CA2273094C - Gel formulations for topical drug delivery - Google Patents
Gel formulations for topical drug delivery Download PDFInfo
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- CA2273094C CA2273094C CA002273094A CA2273094A CA2273094C CA 2273094 C CA2273094 C CA 2273094C CA 002273094 A CA002273094 A CA 002273094A CA 2273094 A CA2273094 A CA 2273094A CA 2273094 C CA2273094 C CA 2273094C
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Abstract
Pharmaceutical gel formulations for topical drug delivery include drug, colloidal silicon dioxide, triacetin and, preferably, propylene glycol. The gel formulations are well suited for topical delivery of the dru g 4-amino-2-ethoxymethyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1 - ethanol, which when applied topically induces cytokines, such as interferon and tumor necrosis factor, locally in the skin or mucous membranes of a mammal. The gel formulations ar e also well suited for topical delivery of drugs for treatment of diseases involvin g skin and/or mucosal lesions because the gel formulations do not need to include irritati ng components.
Description
GEL FORMULATIONS FOR TOPICAL DRUG DELIVERY
Background of the Invention This invention relates to improved pharmaceutical gel formulations for the topical delivery of drugs. In another aspect, this invention relates to pharmaceutical topical gel formulations containing 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.
Pharmaceutical gel and cream formulations for topical delivery of drugs are well known. However, many such formulations are not suitable for certain applications due to problems with, for example, insolubility and/or degradation of the drug in the formulation, physical instability of the formulation (separation of components, thickening, precipitation/agglomerization of active ingredient, and the like), and due to irritation of the skin or mucosa to which the formulation is applied.
Also, depending on the purpose of the formulation, it may be desirable if the formulation avoids systemic delivery of the active ingredient, particularly where side effects may result from such systemic delivery.
U.S. Patent 5,238,944 discloses a topical formulation of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine which is effective for the treatment of genital warts and other diseases. However, although useful for its intended purpose, this formulation is a cream, subject to potential separation problems, and includes isostearic acid which makes it painful if applied to open lesions such as occur in the case of herpes simplex virus infection.
The compound 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol disclosed in U.S. Patent 5,389,640 is from the same chemical class of compounds as 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, although having some significantly different chemical, physical, and biological properties.
The compound has been shown to induce interferon and tumor necrosis factor in mice and rats following oral administration. The compound has also been shown to induce interferon-a, tumor necrosis factor, interleukin-la, interleukin-1 [i, interleukin-6 and interleukin-8 in cultures of human peripheral blood mononuclear cells. The compound has also shown antiviral activity against herpes simplex virus-challenged guinea pigs when administered subcutaneously, dermally or intravaginally 24 hours before infection.
However, systemic administration of 4-amino-2-ethoxymethyl a,a-dimethyl-1H-imidazo[4,5-c]quinoline -1-ethanol may also be associated with certain side effects, including fever, malaise, headache, nausea and vomiting. Non-systemic topical cytokine induction would thus have the advantage of avoiding the side effects associated with the systemic induction of these ctyokines.
SLTL~IARY OF THE INVENTION
Accordingly, it is one object of the present to provide a highly stable pharmaceutical gel formulation that is suitable for topical application to the skin and/or mucosa.
A related object is to provide a gel formulation that is suitable for application to skin and/or mucosal lesions.
Another object is to provide a gel formulation in which 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c] quinoline-1-ethanol is soluble and does not substantially degrade during storage.
Yet another object is to provide a topical gel formulation for the topical delivery of 4-amino-2-ethoxymethyl-a,a dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol which does not deliver undue amounts of the active compound systemically.
Background of the Invention This invention relates to improved pharmaceutical gel formulations for the topical delivery of drugs. In another aspect, this invention relates to pharmaceutical topical gel formulations containing 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.
Pharmaceutical gel and cream formulations for topical delivery of drugs are well known. However, many such formulations are not suitable for certain applications due to problems with, for example, insolubility and/or degradation of the drug in the formulation, physical instability of the formulation (separation of components, thickening, precipitation/agglomerization of active ingredient, and the like), and due to irritation of the skin or mucosa to which the formulation is applied.
Also, depending on the purpose of the formulation, it may be desirable if the formulation avoids systemic delivery of the active ingredient, particularly where side effects may result from such systemic delivery.
U.S. Patent 5,238,944 discloses a topical formulation of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine which is effective for the treatment of genital warts and other diseases. However, although useful for its intended purpose, this formulation is a cream, subject to potential separation problems, and includes isostearic acid which makes it painful if applied to open lesions such as occur in the case of herpes simplex virus infection.
The compound 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol disclosed in U.S. Patent 5,389,640 is from the same chemical class of compounds as 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, although having some significantly different chemical, physical, and biological properties.
The compound has been shown to induce interferon and tumor necrosis factor in mice and rats following oral administration. The compound has also been shown to induce interferon-a, tumor necrosis factor, interleukin-la, interleukin-1 [i, interleukin-6 and interleukin-8 in cultures of human peripheral blood mononuclear cells. The compound has also shown antiviral activity against herpes simplex virus-challenged guinea pigs when administered subcutaneously, dermally or intravaginally 24 hours before infection.
However, systemic administration of 4-amino-2-ethoxymethyl a,a-dimethyl-1H-imidazo[4,5-c]quinoline -1-ethanol may also be associated with certain side effects, including fever, malaise, headache, nausea and vomiting. Non-systemic topical cytokine induction would thus have the advantage of avoiding the side effects associated with the systemic induction of these ctyokines.
SLTL~IARY OF THE INVENTION
Accordingly, it is one object of the present to provide a highly stable pharmaceutical gel formulation that is suitable for topical application to the skin and/or mucosa.
A related object is to provide a gel formulation that is suitable for application to skin and/or mucosal lesions.
