EP0522006A1 - Cytotoxisches mittel und hautpermeabilitäterhöher enthaltende zusammensetzung - Google Patents

Cytotoxisches mittel und hautpermeabilitäterhöher enthaltende zusammensetzung

Info

Publication number
EP0522006A1
EP0522006A1 EP91907120A EP91907120A EP0522006A1 EP 0522006 A1 EP0522006 A1 EP 0522006A1 EP 91907120 A EP91907120 A EP 91907120A EP 91907120 A EP91907120 A EP 91907120A EP 0522006 A1 EP0522006 A1 EP 0522006A1
Authority
EP
European Patent Office
Prior art keywords
weight
permeation
present
fluorouracil
composition according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP91907120A
Other languages
English (en)
French (fr)
Inventor
Michel J. N. Cormier
Lina T. Taskovich
Su Il Yum
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alza Corp
Original Assignee
Alza Corp
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 Alza Corp filed Critical Alza Corp
Publication of EP0522006A1 publication Critical patent/EP0522006A1/de
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • This invention relates to the delivery of cytotoxic agents. More particularly, this invention relates to novel compositions for enhancing the percutaneous absorption of cytotoxic agents. Still more particularly, but without limitation thereto, this invention relates to the delivery of a cytotoxic agent such as 5-fluorouracil to the skin utilizing a permeation-enhancing mixture of a lower alkanol, propylene glycol or a mixture of polyethylene glycols, and a third permeation enhancer.
  • a cytotoxic agent such as 5-fluorouracil
  • cytotoxic agents such as fluorouracil
  • Penetrating solvents have been investigated for enhancing percutaneous absorption of certain cytotoxic agents in an effort to more successfully treat more resistive conditions. Severe skin inflammation from damage to treated tissue by the cytotoxic agent typically occurs with this treatment, severely limiting its usefulness.
  • a method based on the timing of administration of a cytotoxic agent in a penetrating solvent, preferably without occlusion, is disclosed in U.S. Pat. Nos. 4,820,711, 4,849,426 and 4,853,388 for the treatment of actinic keratosis or psoriasis with less damage to treated tissue.
  • Fluorouracil (5-fluorouracil or 5-FU) is a fluorinated pyri idine antineoplastic agent that acts as an antimetabolite to uracil. It interferes with DNA synthesis by inhibiting thy idylate synthetase activity. Thymidylate synthetase catalyzes the methylation of deoxyuridylic acid to thymidylic acid, a DNA precursor. It also inhibits, to a lesser extent, the formation of RNA. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and which take up fluorouracil at a more rapid pace.
  • Fluorouracil is used topically for the treatment of actinic or solar keratosis and also for the treatment of other tumors of the skin such as Bowen's disease and superficial basal cell carcinoma [U.S. Pat. No. 4,849,426; Physicians Desk Reference. 43rd Ed., Medical Economics Company (1989) p 1729; Martindale, The Extra Pharmacopoeia, 28th Ed., The Pharmaceutical Press, U.K., (1982) pp 210-211]. It has also been reported to be useful in the treatment of psoriasis and other non-malignant skin disorders [U.S. Pat. No. 4,853,388; Pearlman et al . (1986) J. Am. Acad. Dermatol . 15:1247; Martindale, supra, p 211].
  • Fluorouracil is available commercially as a 1% topical solution in propylene glycol under the name FLUOROPLEX ® (Herbert Laboratories division, Allergan Pharmaceuticals). It is also available as a 2% or 5% topical solution in propylene glycol or as a 5% cream under the name EFUDEX® (Roche Laboratories division, Hoffmann-La Roche Inc.).
  • the principal barrier to topical delivery of drugs to the skin is the stratum corneu , the outermost layer of the skin comprising keratin-rich cells embedded in multiple lipid bilayers, which presents a highly impermeable barrier.
  • impermeability of the skin is essential to the well-being of a living organism, preventing ingress of most materials including pharmaceutical agents.
  • methods of increasing skin permeability have been sought.
  • cytotoxic agents such as 5- fluorouracil
  • penetration enhancers include, for example, certain essential oils such as eucalyptus and chenopodium, substituted azacycloalkan-2-ones such as Azone ® (1-dodecylazacyclo- heptan-2-one) , bis-azacyclopentanonyl alkanes, dimethylsulfoxide (DMSO), lower alkyl amides, dimethylacetamide (DMA), dimethyl formamide (DMF) , l-methyl-2-pyrrolidone, n-decylmethyl sulfoxide, propylene glycol, and tertiary amine oxides.
  • certain essential oils such as eucalyptus and chenopodium
  • substituted azacycloalkan-2-ones such as Azone ® (1-dodecylazacyclo- heptan-2-one)
