosphoethanolamine (O.lmM), transferrin (lOug/ml), bovine pituitary extract (50ug protein/ml) and additional amino acids (glutamme (1.2x10 -2M) , histidine
  • Basal MCDB-153 contained 3uM thymidine.
  • MCDB-153 without thymidine was formulated by Clonetics, Inc. (Boulder r CO) .
  • a suspension of keratinocytes produced by the method described in Example I was shaken in a water bath at 37 * C in medium with or without inhibitors. Ten minutes
  • dipyridamole inhibited the transport of H-thymidine into keratinocytes by over 50% over a ten minute period.
  • a cell culture was prepared as in Example 1.
  • Example 1 Cell cultures were prepared as in Example 1. A composition of 0.5 micromolar 5-fluorouracil and 1 micromolar dipyridamole was applied to the cell culture. As determined by counting the cells r cell growth was inhibited by 86% over a seven day period. These results are illustrated in Fig. 1.
  • composition of 0.1 micromolar methotrexate and 1 micromolar dipyridamole when applied to a separate cell culture prepared in accordance with
  • Example 1 demonstrated a 93% inhibition of growth of keratinocytes over a seven day period, as determined by counting the cells. These results are illustrated in Fig. 2.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouvelles compositions et leurs procédés d'utilisation pour le traitement de maladies hyperprolifératives de la peau et d'autres tissus épithéliaux de revêtement. On administre à un patient nécessitant un tel traitement au moins un inhibiteur de la voie de novo de synthèse de l'ADN et au moins un inhibiteur de la voie de récupération de nucléosides pour la synthèse de l'ADN. Dans un mode préférentiel de réalisation, au moins un type de ces inhibiteurs est appliqué topiquement sur le site de la maladie hyperproliférative. Méthotrexate, 5-fluorouracile et dipyridamole sont des inhibiteurs préférés.
PCT/US1989/001767 1988-04-27 1989-04-26 Procedes et compositions de traitement de troubles hyperproliferatifs cutanes WO1989010122A1 (fr)

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US18748988A 1988-04-27 1988-04-27
US187,489 1988-04-27

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0672417A1 (fr) * 1994-03-17 1995-09-20 Rohto Pharmaceutical Co., Ltd. Réduction de la pression intra-oculaire
WO2003015759A2 (fr) * 2001-08-14 2003-02-27 Valderm Aps Traitement d'etats hyperproliferatifs des surfaces corporelles
US7915265B2 (en) 2001-10-05 2011-03-29 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3896238A (en) * 1972-04-05 1975-07-22 Procter & Gamble Dermatological compositions
US4751224A (en) * 1983-07-21 1988-06-14 Brown University Research Foundation Treatment of metastasis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3896238A (en) * 1972-04-05 1975-07-22 Procter & Gamble Dermatological compositions
US4751224A (en) * 1983-07-21 1988-06-14 Brown University Research Foundation Treatment of metastasis

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0672417A1 (fr) * 1994-03-17 1995-09-20 Rohto Pharmaceutical Co., Ltd. Réduction de la pression intra-oculaire
WO2003015759A2 (fr) * 2001-08-14 2003-02-27 Valderm Aps Traitement d'etats hyperproliferatifs des surfaces corporelles
WO2003015759A3 (fr) * 2001-08-14 2004-03-04 Valderm Aps Traitement d'etats hyperproliferatifs des surfaces corporelles
US8263567B2 (en) 2001-08-14 2012-09-11 Valderm Aps Treatment of hyperproliferative conditions of body surfaces
US7915265B2 (en) 2001-10-05 2011-03-29 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders

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AU3554089A (en) 1989-11-24

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