Another object is to provide a gel formulation in which 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c] quinoline-1-ethanol is soluble and does not substantially degrade during storage.
Yet another object is to provide a topical gel formulation for the topical delivery of 4-amino-2-ethoxymethyl-a,a dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol which does not deliver undue amounts of the active compound systemically.
i i These objects, as well as others that will become apparent upon reference to the following description, are provided by pharmaceutical gel formulations including a drug, colloidal silicon dioxide, triacetin and, preferably, propylene glycol. The drug is 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, which has been found to be sufficiently soluble and chemically stable in gel formulations of the present invention. Moreover, it has been found that gel formulations of the present invention, unlike certain other gel formulations, provide excellent topical delivery of the drug while substantially avoiding unwanted systemic delivery (thereby avoiding side effects).
As noted, the gel formulations of the invention preferably include propylene glycol. One reason is because it appears, surprisingly, that inclusion of propylene glycol thickens the gel formulations and that the integrity of the resulting gel is maintained at body temperature. It should be noted, however, that gel formulations without propylene glycol, but including 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, colloidal silicon dioxide, and triacetin have been found to be suitable, although less preferred.
The present invention also provides a method of inducing cytokines, such as interferon and tumor necrosis factor, locally in the skin or mucous membranes of a mammal, comprising placing on the skin or mucous membranes of a mammal an amount of a formulation as described above effective to induce cytokines. The formulations of the i i present invention are also well-suited for treatment of diseases by application of the formulation to skin and/or mucosal lesions because the gel formulations do not need to include irritating components.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described below with reference to tests conducted using apparatus shown in the accompanying drawings, wherein:
FIG. 1 is a modified Franz diffusion cell drug release test apparatus; and FIG. 2 is an alternative modified Franz diffusion cell drug release test apparatus.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
All weight percentages recited herein are based on the total weight of the formulation unless otherwise indicated.
The present invention provides gel formulations preferably containing 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c]quinoline-1-ethanol (sometimes referred to herein as "the drug" ) .
The compound 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c]quinoline -1-ethanol is a known immune response enhancer with antiviral properties. It can be synthesized using the method disclosed in U. S . Pat . No. 5, 389, 640 . The 3a compound can be used to treat viral infections such as Type 3b I or Type II Herpes simplex viral infections and genital warts. Furthermore, the fact that the compound induces a variety of cytokines including interferon suggests that it and topical formulations containing it may be useful in the treatment of other diseases where interferon has been shown to be effective. The 4-amino-2-ethoxymethyl-a,a-dimethyl-IH-invdazo[4,5-c]quinoline-1-ethanol will preferably be present in a formulation of the invention in a therapeutically effective amount i.e., an amount effective to treat the targeted disease state or to prevent the recurrence of such a disease. Generally 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol will preferably be present in a formulation ofthe invention in an amount of 0.001 to about 0.6 percent by weight, more preferably about 0.01 to about 0.5 percent by weight based on the total weight of the formulation.
As noted, the gel formulations of the invention preferably include propylene glycol. One reason is because it appears, surprisingly, that inclusion of propylene glycol thickens the gel formulations and that the integrity of the resulting gel is maintained at body temperature. It should be noted, however, that gel formulations without propylene glycol, but including 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, colloidal silicon dioxide, and triacetin have been found to be suitable, although less preferred.
The present invention also provides a method of inducing cytokines, such as interferon and tumor necrosis factor, locally in the skin or mucous membranes of a mammal, comprising placing on the skin or mucous membranes of a mammal an amount of a formulation as described above effective to induce cytokines. The formulations of the i i present invention are also well-suited for treatment of diseases by application of the formulation to skin and/or mucosal lesions because the gel formulations do not need to include irritating components.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described below with reference to tests conducted using apparatus shown in the accompanying drawings, wherein:
FIG. 1 is a modified Franz diffusion cell drug release test apparatus; and FIG. 2 is an alternative modified Franz diffusion cell drug release test apparatus.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
All weight percentages recited herein are based on the total weight of the formulation unless otherwise indicated.
The present invention provides gel formulations preferably containing 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c]quinoline-1-ethanol (sometimes referred to herein as "the drug" ) .
The compound 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c]quinoline -1-ethanol is a known immune response enhancer with antiviral properties. It can be synthesized using the method disclosed in U. S . Pat . No. 5, 389, 640 . The 3a compound can be used to treat viral infections such as Type 3b I or Type II Herpes simplex viral infections and genital warts. Furthermore, the fact that the compound induces a variety of cytokines including interferon suggests that it and topical formulations containing it may be useful in the treatment of other diseases where interferon has been shown to be effective. The 4-amino-2-ethoxymethyl-a,a-dimethyl-IH-invdazo[4,5-c]quinoline-1-ethanol will preferably be present in a formulation of the invention in a therapeutically effective amount i.e., an amount effective to treat the targeted disease state or to prevent the recurrence of such a disease. Generally 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol will preferably be present in a formulation ofthe invention in an amount of 0.001 to about 0.6 percent by weight, more preferably about 0.01 to about 0.5 percent by weight based on the total weight of the formulation.
4-Amino-2-ethoxymethyl-a, a-dimethyl-1 H-imidazo [4, S-c] quinoline-1-ethanol exhibits substantial solubility in formulations of the invention.
Accordingly in a preferred embodiment of the invention the drug is substantially fully dissolved in the formulation.
