EP0663831A1 - Transdermal azidothymidine - Google Patents
Transdermal azidothymidineInfo
- Publication number
- EP0663831A1 EP0663831A1 EP92925024A EP92925024A EP0663831A1 EP 0663831 A1 EP0663831 A1 EP 0663831A1 EP 92925024 A EP92925024 A EP 92925024A EP 92925024 A EP92925024 A EP 92925024A EP 0663831 A1 EP0663831 A1 EP 0663831A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- azidothymidine
- transdermal
- skin
- patch
- azt
- 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.)
- Withdrawn
Links
Classifications
-
- 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
-
- 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
- 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
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention is for a method of transdermal delivery of azidothymidine which uses a penetration enhancer to facilitate the percutaneous and transepidermal delivery of the azidothymidine.
- Azidothymidine also known as zidovudine and S'-azido-S'-deoxythymidine is an antiretroviral agent. It is used in the treatment of patients with symptomatic human immunodeficiency virus (HIV) infection which includes Acquired Immune Deficiency Syndrome (AIDS) and advanced AIDS-Related Complex (ARC) . Azidothymidine is currently administered orally and by intravenous infusion.
- HIV human immunodeficiency virus
- AIDS Acquired Immune Deficiency Syndrome
- ARC advanced AIDS-Related Complex
- the present invention results in a new method for administering azidothymidine by formulating it into a transdermal pharmaceutical composition which can be applied directly to the skin or via a transdermal patch.
- the pharmaceutical composition includes a penetration enhancer to achieve effective blood levels of azidothymidine for the treatment of AIDS and ARC.
- Transdermal delivery of azidothymidine offers advantages over other methods of delivery of azidothymidine.
- An advantage is the ease of application and removal of a transdermal formulation. This convenience of use offers the benefit of a lifestyle uninterrupted by hospital visits, which are needed when administering azidothymidine intravenously.
- a further advantage would be for pediatric use where oral and I.V. administration is difficult.
- Transdermal AZT offers continuous administration of AZT which would maintain effective amounts of AZT in the blood for longer periods and without spiking.
- various enhancing agents have been used to deliver drugs transdermally.
- Substances that help promote drug diffusion through the stratum corneum and epidermis are referred to as skin- penetration enhancers, accelerants, adjuvants and sorption promoters.
- skin- penetration enhancers accelerants, adjuvants and sorption promoters.
- U.S. 4,863,970, U.S. 4,722,941, U.S. 4,931,283 and EP 351,897 disclose some representative penetration enhancers used in transdermal compositions and for topical administration.
- the present invention provides a method for transdermal delivery of azidothymidine using a penetration enhancer.
- the present inventors have determined that various compounds, selected from the group consisting of linalool, carvacrol, thymol, citral, menthol and t-anethole are effective penetration enhancers for delivery of azidothymidine transdermally.
- the method is practiced by transdermally administering an effective amount of azidothymidine together with a penetration enhancer.
- a further object of this invention is to provide a transdermal composition or patch for effective transdermal delivery of azidothymidine.
- FIG. 1 illustrates a cross sectional view of a transdermal patch for placement on the skin for transdermal delivery of azidothymidine.
- FIG. 2 is a bottom plan schematic view of the embodiment illustrated in Fig. 1.
- FIG. 3 illustrates a template used for topical administration of a transdermal azidothymidine formulation.
- FIG. 4 illustrates a sectional schematic view of a second embodiment of a transdermal patch for the transdermal delivery of azidothymidine.
- FIG. 5 illustrates a sectional schematic view of a third embodiment of a transdermal patch.
- FIG. 6 is a graphical representation of the results of in vitro experiments using AZT compositions with various penetration enhancers.
- FIG. 7 is a graphical representation of the results of .in vitro experiments using AZT compositions with various pharmaceutical carriers.
- FIG. 8 is a graphical representation of the results of in vitro experiments using AZT compositions with varying amounts of AZT.
- FIG. 9 is a graphical representation of the results of in vivo experiments using various AZT formulations.
- ⁇ composition means a product which results from the mixing or combining of more than one element or ingredient.
- pharmaceutically-acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent involved in carrying or transporting a chemical agent from one organ or portion of the body to another organ or portion of the body.