  • bis-azacyclopentanonyl alkanes dimethylsulfoxide (DMSO), lower alkyl
  • the present invention greatly increases drug permeability through the skin. While it is known in the art to use permeation enhancers singly or together in a binary system in combination with pharmaceutical agents, this invention utilizes a novel combination of three enhancers in a permeation-enhancing mixture with a cytotoxic agent such as 5-fluorouracil. The combined effect produces a significant improvement.
  • the present invention is directed to a composition of matter for the percutaneous administration of a cytotoxic agent, and particularly to the percutaneous administration of 5-fluorouracil.
  • the composition comprises, in combination, the cytotoxic agent to be administered and a permeation-enhancing mixture that includes a lower alkanol, propylene glycol or a mixture of polyethylene glycols, a third permeation enhancer and, optionally, a covehicle.
  • the invention is also directed to a method for treating malignant and non-malignant skin disorders and comprises applying to an area of skin affected by a skin disorder, a therapeutically effective amount of the composition of this invention.
  • FIG. 1 shows the distribution of 5-fluorouracil in epidermis and dermis of the hairless guinea pig after 24 h permeation from various permeation-enhancing mixtures.
  • FIG. 2 presents a comparison of 5-fluorouracil distribution between stratum corneum (SC), epidermis (E) and dermis (D) in hairless guinea pig after 24 h permeation from various permeation- enhancing mixtures.
  • This invention codelivers a lower alkanol, propylene glycol or a mixture of polyethylene glycols, and a third permeation enhancer to aid in delivery of cytotoxic agents such as 5-fluorouracil across the skin.
  • Their combined effect according to this invention has been shown to produce dramatic increases in the permeation of 5-FU together with a significant reduction on lag time. Improved enhancement of permeation according to this invention can be obtained over a relatively wide range of weight ratios.
  • the present invention in one embodiment is directed to a composition of matter for percutaneous administration of a cytotoxic agent, the composition comprising, in combination: a) the cytotoxic agent to be administered; and b) a permeation-enhancing mixture comprising: i) a lower alkanol, ii) propylene glycol or a mixture of polyethylene glycols, iii) a third permeation enhancer, and iv) optionally, a covehicle.
  • Suitable concentrations of the cytotoxic agent in the composition will depend upon the choice of agent.
  • the cytotoxic agent is 5-fluorouracil
  • it may be present in the composition in an amount ranging from about 0.001 to about 10% by weight, preferably from about 0.1 to about 5% by weight, and more preferably from about 0.5 to about 3% by weight.
  • the permeation-enhancing mixture may be present in an amount ranging from about 90 to about 99.999% by weight, preferably from about 95 to a out 99.9% by weight, and more preferably from about 97 to about 99.5% by weight.
  • Suitable cytotoxic agents for use in this invention include 5-fluorouracil, colchicine, vinblastine sulfate, cyclophosphamide, azathioprine, cyclocytidine, azocytidine, azaserine, cisplatin, cyclohexi ide, mechlorethamine, cycloleucine, cytarabine, dacarbazine, dactinomycin, dichloromethotrexate, emetrine hydrochloride, etoposide, quanazole, hydroxyurea, idoxuridine, mercaptopurine, ethotrexate, methyl GAG (methylglyoxal bis(guanylhydrazone)), metoprine, pyrimetha ine, thioguanine, thiotepa, vincristine sulface, and cyclosporin A. 5-Fluorouracil is preferred.
  • lower alkanol refers to an alkanol of two to four carbon atoms. An alkanol of two or three carbons is preferred, and ethanol is more preferred.
  • the lower alkanol is present in the permeation-enhancing mixture in an amount of between about 5% and about 75% by weight, preferably between about 10% and about 50% by weight.
  • the propylene glycol in the permeation-enhancing mixture may be partially or totally replaced by a mixture of polyethylene glycols of different molecular weight (from 100 to 10,000) in order to modify the rheology of the formulation.
  • the total amount of propylene glycol and/or polyethylene glycols present in the permeation- enhancing mixture is between about 5% and about 75% by weight, preferably between about 10% and about 50% by weight.
  • an enhancer will be compatible in a mixture with the lower alkanol and propylene glycol or polyethylene glycols and in combination will enhance percutaneous penetration of the cytotoxic agent such that the drug delivery rate is at therapeutic levels. Additionally, the enhancer, when applied to the skin surface, should be non-toxic, non-irritating on prolonged exposure and under occlusion, non-sensitizing on repeated exposure and essentially free from other adverse side effects.