Formulations of the invention contain colloidal silicon dioxide as a gelling agent. Colloidal silicon dioxide is commercially available under several trade names: AEROSIL from Degussa (Deutsche Gold- and Silber-Schneideanstalt vormals Roessler, Frankfurt, Germany), CAB-O-SII, from Cabot Corporation (Tuscola, IL, USA), and Wacker HDK from Wacker-Chemie GmbH (Munich, German).-Several grades of colloidal silicon dioxide having different surface areas are commercially available. A preferred grade has a specific surface area of about 200 m2/g and is available under the trade designation AEROSIL 200. Colloidal silicon dioxide will generally be present in a formulation of the invention in an amount of about 7 to about 12 percent, preferably about 8 to about 11 percent by weight based on the total weight of the formulation.
Formulations of the invention preferably contain propylene glycol (1,2-propanediol). The addition of propylene glycol has been found, surprisingly, to thicken the gel formulations and to provide a gel that maintains its integrity at body temperature. It is believed that the propylene glycol may act as a solvent for the colloidal silicon dioxide and as a solubilizer for the drug. Generally propylene WO 98/24436 PCT/US97/21995w"
glycol will preferably be present in a formulation of the invention in an amount of about 1 to about 30 percent, and more preferably about 5 to about 25 percent by weight based on the total weight of the formulation.
Formulations of the invention also contain triacetin (1,2,3-propanetriol triacetate). The triacetin is believed to act as a solvent for the colloidal silicon dioxide and as a solubilizer for the drug. In those formulations of the invention that do not contain propylene glycol, triacetin will generally be present in amount of about 88 to about 93 percent by weight based on the total weight of the formulation. In those formulations of the invention that do contain propylene glycol, triacetin will generally be present in an amount of about 58 to about percent, preferably about 63 to about 88 percent by weight based on the total weight of the formulation. However, the actual percentages of the triacetin and other ingredients will depend on whether other ingredients are included in the formulation.
A formulation of the present invention can be prepared by combining the 4-anuno-2-ethoxymethyl-a,a-dimethyl-1H-imidazoj4,5-c]quinoline-1-ethanol with the triacetin and propylene glycol, if present, and then heating with mixing to a temperature of about SO-55°~. When the 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol appears to be completely dissolved, the colloidal silicon dioxide is added and mixed until wetted. The resulting mixture is sheared on a high speed propeller mixer until a homogeneous gel is formed.
Formulations of the invention have been found to induce interferon and tumor necrosis factor locally in the skin of mice. Local induction helps avoid the side effects associated with the systemic induction of these cytokines. As previously mentioned, these side effects include fever, malaise, headache, nausea and vomiting. The ability of the formulations of the invention to induce interferon and tumor necrosis factor in the skin suggests that they will be useful for the topical treatment of diseases such as Type I and Type II Herpes simplex infections, warts including genital warts, basal cell carcinoma, cervical intraepithelial neoplasia and actinic keratosis.
The examples set forth below are intended to illustrate the invention.
Accordingly in a preferred embodiment of the invention the drug is substantially fully dissolved in the formulation.
Formulations of the invention contain colloidal silicon dioxide as a gelling agent. Colloidal silicon dioxide is commercially available under several trade names: AEROSIL from Degussa (Deutsche Gold- and Silber-Schneideanstalt vormals Roessler, Frankfurt, Germany), CAB-O-SII, from Cabot Corporation (Tuscola, IL, USA), and Wacker HDK from Wacker-Chemie GmbH (Munich, German).-Several grades of colloidal silicon dioxide having different surface areas are commercially available. A preferred grade has a specific surface area of about 200 m2/g and is available under the trade designation AEROSIL 200. Colloidal silicon dioxide will generally be present in a formulation of the invention in an amount of about 7 to about 12 percent, preferably about 8 to about 11 percent by weight based on the total weight of the formulation.
Formulations of the invention preferably contain propylene glycol (1,2-propanediol). The addition of propylene glycol has been found, surprisingly, to thicken the gel formulations and to provide a gel that maintains its integrity at body temperature. It is believed that the propylene glycol may act as a solvent for the colloidal silicon dioxide and as a solubilizer for the drug. Generally propylene WO 98/24436 PCT/US97/21995w"
glycol will preferably be present in a formulation of the invention in an amount of about 1 to about 30 percent, and more preferably about 5 to about 25 percent by weight based on the total weight of the formulation.
Formulations of the invention also contain triacetin (1,2,3-propanetriol triacetate). The triacetin is believed to act as a solvent for the colloidal silicon dioxide and as a solubilizer for the drug. In those formulations of the invention that do not contain propylene glycol, triacetin will generally be present in amount of about 88 to about 93 percent by weight based on the total weight of the formulation. In those formulations of the invention that do contain propylene glycol, triacetin will generally be present in an amount of about 58 to about percent, preferably about 63 to about 88 percent by weight based on the total weight of the formulation. However, the actual percentages of the triacetin and other ingredients will depend on whether other ingredients are included in the formulation.
A formulation of the present invention can be prepared by combining the 4-anuno-2-ethoxymethyl-a,a-dimethyl-1H-imidazoj4,5-c]quinoline-1-ethanol with the triacetin and propylene glycol, if present, and then heating with mixing to a temperature of about SO-55°~. When the 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol appears to be completely dissolved, the colloidal silicon dioxide is added and mixed until wetted. The resulting mixture is sheared on a high speed propeller mixer until a homogeneous gel is formed.
Formulations of the invention have been found to induce interferon and tumor necrosis factor locally in the skin of mice. Local induction helps avoid the side effects associated with the systemic induction of these cytokines. As previously mentioned, these side effects include fever, malaise, headache, nausea and vomiting. The ability of the formulations of the invention to induce interferon and tumor necrosis factor in the skin suggests that they will be useful for the topical treatment of diseases such as Type I and Type II Herpes simplex infections, warts including genital warts, basal cell carcinoma, cervical intraepithelial neoplasia and actinic keratosis.
The examples set forth below are intended to illustrate the invention.
i I
Cytokine Induction Test Method The cytokine induction data given in the examples below were obtained using the following test method.