- transdermal delivery means administration of the pharmaceutical composition topically to the skin wherein the active ingredient, azidothymidine, will be percutaneously delivered in a therapeutically effective amount.
- transdermal patch means a skin patch to be applied to the patient's skin containing the pharmaceutical composition.
- the technology for constructing transdermal patches is well known in the pharmaceutical art.
- backing layer and “reservoir” as used herein are components of the transdermal patch. Suitable materials and designs are well known in the transdermal drug delivery art. See for example D. Hsieh, “Multiple Lamination for Transdermal Patches,” Controlled Release Systems Fabrication. Technology. Vol. 1, pp. 167-188, 1988.
- penetration enhancers means compounds which enhance the percutaneous absorption of drugs and selected from the group consisting of linalool, carvacrol, thymol, citral, menthol and t-anethole. Selection of an effective penetration enhancer for a particular drug must be experimentally deduced. A penetration enhancer which works for one drug will not necessarily work for every other drug. By virtue of its activity as an antiviral azidothymidine is useful in the treatment of AIDS and ARC (HIV-infection) .
- azidothymidine is administered transdermally by topical application of an azidothymidine composition to the skin. More preferably azidothymidine can be administered in the form of a gel and covered with an occlusive bandage or it can be administered using a transdermal patch in which the azidothymidine is incorporated.
- the pharmaceutical compositions and patches of the present invention can administer azidothymidine in admixture with a penetration enhancer and suitable pharmaceutical diluents, carriers and excipients such as gelling agents, emollients, preservatives.
- the azidothymidine is administered in admixture with the penetration enhancer thymol.
- the practicality of administering a given drug percutaneously on a continuous basis depends upon the concentration of drug in the blood that is required to provide the desired pharmacologic effect, the degree to which the skin is permeable to the drug, and the amount of skin surface area that is available for drug administration.
- the skin surface area which is available for drug administration, while theoretically being unlimited, is, for practical reasons, typically confined to a range of from about 1 square centimeter to about 100 square centimeters. With the available skin surface area fixed within this range, the matter then narrows as to whether sufficient drug will pass through the defined skin surface area to provide the desired therapy. If it will, then it is possible to effectively administer the drug percutaneously. If, however, the inherent permeability of the skin to the drug is so high or so low that too much or too little drug will pass through that area of skin, then the rate of administration of the drug to the skin must be controlled, or the permeability of the skin to the drug must be increased, as the case may be, to make percutaneous administration practical.
- the present invention involves a drug delivery system in which the percutaneous administration of the drug is enhanced by the presence of a penetration enhancer.
- the compound In order for a compound to be useful as a percutaneous penetration enhancer the compound must meet a number of different requirements. Firstly, the compound must be a dermatologically acceptable compound which when used topically on the skin does not cause adverse side effects. Secondly, the compound must be compatible with the active ingredient in the transdermal delivery system. Thirdly, it is preferable for the compound to be safe for use in humans, preferably approved or approvable by the Food and Drug Administration of the United States. Further, the compound must increase the transdermal rate of delivery of the pharmaceutically active drug.
- Suitable penetration enhancers for azidothymidine include any compound selected from the group consisting of linalool, carvacrol, thymol, citral, menthol and t-anethole.
- a non-toxic but therapeutically effective amount of azidothymidine is employed.
- the dosage regimen for treating AIDS or ARC with azidothymidine is selected in accordance with a variety of factors including the type, age, weight, sex and medical condition of the patient. A physician of ordinary skill can readily determine and prescribe an effective amount of the drug required to treat the condition.
- the minimum inhibitory concentration of AZT in humans is reported to be 0.27 mcg/ml.
- the clearance of AZT in humans is about 1.3 1/hr/kg. With a delivery rate of 1 mg/cm 2 /h, it would take about a 20 cm 2 patch to give the minimum inhibitory concentration of AZT in humans.
- Therapeutic levels are maintained with 5 mg/kg given as a 1 hr infusion every 4 hr. or 10 mg/kg given orally every 4 hr. Assuming a typical body weight of 55 kg, this equals 1650 mg/day, I.V., or 3300 mg/day orally. Based on the minimum inhibitory concentration of AZT (0.27 mcg/ml) for transdermal delivery of AZT a minimum of 460 mg/day is required to maintain the blood levels at minimum inhibitory concentration.