  • Such a permeation enhancer may be chosen from, but is not limited to, lactones, particularly butyrolactone; substituted azacycloalkan-2- ones, particularly those having 5 to 7 carbons in the cycloalkyl group such as Azone ® ; amides such as dimethylacetamide (DMA), dimethyl formamide (DMF) and dimethyl lauramide; propylene carbonate: polyethylene glycol monolaurate; sorbitan monolaurate; sucrose monolaurate; sucrose monococoate; pyrrolidones such as octyl pyrrolidone; dimethylbutylurea; methyl gluceth-10; glycerol monooleate; oleic acid; and propionic acid.
  • lactones particularly butyrolactone
  • substituted azacycloalkan-2- ones particularly those having 5 to 7 carbons in the cycloalkyl group
  • Azone ® amides such as dimethylacetamide (DMA
  • the third permeation enhancer are propylene carbonate, butyrolactone, sucrose monolaurate and sucrose monococoate.
  • the third permeation enhancer • is present in the permeation-enhancing mixture in an amount between about 1% and about 75% by weight, preferably between about 10% and about 40% by weight.
  • the covehicle when present in the permeation-enhancing mixture, is chosen to be soluble within the enhancer composition.
  • Representative covehicles include water, mineral oil, silicone oil, ethylene-vinyl acetate polymers or other low molecular weight polymers soluble in water, lower alcohols or suitable oils. Preferred are water and mineral oil, with water more preferred.
  • the covehicle is generally present in the permeation-enhancing mixture in an amount from 0% to about 60% by weight.
  • the pH of the formulation is conveniently in the range of 2 to 10 and is preferably in the range of 4 to 8.
  • the pH of the formulation may be adjusted with sodium hydroxide or hydrochloric acid and/or a buffering agent such as, for example, phosphate, TRIS, HEPES, or EPPS.
  • a buffering agent such as, for example, phosphate, TRIS, HEPES, or EPPS.
  • an aqueous buffer as the covehicle.
  • the present invention greatly increases drug permeability through the skin. It also significantly reduces the lag time between application of the drug to the skin and delivery of the drug through the s ratum corneum. These are very desirable attributes because many cytotoxic agents, such as 5-fluorouracil, are toxic if allowed to remain on the skin surface. Therefore, a short surface exposure time is better. To obtain a short exposure time while delivering a therapeutically useful amount of agent, a high flux rate is needed; a short lag time is also helpful. As a result, less of the cytotoxic agent is required to be applied to the treated sites to deliver equal or greater amounts of drug through the stratum corneum into the epidermis and especially into the dermis.
  • the agent is removed quickly from the surface of the skin into the epidermis and dermis. This, in turn, provides greater efficiency by using less of the toxic material and also results in less irritation and other der atological side effects to the skin during relatively short exposure (i.e., about one to 24 hours).
  • the cytotoxic agent and the permeation-enhancing mixture are placed in transmitting relationship to the skin area having the skin disorder, preferably in a pharmaceutically acceptable carrier therefor.
  • the drug and the permeation-enhancing mixture are typically dispersed within a physiologically compatible matrix or carrier which may be applied directly to the body as a lotion, cream, ointment, gel or solution, preferably a lotion, cream or solution.
  • a physiologically compatible matrix or carrier which may be applied directly to the body as a lotion, cream, ointment, gel or solution, preferably a lotion, cream or solution.
  • Such compositions can also contain stabilizers, dyes, diluents, pigments, vehicles, inert fillers, excipients, gelling agents, buffers and other components of topical compositions as is known to the art.
  • the composition When the composition is applied to the skin, it may be desirable to occlude the site of administration. Occlusion has been found, in treatment of psoriasis with corticosteroids for example, to increase the effectiveness of the treatment.
  • Occlusion of prior art topical solutions of 5-FU has resulted in reported serious local toxicities such as erosions and even severe burns. But because • the present invention gives greatly enhanced permeability, less 5-FU is required in a topical composition, resulting in a much lower and acceptable degree of local toxicity to the treated site during relatively short exposure (i.e., about one to 24 hours), whether the site is occluded or not.