For each formulation being tested, two groups of hairless SKH-1 female mice (four mice per group) are dosed. A 10 ~,L
portion of the drug containing formulation is applied to the right flank and rubbed in for 1 minute. A 10 ~,L portion of placebo gel (which contains the same weight percent of silicon dioxide and propylene glycol as the test gel with the remainder being triacetin) is applied to the left flank and rubbed in for 1 minute. One hour after dosing the first group of mice is sacrificed. Two hours after dosing the second group of mice is sacrificed. The skin is washed and tissue samples (100 mg) are removed from the right flank (drug treated) and the left flank (placebo treated).
Individual samples are placed in cryovials and snap frozen in liquid nitrogen. The samples are then homogenized in 1 mL of RPMI medium containing loo fetal calf serum and centrifuged at 2000 rpm for 10 minutes. The supernatants are collected and frozen until assayed for tumor necrosis factor (TNF) and interferon (INF). TNF is assayed using a commercially available ELISA kit (Genzyme, Cambridge, Mass.) and results are expressed as pg/mL ~SEM. Interferon is measured by bioassay using L929 mouse fibroblasts challenged with encephalomyocarditis virus. The details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in "Automated Bioassay of Interferons in Micro-test Plates", Biotechniques, June/July, 78, 1983.
Briefly stated, the method is as follows: interferon i I
dilutions and L929 cells are incubated at 37°C for 12 to 24 hours. The incubated cells are infected with an inoculum of encephalomyocarditis virus. The infected cells are incubated for an additional period at 37°C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining followed by spectrophotometric absorbance measurements. Results are expressed as units/mL ~SEM based on the value obtained for NIH mouse interferon reference standard.
6a WO 98/24436 PCT/US97/21995' r"
Drug Release Test Method The drug release data given in the examples below were obtained using the following test method.
A modified Franz diffusion cell 10 of the type shown in Figure 1 is used.
The cell is made of glass and holds approximately 11 mL of receptor fluid in the cell body. The cell body opening is 1.6 cm in diameter (2.0 cm2 area). A section of synthetic membrane 11 (microporous polyethylene film, CoTranTM 9711 from 3M
Company) is mounted between the upper portion 13 and lower portion 15 of the cell. The membrane is held in place by means of a Teflon~ O-ring 14. The upper and lower portions are held together by means of a clamp (not illustrated).
The portion of the cell below the mounted membrane is completely filled with receptor fluid (0.1 M sodium acetate buffer, pH 4.0) such that the receptor fluid is in contact with the membrane. The receptor fluid is stirred by means of magnetic stir bar 17 and a magnetic stirrer (not illustrated). The sampling port 19 is covered except when in use.
When a gel formulation is evaluated, the membrane is placed across the opening of the lower portion of the diffusion cell. The O-ring is positioned on top of the membrane. A 1: SO g portion of formulation is placed on top of the membrane and spread evenly over the portion of the membrane surface which lies inside the O-ring. The diffusion cell is assembled and the lower portion is filled with 11 mL of warm (32 t 1 °C) receptor fluid.
The sampling port is covered and the cell is placed in a constant temperature (32 ~ 1°C) and humidity (SO% t 15% relative humidity) chamber. The receptor fluid is stirred throughout the experiment. The entire volume of receptor fluid is withdrawn at intervals of 30, 60, 120, 240 and 360 minutes elapsed time and immediately replaced with fresh fluid. The withdrawn fluid is analyzed for 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol using a uv - spectrophotometer equipped with a flow cell ( 1.0 cm for gels containing 0.05% or 0.01% drug; 0.2 cm for gels containing 0.25% drug) and measuring the absorbance at 247 nm. Results are reported as the cumulative amount of drug released at 30, 60, 120, 240 and 360 minutes and are expressed in units of mg/cm2.
WO 98/24436 PCT/US97/2199~ r' In Vitro Skin Penetration Test Method The skin penetration data given in the examples below was obtained using the following test method.
A modified Franz diffusion cell 20 of the type shown in Figure 2 is used.
Two types of skin are used, hairless mouse skin and human cadaver skin. As shown in Figure 2, the skin 22 is mounted between the upper portion 23 and the lower portion 25 of the cell, which are held together by means of a clamp 28.
The portion of the cell below the mounted membrane is completely filled with receptor fluid (0.1 M sodium acetate buffer, pH 4.0) such that the receptor fluid is in contact with the skin. The receptor fluid is stirred by means of a magnetic stir bar 27 and a magnetic stirrer (not illustrated). The sampling port 29 is covered except when in use.
When a gel formulation is evaluated, the skin is placed across the opening of the lower portion of the diffusion cell. A 300 mg portion of formulation is spread evenly over the skin. The diffusion cell is assembled and the lower portion is filled with 10 mL of warm (32 ~ 1 °C) receptor fluid.
The sampling port is covered and the cell is placed in a constant temperature (32 t 1 °C) and humidity (45% t 15% relative humidity) chamber. The receptor fluid is stirred throughout the experiment. The entire volume of receptor fluid is withdrawn at intervals of 3, 6, 12, 24, 48 and 72 hours elapsed time and immediately replaced with fresh fluid. The first 5 mL of withdrawn fluid is filtered through a 0.45 p Acrodisc CRPTFE 25 mm filter (Miltex Instument Company, Ohio) and discarded. Then a 1 mL portion is filtered and placed in a high performance liquid chromatography vial. The vial is capped then refrigerated until analysis. The sample is analyzed for 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol using high performance liquid chromatography (Column: 15 cm X 0.46 cm Supelcosil LC-8-DB (Supelco, Inc., Bellefonte, PA, USA), 5 pm particle size; Mobile phase: acetonitrile/75mM ammonium phosphate aqueous buffer with 5 mM triethyl amine, pH 2.5, 19%/81% v/v; Flow rate:
WO 98/24436 PCT/US97/2199g 2.OL/min; Detector: uv at 245 nm). Results are reported as the cumulative amount of drug penetrating at 3, 6, 12, 24, 48 and 72 hours and are expressed in units of ug/mL.