- the concentration of azidothymidine in the composition can be from about 3 to about 30% w/v.
- the concentration of azidothymidine is however, preferably from about 5 to about 25%, and more preferably from 15 to 25%.
- the concentration of the penetration enhancer in the composition can be from about 0.5% to about 20% w/v.
- the concentration of the penetration enhancer is, however, preferably from about 1 to about 10% and more preferably from about 2 to about 5%.
- concentrations of azidothymidine and penetration enhancers are given herein in ranges .with a maximum and a minimum concentration, amounts greater than or less than such limits can be used without varying from the invention as is understood by one having skill in the art.
- the amount of azidothymidine and penetration enhancer incorporated in the reservoir of the transdermal patch of the invention to obtain the desired therapeutic effect can vary depending upon the desired dosage of the azidothymidine, the length of time the patch is to remain on the skin of the patient and the area and thickness of the patch.
- Patient serum concentrations of the azidothymidine can thus be adjusted by varying the concentration of the azidothymidine in the patch, the length of time the patch is to remain on the skin of the patient or the patch size.
- the effective rate of release of the azidothymidine from the patch to the skin of a patient can be in the range of from about 10 to about 70 milligrams of active agent per square centimeter of skin per day (mg.cm ⁇ .day *1 ) . A more preferred range is from about 24 to about 50 milligrams of active agent per square centimeter of skin per day. The exact amount depends on the desired dosage of the active agent and whether the treatment is in an HIV asymptomatic patient or in an HIV symptomatic patient.
- excipients and pharmaceutical carriers can be present in the compositions and patches of the present application.
- An example of an excipient useful as a gelling agent for preparing a topical gel is hydroxypropyl cellulose (HPC) .
- Pharmaceutical carriers which can be used include for example mixtures of isopropanol (IPA) and water or propylene glycol (PG) and water.
- IPA isopropanol
- PG propylene glycol
- the parabens can be suitable preservatives for use in transdermal azidothymidine compositions.
- the azidothymidine compositions herein can be incorporated in a transdermal patch for delivery of the azidothymidine percutaneously. Methodology and design of transdermal patches for drug delivery are well known in the pharmaceutical art.
- Transdermal patch (10) that is designed to be placed on a patient's skin.
- Transdermal patch (10) comprises a backing layer (12) ; a drug reservoir (18) ; an adhesive layer (16) ; and a removable protective undercoating lamina (19) .
- the backing layer (12) defines the top (outward surface) of the patch.
- the backing layer can be made from a material or a combination of materials that is substantially impermeable to the components of the reservoir layer.
- the backing layer serves as a protective cover for the transdermal patch and keeps the components of the reservoir layer from escaping.
- occlusive and non-occlusive, flexible and non-flexible backing members can be used as backing layers in the transdermal patches of the present invention.
- suitable backing layers for use in the transdermal patches herein include cellophane, cellulose acetate, ethylcellulose, plasticized vinylacetate, vinylchloride copoly ers, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidenechloride, paper, cloth, foam and aluminum foil.
- the drug reservoir (18) is immediately below the backing layer (12) and contains the transdermal azidothymidine composition.
- the amount of azidothymidine incorporated in the reservoir of the patch of the invention to obtain the desired therapeutic effect can vary depending upon the desired dosage of the azidothymidine, the length of time the patch is to remain on the skin of the patient and the area and thickness of the patch.
- Patient serum concentrations of azidothymidine can be adjusted by varying the concentration of the azidothymidine in the patch, the length of time the patch is to remain on the skin of the patient or the patch size.
- the adhesive layer (16) is affixed to the backing layer surrounding the drug reservoir. This is better illustrated by a view of the patch from the bottom (patient side) as illustrated in Fig. 2 with the undercoating lamina removed.
- the adhesive layer is the means by which the transdermal patch is affixed to the skin.
- Contact adhesive compositions can be selected from pressure sensitive adhesives many of which are commonly used on transdermal patches.
- the transdermal patch (10) can include a removable protective undercoating lamina (19) which covers the entire patient side of the transdermal patch. Prior to use, the undercoating lamina (19) is pulled away from the adhesive layer (16) and discarded to expose the adhesive layer and drug reservoir.