  • the cytotoxic agent and the permeation- enhancing mixture would be administered from a transdermal delivery device, such as those described in, for example, U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557 and 4,568,343.
  • the composition containing the cytotoxic agent and the permeation-enhancing mixture is applied to an area of skin having the skin disorder in a quantity sufficient to wet or cover the surface and to provide a therapeutically effective amount of the cytotoxic agent to the skin.
  • therapeutically effective amount is meant an amount of cytotoxic agent that provides a desired effective therapeutic treatment of the targeted skin disorder.
  • the treated area may or may not be occluded. In a preferred embodiment, the treated area is not occluded.
  • permeation enhancer/vehicle mixtures used in the following examples were chosen from those listed in Table A below, to which was added an amount of 5-fluorouracil and trace amounts of radio!abelled 5-FU (available from New England Nuclear), to 80% of saturation.
  • the Efudex ® used in the following examples was a commercial preparation from Roche consisting of 5% wt/wt fluorouracil compounded with propylene glycol, tris(hydroxy ethyl) aminomethane, hydroxypropyl cellulose, parabens (methyl and propyl) and disodium edetate.
  • the Efudex was labelled with a tracer amount of 3 H-5-FU.
  • the receptor solutions were removed and replaced with equal volumes of fresh receptor solution previously equilibrated to 37 ⁇ C. To determine the drug concentration in the removed receptor solutions, aliquots pf the receptor solutions were filtered and weighed in scintillation vials and counted with Aquassure ® scintillation fluor (New England Nuclear).
  • the pieces of epidermis were removed and rinsed once with the corresponding permeation- enhancing mixture, followed by a rinse in 25% EtOH and two rinses in water.
  • the epidermis was then blotted between two pieces of filter paper and weighed in a scintillation vial, digested with NCS solubilizer and counted with toluene fluor to determine the drug concentration in the epidermis.
  • each drug donor solution 100 ⁇ L was applied to 3.63 cm 2 sites within glass rings cemented to the dorsal skin.
  • the open end of the glass ring was sealed with a plastic disc, and the animals were wrapped with gauze and placed in individual cages with food and water ad libitum.
  • the glass ring was removed, the excess donor solution was wiped off the skin, and the sites were washed three times with a soap solution.
  • the sites were then rinsed with water and examined for erythema.
  • the guinea pigs were sacrificed, and a large piece of skin including the application site was excised from each guinea pig for stripping and sectioning.
  • a piece of adhesive tape larger than the application site was placed on the skin and a pressure of 40 g/cm 2 was applied over the entire site. The tape was then "stripped" off with a swift motion. The skin was stripped in this way 20 to 25 times to remove as much stratum corneum as possible.
  • Each piece of tape was incubated 24 h at room temperature in 15 ml of Aquassure and the radioactive content was measured by scintillation counting. The full thickness of remaining skin was then inverted and frozen at -80 ⁇ C.
  • Three punch biopsies 6 mm in diameter were cut out from each site and each biopsy was frozen and sectioned parallel to the surface of the epidermis in a cryostat. Each section was then incubated 24 h in 15 ml of Aquassure and the radioactive content was measured.
  • results of 5-FU distribution in tape strips of the stratum corneum are expressed as ⁇ g/cm 2 , calculated from its known specific activity. Drug concentrations were not calculated, as the volume of stratum corneum recovered on each tape could not be determined.
  • 5-FU distribution is expressed as ⁇ g/cm 3 of tissue.
  • the total quantities of the drug in the stratum corneum, epidermis and dermis are expressed in ⁇ g/cm 2 .
  • two animals were used (one site per animal). The stripping was performed on the entire site and the sectioning on three biopsies, of 0.28 cm 2 . After tape stripping, the guinea pig skin presented only a few remaining cornified layers at the surface of the epidermis.
  • the epidermis was 30 to 40 ⁇ m thick.
  • the total thickness of the skin was about 1200 ⁇ m.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP91907120A 1990-03-30 1991-03-25 Cytotoxisches mittel und hautpermeabilitäterhöher enthaltende zusammensetzung Ceased EP0522006A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50248890A 1990-03-30 1990-03-30
US502488 1990-03-30