Example 1 4-Amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c)quinoline-1-ethanol (0.75 g) was added to triacetin (272.25 g) in a 600 mL glass beaker.
The resulting mixture was heated (about 55°C) with stirring until all of the drug was dissolved. Colloidal silicon dioxide (27.0 g, AEROSII,~ 200 from Degussa, Frankfurt, Germany) was added to the solution and mixed with a spatula until wetted. The mixture was sheared on a high speed propeller mixer until a homogeneous gel was formed. The gel contained 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-cJquinoline-1-ethanol, 9.0% colloidal silicon dioxide, and 90.75% triacetin.
Example 2 Propylene glycol (20.0 g), triacetin (343.0 g) and 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol ( l.Og) were placed in a 600mL glass beaker then heated (50° t 5°C) with stirring until all of the drug was dissolved. Colloidal silicon dioxide (36.0 g) was added to the solution and mixed with a spatula until wetted. The mixture was sheared on a high speed propeller mixer until a homogeneous gel was formed. The gel contained 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-cJquinoline-I-ethanol, 5.0% propylene glycol, 9.0% colloidal silicon dioxide, and 85.75% triacetin.
Example 3 Propylene glycol (80.0 g) and 4-amino-2-ethoxymethyl-a,a-dimethyl-iH-imidazo[4,5-cJquinoline-1-ethanol (1.0 g) were placed in a 600mL glass beaker then heated (about SO°C) with stirring until all of the drug was dissolved.
Triacetin (283.0 g) was added and the resulting mixture was stirred until a solution was obtained. The heat was turned off. Colloidal silicon dioxide (36.0 g) was added to the solution and mixed with a spatula until wetted. The mixture was sheared on a high speed propeller mixer until a homogeneous gel was formed. The gel contained 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1 ethanol, 20.0% propylene glycol, 9.0% colloidal silicon dioxide, and 70.75%
triacetin.
The gel formulations of Examples 1-3 were tested for their ability to induce cytokines using the test method described above. The results shown in Table 1 below demonstrate that all three formulations produced significant interferon and tumor necrosis factor induction at the site of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol application. Results are presented as the mean f standard error mean of 4 animals assayed individually. ND means not done.
Table 1 Cytokine Induction FormulationTime Cytokine Concentration (hr) Right Flank Left Flank IFN TNF IFN TNF
(p~~-) (IJ~mL) (Pt~~-) 1 1 346 t 54 699 t 187 86 t 37 273 t 65 1 2 215 ~ 107 496 t 123 106 t 98 344 ~ 95 2 1 277 t 80 340 t 97 127 t 71 163 t 24 3 1 <1 f 0 304 ~ 39 <1 f 0 165120 3 2 577 f 210 1138 ~ 232 105 ~ 98 454 ~ 175 Untreated 0 3 f 1 120 ~ 15 ND ND
Example 4 Using the method of Example 1, a gel containing 0.05% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 9.0% colloidal silicon dioxide, and 90.95% triacetin was prepared.
-io-WO 98/24436 PCT/US97/21995' Example 5 Using the method of Example 2, a gel containing 0.05% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 5.0% propylene glycol, 9.0% colloidal silicon dioxide, and 85.95% triacetin was prepared.
Example 6 Using the method of Example 3, a gel containing 0.05% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 9.0% colloidal silicon dioxide, and 70.95% triacetin was prepared.
The gel formulations of Examples 4-6 were tested for their ability to induce cytokines using the test method described above. The results shown in Table 2 below demonstrate that all three formulations produced significant interferon and tumor necrosis factor induction at the site of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol application. Results are presented as the mean t standard error mean of 4 animals assayed individually. ND means not done.
Table 2 Cytokine Induction FormulationTime Cytokine Concentration (hr) Right Flank Left Flank IFN TNF IFN TNF
(LJ~mI-) ~Pl~~) (U~mI-y PP~~) 4 I 0.910.5 412 ~ 105 <1.0 280 f 51 4 2 20 ~ 10 345 t 72 <1.0 153 t 19 5 1 0.310.3 348 ~ 35 <I.0 262 ~ 26 5 2 69 ~ 58 346 ~ 24 <1.0 194 t 19 6 1 <1 t 0 279 f 45 <1.0 170 ~ 40 6 2 43 ~ 32 260 t 47 <1.0 129 t 41 Untreated 0 < 1.0 220 t 28 ND ND
WO 98/24436 PCTlUS97/21995 "' Example 7 Using the method of Example 1, a gel containing 0.01% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 9.0% colloidal silicon dioxide, and 90.99% triacetin was prepared.
Example 8 Using the method of Example 2, a gel containing 0.01 % 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 5.0% propylene glycol, 9.0% colloidal silicon dioxide, and 85.99% triacetin was prepared.
Example 9 Using the method of Example 3, a gel containing 0.01% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 9.0% colloidal silicon dioxide, and 70.99% triacetin was prepared.
The gel formulations of Examples 7-9 were tested for their ability to induce cytokines using the test method described above. The results shown in Table 3 below demonstrate that the formulation of Example 8 produced significant tumor necrosis factor induction at the site of 4-amino-2-ethoxymethyl-a,a-dimethyl-imidazo[4,5-c]quinoline-1-ethanol application. Results are presented as the mean t standard error mean of 4 animals assayed individually. ND means not done.