- Fig. 3 and Fig. 4 depict another embodiment of a transdermal patch for the azidothymidine composition which is formed on the patient.
- Fig 3. depicts a template (20) applied to an area of the patient's skin.
- the inner circumference of the template (20) defines an area (22) of skin to which the transdermal azidothymidine composition is to be delivered.
- the area of skin can be determined by the age, sex, and weight of the patient, whether treatment is prophylactic or remedial, and the blood level of - azidothymidine to be achieved, discussed supra.
- a sealable gel tube or syringe containing the transdermal azidothymidine composition in a predetermined dosage is opened. The dosage is determined by the factors discussed above.
- the transdermal azidothymidine composition is applied within the inner circumference of the template and then the template is removed from the skin.
- Fig 4. depicts an occlusive covering (36) which is placed over the azidothymidine composition and the same area of the patient's skin after the template has been removed.
- the occlusive covering can include a backing layer (42) and an adhesive layer (40) which have the same properties and are chosen for the same reasons as stated above for the transdermal patch.
- the adhesive layer can be the same width and circumference as the template defining the area to which the azidothymidine is applied to the skin, i.e. it forms a perimeter or surrounding barrier to such area.
- the occlusive covering keeps the transdermal azidothymidine composition in a predefined space or reservoir (38) on the skin (44) .
- the dosage of the transdermal azidothymidine composition to be administered can be applied from a dispenser to the occlusive covering (36) within the boundaries of the adhesive layer (38) depicted in Fig. 3.
- the then-formed transdermal patch can be applied to the skin of the patient to be treated.
- the methods of administration described with regard to Figs. 3 and 4 are particularly advantageous because they permit dose titration to meet individual patient needs.
- Fig. 5 illustrates another embodiment of a transdermal patch of the invention, generally designated as 26.
- the transdermal patch (26) includes a backing layer (28) , a transdermal composition layer (30) and an adhesive layer (34) .
- the backing layer and transdermal composition layer can have the same properties as the backing layer and the transdermal azidothymidine composition respectively discussed above and are chosen for the reasons stated above.
- the adhesive layer can have the same properties as the adhesive layer discussed above and is chosen for the same reasons as above. Additionally, the adhesive layer (34) must be permeable to the transdermal composition and can not constitute a significant barrier to its passage.
- the transdermal patch (26) can also include a protective undercoating lamina (not shown) .
- the undercoating lamina Prior to use the undercoating lamina is pulled away from the adhesive layer (34) and discarded to expose the adhesive layer.
- the undercoating lamina can be made from materials that are substantially impermeable to the azidothymidine, the penetration enhancer and any other components of the transdermal composition layer and adhesive layer (34) .
- the transdermal patch of the invention can be applied to the skin of patients.
- the transdermal patch is positioned in firm contact with the patient's skin, preferably forming a tight seal therewith.
- the azidothymidine in the patch migrates from the patch to the patient's skin by diffusion.
- azidothymidine molecules along the outer surface of the transdermal patch migrate through, and are absorbed by, the skin, entering the patient's circulation through the capillary network.
- the transdermal patch can be applied to any area of the patient's skin.
- the in vitro studies described herein measured the rate of azidothymidine transport across skin excised from a hairless (NU/NU) , male mouse.
- the skin was placed between the donor and receptor compartment of the Franz cells.
- the skin (1.77 cm 2 ) partitions a donor compartment containing an azidothymidine formulation to be tested in contact with the outside of the skin and a receptor compartment containing a saline medium in contact with the inside of the skin.
- a constant temperature of 37°C is maintained.
- the receptor aqueous medium was changed at the following time points during the assay: 4 hr, 8 hr and 24 hr.
- the concentrations of azidothymidine were determined using HPLC. Most formulations in the in vitro studies were tested in triplicate.
- compositions 1-12 were prepared by the following method except for variations in the amounts of ingredients.
- AZT was weighed and added to a vial.
- the enhancer was then weighed and added to the AZT.
- IPA/water and/or PG/water was weighed into each vial until all particulate was dissolved.
- Table II shows the results of AZT transport in excised hairless (NU/NU) , male mouse skin using compositions 1-7. These results show the effect that varying the penetration enhancer has on AZT transport in vitro.