Publications (1)

Publication Number Publication Date
EP0522006A1 true EP0522006A1 (de) 1993-01-13

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ID=23998069

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Application Number Title Priority Date Filing Date
EP91907120A Ceased EP0522006A1 (de) 1990-03-30 1991-03-25 Cytotoxisches mittel und hautpermeabilitäterhöher enthaltende zusammensetzung

Country Status (9)

Country Link
EP (1) EP0522006A1 (de)
JP (1) JPH05505807A (de)
AU (1) AU633207B2 (de)
CA (1) CA2038969A1 (de)
FI (1) FI924344A7 (de)
IE (1) IE910976A1 (de)
PT (1) PT97139A (de)
WO (1) WO1991015210A1 (de)
ZA (1) ZA912228B (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0869810T3 (da) * 1996-06-19 2005-02-07 Novartis Ag Cyclosporinholdige blöde kapselpræparater
AU753018B2 (en) * 1996-06-19 2002-10-03 Novartis Ag Cyclosporin-containing soft capsule preparations
AU722285B2 (en) * 1996-06-19 2000-07-27 Novartis Ag Cyclosporin-containing soft capsule preparations
US5958876A (en) * 1996-06-19 1999-09-28 Novartis Ag Cyclosporin-containing pharmaceutical compositions
US5993787A (en) * 1996-09-13 1999-11-30 Johnson & Johnson Consumer Products, Inc. Composition base for topical therapeutic and cosmetic preparations
NZ314702A (en) * 1997-04-29 1998-07-28 Bernard Charles Sherman Pharmaceutical composition comprising a cyclosporin in a solvent system of acetylated monoglycerides and a surfactant and optionally a hydrophilic solvent
WO2005079855A1 (es) * 2004-02-23 2005-09-01 David Quintanar Guerrero Composicion promotora de penetracion a base de esteres de acidos grasos de sacarosa
JP7604458B2 (ja) 2019-08-14 2024-12-23 ナノメティクス エルエルシー （ディー．ビー．エー ピーエイチディー バイオサイエンシズ） ウラシル皮膚医薬製剤

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE37447B1 (en) * 1972-04-05 1977-07-20 Procter & Gamble Dermatological compositions
US4865848A (en) * 1987-02-26 1989-09-12 Alza Corporation Skin permeation enhancer compositions using sucrose esters
US4849426A (en) * 1987-05-15 1989-07-18 Pearlman Dale L Method for treating actinic keratosis with cytotoxic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9115210A1 *

Also Published As

Publication number Publication date
FI924344A0 (fi) 1992-09-28
CA2038969A1 (en) 1991-10-01
JPH05505807A (ja) 1993-08-26
AU633207B2 (en) 1993-01-21
FI924344L (fi) 1992-09-28
IE910976A1 (en) 1991-10-09
ZA912228B (en) 1991-12-24
WO1991015210A1 (en) 1991-10-17
FI924344A7 (fi) 1992-09-28
PT97139A (pt) 1991-11-29
AU7562091A (en) 1991-10-30

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