WO 98/24436 PCT/US97/21995' -"
Table 3 Cytokine Induction FormulationTime Cytokine Concentration (hr) Right Flank Left Flank IFN TNF IFN TNF
(P~~) (U~mI-) (P~~-) 7 1 <1.0 455 t 93 <1.0 421 ~ 63 7 2 <1.0 382 t 86 <1.0 398 ~ 54 8 1 <1.0 406125 <1.0 31631 8 2 <1.0 296 t 23 <1.0 375 t 18 9 1 <1.0 380 t 43 <1.0 352 ~ 52 9 2 <1.0 296 ~ 23 <I.0 366 t 56 Untreated 0 <1.0 273 ~ 44 ND ND
Example 10 Using the method of Example 3, a gel containing 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 8.0% colloidal silicon dioxide, and 71.75% triacetin was prepared.
Example 11 Using the method of Example 3, a gel containing 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 10.0% colloidal silicon dioxide, and 69.75% triacetin was prepared.
The gel formulations of Examples 2, 3, 5, 6, 8, 10 and 11 were tested for their ability to release 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol using the test method described above. The results shown in 1 S Table 4 below demonstrate that all five formulations release 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. Each value is the mean of the values from 6 diffusion cells.
WO 98!24436 PCT/US97I2199s ="
Table 4 Drug Release FormulationCumulative Amount Released (mg/cm') 30 min 60 min 120 min 240 min 360 min Example 0.13 0.18 0.24 0.41 0.56 Example 0.15 0.23 0.33 0.50 0.62 Example 0.03 0.04 0.05 0.09 0.11 Example 0.03 0.04 0.07 0.12 0.15 Example 0.024 0.041 0.062 0.091 0.108 Example 0.14 0.22 0.33 0.58 0.72 Example 0.12 0.17 0.25 0.45 0.59 The in vitro penetration of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol through hairless mouse skin or human cadaver 5 skin from a gel formulation of Example 3 was determined using the test method described above. The results shown in Table 5 below demonstrate that the gel releases 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol to and through the skin. Each value shown is the average of six independent determinations with the standard deviation.
WO 98/24436 PCT/ITS97/21995 "' Table 5 In Vitro Skin Penetration Time (hours) Cumulative Amount Penetrating (~g/mL) Hairless Mouse SkinHuman Cadaver Skin 3 0.073 f 0.08 0 6 0.147 t 0.133 0 l2 0.413 ~ 0.210 0 24 1.085 t 0.380 0 48 2.89 ~ 1.18 0.292 t 0.088 72 5.455 ~ 3.88 0.493 t 0.158
Cytokine Induction Test Method The cytokine induction data given in the examples below were obtained using the following test method.
For each formulation being tested, two groups of hairless SKH-1 female mice (four mice per group) are dosed. A 10 ~,L
portion of the drug containing formulation is applied to the right flank and rubbed in for 1 minute. A 10 ~,L portion of placebo gel (which contains the same weight percent of silicon dioxide and propylene glycol as the test gel with the remainder being triacetin) is applied to the left flank and rubbed in for 1 minute. One hour after dosing the first group of mice is sacrificed. Two hours after dosing the second group of mice is sacrificed. The skin is washed and tissue samples (100 mg) are removed from the right flank (drug treated) and the left flank (placebo treated).
Individual samples are placed in cryovials and snap frozen in liquid nitrogen. The samples are then homogenized in 1 mL of RPMI medium containing loo fetal calf serum and centrifuged at 2000 rpm for 10 minutes. The supernatants are collected and frozen until assayed for tumor necrosis factor (TNF) and interferon (INF). TNF is assayed using a commercially available ELISA kit (Genzyme, Cambridge, Mass.) and results are expressed as pg/mL ~SEM. Interferon is measured by bioassay using L929 mouse fibroblasts challenged with encephalomyocarditis virus. The details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in "Automated Bioassay of Interferons in Micro-test Plates", Biotechniques, June/July, 78, 1983.
Briefly stated, the method is as follows: interferon i I
dilutions and L929 cells are incubated at 37°C for 12 to 24 hours. The incubated cells are infected with an inoculum of encephalomyocarditis virus. The infected cells are incubated for an additional period at 37°C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining followed by spectrophotometric absorbance measurements. Results are expressed as units/mL ~SEM based on the value obtained for NIH mouse interferon reference standard.
6a WO 98/24436 PCT/US97/21995' r"
Drug Release Test Method The drug release data given in the examples below were obtained using the following test method.
A modified Franz diffusion cell 10 of the type shown in Figure 1 is used.
The cell is made of glass and holds approximately 11 mL of receptor fluid in the cell body. The cell body opening is 1.6 cm in diameter (2.0 cm2 area). A section of synthetic membrane 11 (microporous polyethylene film, CoTranTM 9711 from 3M
Company) is mounted between the upper portion 13 and lower portion 15 of the cell. The membrane is held in place by means of a Teflon~ O-ring 14. The upper and lower portions are held together by means of a clamp (not illustrated).
The portion of the cell below the mounted membrane is completely filled with receptor fluid (0.1 M sodium acetate buffer, pH 4.0) such that the receptor fluid is in contact with the membrane. The receptor fluid is stirred by means of magnetic stir bar 17 and a magnetic stirrer (not illustrated). The sampling port 19 is covered except when in use.
When a gel formulation is evaluated, the membrane is placed across the opening of the lower portion of the diffusion cell. The O-ring is positioned on top of the membrane. A 1: SO g portion of formulation is placed on top of the membrane and spread evenly over the portion of the membrane surface which lies inside the O-ring. The diffusion cell is assembled and the lower portion is filled with 11 mL of warm (32 t 1 °C) receptor fluid.