- Fig. 6 is a graphical representation of the results of this study.
- Fig. 7 shows the graphical results of the in vitro studies using composition 1 and 8-10. These results show the effect that varying the pharmaceutical carrier has on AZT transfer in vitro.
- Fig. 8 is the graphical representation of the results of in vitro studies using compositions 5, 11 and 12. These results show the effect that varying the concentration of AZT has on AZT transfer in vitro.
- Formulations were made with 150 mg/ml AZT, 5% t-anethole, menthol, carvacrol or thymol as enhancers, with and without PG.
- 3% HPC was added at 60°C and then allowed to cool to form a gel.
- the Hill Top Chamber was removed and skin was observed for any changes.
- Exa ples 13-16 Gel formulations (Examples 13-16) were prepared in the same manner as Examples 1-12 except after all the particulate was dissolved, the mixture was heated to 60'C and 3% HPC was weighed and added to the vial. After thorough mixing the mixture was allowed to cool and gel.
- HPC 0.12 0.12 0.15 0.15 Fig 9. is a graphical representation of the results of the in vivo experiments using these compositions.
- the absolute bioavailability values are given in Table I.V.
- transdermal compositions and transdermal patches according to the present invention are advantageous in that they offer ease of application and they offer continuous administration of AZT which maintains the required amount of AZT in the blood. After 24 hrs. no observable changes were seen in the skin under the gel containing chamber compared to before gel application.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US80728991A | 1991-12-13 | 1991-12-13 | |
PCT/US1992/009013 WO1993011775A1 (en) | 1991-12-13 | 1992-10-29 | Transdermal azidothymidine |
US80728 | 1993-06-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0663831A1 true EP0663831A1 (en) | 1995-07-26 |
Family
ID=25196026
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92925024A Withdrawn EP0663831A1 (en) | 1991-12-13 | 1992-10-29 | Transdermal azidothymidine |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0663831A1 (en) |
JP (1) | JPH07500114A (en) |
AU (1) | AU3123193A (en) |
CA (1) | CA2122585A1 (en) |
DK (1) | DK0663831T3 (en) |
WO (1) | WO1993011775A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9605293D0 (en) * | 1996-03-13 | 1996-05-15 | Glaxo Group Ltd | Medicaments |
WO2000033857A1 (en) * | 1998-12-07 | 2000-06-15 | Ecosmart Technologies, Inc. | Cancer treatment composition and method using natural plant essential oils |
DE102013020633A1 (en) * | 2013-12-16 | 2015-06-18 | Epinamics Gmbh | Dermal and / or transdermal pharmaceutical composition containing a terpenoid compound |
JP2020121938A (en) * | 2019-01-30 | 2020-08-13 | 国立大学法人九州大学 | Water-containing transdermal absorption composition with controlled release of water-soluble active ingredient |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4804651A (en) * | 1987-06-09 | 1989-02-14 | Board Of Regents, The University Of Texas System | Methods and compositions for the treatment of psoriasis |
JP2831030B2 (en) * | 1989-05-12 | 1998-12-02 | 学校法人城西大学 | Composition for transdermal administration preparation containing 3'-azido-3'deoxythymidine as active ingredient |
EP0572494B1 (en) * | 1991-02-18 | 1999-08-25 | Commonwealth Scientific And Industrial Research Organisation | Composition for use in transdermal administration |
-
1992
- 1992-10-29 DK DK92925024.9T patent/DK0663831T3/en active
- 1992-10-29 WO PCT/US1992/009013 patent/WO1993011775A1/en not_active Application Discontinuation
- 1992-10-29 JP JP5510885A patent/JPH07500114A/en active Pending
- 1992-10-29 EP EP92925024A patent/EP0663831A1/en not_active Withdrawn
- 1992-10-29 AU AU31231/93A patent/AU3123193A/en not_active Abandoned
- 1992-10-29 CA CA002122585A patent/CA2122585A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9311775A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1993011775A1 (en) | 1993-06-24 |
JPH07500114A (en) | 1995-01-05 |
DK0663831T3 (en) | 1995-07-26 |
CA2122585A1 (en) | 1993-06-24 |
AU3123193A (en) | 1993-07-19 |
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