The sampling port is covered and the cell is placed in a constant temperature (32 ~ 1°C) and humidity (SO% t 15% relative humidity) chamber. The receptor fluid is stirred throughout the experiment. The entire volume of receptor fluid is withdrawn at intervals of 30, 60, 120, 240 and 360 minutes elapsed time and immediately replaced with fresh fluid. The withdrawn fluid is analyzed for 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol using a uv - spectrophotometer equipped with a flow cell ( 1.0 cm for gels containing 0.05% or 0.01% drug; 0.2 cm for gels containing 0.25% drug) and measuring the absorbance at 247 nm. Results are reported as the cumulative amount of drug released at 30, 60, 120, 240 and 360 minutes and are expressed in units of mg/cm2.
WO 98/24436 PCT/US97/2199~ r' In Vitro Skin Penetration Test Method The skin penetration data given in the examples below was obtained using the following test method.
A modified Franz diffusion cell 20 of the type shown in Figure 2 is used.
Two types of skin are used, hairless mouse skin and human cadaver skin. As shown in Figure 2, the skin 22 is mounted between the upper portion 23 and the lower portion 25 of the cell, which are held together by means of a clamp 28.
The portion of the cell below the mounted membrane is completely filled with receptor fluid (0.1 M sodium acetate buffer, pH 4.0) such that the receptor fluid is in contact with the skin. The receptor fluid is stirred by means of a magnetic stir bar 27 and a magnetic stirrer (not illustrated). The sampling port 29 is covered except when in use.
When a gel formulation is evaluated, the skin is placed across the opening of the lower portion of the diffusion cell. A 300 mg portion of formulation is spread evenly over the skin. The diffusion cell is assembled and the lower portion is filled with 10 mL of warm (32 ~ 1 °C) receptor fluid.
The sampling port is covered and the cell is placed in a constant temperature (32 t 1 °C) and humidity (45% t 15% relative humidity) chamber. The receptor fluid is stirred throughout the experiment. The entire volume of receptor fluid is withdrawn at intervals of 3, 6, 12, 24, 48 and 72 hours elapsed time and immediately replaced with fresh fluid. The first 5 mL of withdrawn fluid is filtered through a 0.45 p Acrodisc CRPTFE 25 mm filter (Miltex Instument Company, Ohio) and discarded. Then a 1 mL portion is filtered and placed in a high performance liquid chromatography vial. The vial is capped then refrigerated until analysis. The sample is analyzed for 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol using high performance liquid chromatography (Column: 15 cm X 0.46 cm Supelcosil LC-8-DB (Supelco, Inc., Bellefonte, PA, USA), 5 pm particle size; Mobile phase: acetonitrile/75mM ammonium phosphate aqueous buffer with 5 mM triethyl amine, pH 2.5, 19%/81% v/v; Flow rate:
WO 98/24436 PCT/US97/2199g 2.OL/min; Detector: uv at 245 nm). Results are reported as the cumulative amount of drug penetrating at 3, 6, 12, 24, 48 and 72 hours and are expressed in units of ug/mL.
Example 1 4-Amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c)quinoline-1-ethanol (0.75 g) was added to triacetin (272.25 g) in a 600 mL glass beaker.
The resulting mixture was heated (about 55°C) with stirring until all of the drug was dissolved. Colloidal silicon dioxide (27.0 g, AEROSII,~ 200 from Degussa, Frankfurt, Germany) was added to the solution and mixed with a spatula until wetted. The mixture was sheared on a high speed propeller mixer until a homogeneous gel was formed. The gel contained 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-cJquinoline-1-ethanol, 9.0% colloidal silicon dioxide, and 90.75% triacetin.
Example 2 Propylene glycol (20.0 g), triacetin (343.0 g) and 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol ( l.Og) were placed in a 600mL glass beaker then heated (50° t 5°C) with stirring until all of the drug was dissolved. Colloidal silicon dioxide (36.0 g) was added to the solution and mixed with a spatula until wetted. The mixture was sheared on a high speed propeller mixer until a homogeneous gel was formed. The gel contained 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-cJquinoline-I-ethanol, 5.0% propylene glycol, 9.0% colloidal silicon dioxide, and 85.75% triacetin.
Example 3 Propylene glycol (80.0 g) and 4-amino-2-ethoxymethyl-a,a-dimethyl-iH-imidazo[4,5-cJquinoline-1-ethanol (1.0 g) were placed in a 600mL glass beaker then heated (about SO°C) with stirring until all of the drug was dissolved.
Triacetin (283.0 g) was added and the resulting mixture was stirred until a solution was obtained. The heat was turned off. Colloidal silicon dioxide (36.0 g) was added to the solution and mixed with a spatula until wetted. The mixture was sheared on a high speed propeller mixer until a homogeneous gel was formed. The gel contained 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1 ethanol, 20.0% propylene glycol, 9.0% colloidal silicon dioxide, and 70.75%
triacetin.
The gel formulations of Examples 1-3 were tested for their ability to induce cytokines using the test method described above. The results shown in Table 1 below demonstrate that all three formulations produced significant interferon and tumor necrosis factor induction at the site of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol application. Results are presented as the mean f standard error mean of 4 animals assayed individually. ND means not done.
Table 1 Cytokine Induction FormulationTime Cytokine Concentration (hr) Right Flank Left Flank IFN TNF IFN TNF
(p~~-) (IJ~mL) (Pt~~-) 1 1 346 t 54 699 t 187 86 t 37 273 t 65 1 2 215 ~ 107 496 t 123 106 t 98 344 ~ 95 2 1 277 t 80 340 t 97 127 t 71 163 t 24 3 1 <1 f 0 304 ~ 39 <1 f 0 165120 3 2 577 f 210 1138 ~ 232 105 ~ 98 454 ~ 175 Untreated 0 3 f 1 120 ~ 15 ND ND
Example 4 Using the method of Example 1, a gel containing 0.05% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 9.0% colloidal silicon dioxide, and 90.95% triacetin was prepared.
-io-WO 98/24436 PCT/US97/21995' Example 5 Using the method of Example 2, a gel containing 0.05% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 5.0% propylene glycol, 9.0% colloidal silicon dioxide, and 85.95% triacetin was prepared.
Example 6 Using the method of Example 3, a gel containing 0.05% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 9.0% colloidal silicon dioxide, and 70.95% triacetin was prepared.
The gel formulations of Examples 4-6 were tested for their ability to induce cytokines using the test method described above. The results shown in Table 2 below demonstrate that all three formulations produced significant interferon and tumor necrosis factor induction at the site of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol application. Results are presented as the mean t standard error mean of 4 animals assayed individually. ND means not done.
Table 2 Cytokine Induction FormulationTime Cytokine Concentration (hr) Right Flank Left Flank IFN TNF IFN TNF
(LJ~mI-) ~Pl~~) (U~mI-y PP~~) 4 I 0.910.5 412 ~ 105 <1.0 280 f 51 4 2 20 ~ 10 345 t 72 <1.0 153 t 19 5 1 0.310.3 348 ~ 35 <I.0 262 ~ 26 5 2 69 ~ 58 346 ~ 24 <1.0 194 t 19 6 1 <1 t 0 279 f 45 <1.0 170 ~ 40 6 2 43 ~ 32 260 t 47 <1.0 129 t 41 Untreated 0 < 1.0 220 t 28 ND ND
WO 98/24436 PCTlUS97/21995 "' Example 7 Using the method of Example 1, a gel containing 0.01% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 9.0% colloidal silicon dioxide, and 90.99% triacetin was prepared.
Example 8 Using the method of Example 2, a gel containing 0.01 % 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 5.0% propylene glycol, 9.0% colloidal silicon dioxide, and 85.99% triacetin was prepared.
Example 9 Using the method of Example 3, a gel containing 0.01% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 9.0% colloidal silicon dioxide, and 70.99% triacetin was prepared.
The gel formulations of Examples 7-9 were tested for their ability to induce cytokines using the test method described above. The results shown in Table 3 below demonstrate that the formulation of Example 8 produced significant tumor necrosis factor induction at the site of 4-amino-2-ethoxymethyl-a,a-dimethyl-imidazo[4,5-c]quinoline-1-ethanol application. Results are presented as the mean t standard error mean of 4 animals assayed individually. ND means not done.
WO 98/24436 PCT/US97/21995' -"
Table 3 Cytokine Induction FormulationTime Cytokine Concentration (hr) Right Flank Left Flank IFN TNF IFN TNF
(P~~) (U~mI-) (P~~-) 7 1 <1.0 455 t 93 <1.0 421 ~ 63 7 2 <1.0 382 t 86 <1.0 398 ~ 54 8 1 <1.0 406125 <1.0 31631 8 2 <1.0 296 t 23 <1.0 375 t 18 9 1 <1.0 380 t 43 <1.0 352 ~ 52 9 2 <1.0 296 ~ 23 <I.0 366 t 56 Untreated 0 <1.0 273 ~ 44 ND ND
Example 10 Using the method of Example 3, a gel containing 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 8.0% colloidal silicon dioxide, and 71.75% triacetin was prepared.
Example 11 Using the method of Example 3, a gel containing 0.25% 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 20.0%
propylene glycol, 10.0% colloidal silicon dioxide, and 69.75% triacetin was prepared.
The gel formulations of Examples 2, 3, 5, 6, 8, 10 and 11 were tested for their ability to release 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol using the test method described above. The results shown in 1 S Table 4 below demonstrate that all five formulations release 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. Each value is the mean of the values from 6 diffusion cells.
WO 98!24436 PCT/US97I2199s ="
Table 4 Drug Release FormulationCumulative Amount Released (mg/cm') 30 min 60 min 120 min 240 min 360 min Example 0.13 0.18 0.24 0.41 0.56 Example 0.15 0.23 0.33 0.50 0.62 Example 0.03 0.04 0.05 0.09 0.11 Example 0.03 0.04 0.07 0.12 0.15 Example 0.024 0.041 0.062 0.091 0.108 Example 0.14 0.22 0.33 0.58 0.72 Example 0.12 0.17 0.25 0.45 0.59 The in vitro penetration of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol through hairless mouse skin or human cadaver 5 skin from a gel formulation of Example 3 was determined using the test method described above. The results shown in Table 5 below demonstrate that the gel releases 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol to and through the skin. Each value shown is the average of six independent determinations with the standard deviation.
WO 98/24436 PCT/ITS97/21995 "' Table 5 In Vitro Skin Penetration Time (hours) Cumulative Amount Penetrating (~g/mL) Hairless Mouse SkinHuman Cadaver Skin 3 0.073 f 0.08 0 6 0.147 t 0.133 0 l2 0.413 ~ 0.210 0 24 1.085 t 0.380 0 48 2.89 ~ 1.18 0.292 t 0.088 72 5.455 ~ 3.88 0.493 t 0.158
Claims (6)
1. A gel formulation for the topical administration of 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, which formulation consists essentially of:
- a therapeutically effective amount of 4-amino-2-ethoxy-methyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol;
- colloidal silicon dioxide optionally propylene glycol;
and - triacetin.
- a therapeutically effective amount of 4-amino-2-ethoxy-methyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol;
- colloidal silicon dioxide optionally propylene glycol;
and - triacetin.
2. A gel formulation according to claim 1, wherein 4-amino-2-ethoxymethyl-.alpha.,.alpha.-dimethyl-1H-quinoline-1-ethanol is present in an amount of about 0.01 percent to about 0,5 percent by weight based on the total weight of the formulation.
3. A gel formulation according to claim 1 or 2, wherein the 4-amino-2-ethoxymethyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol is dissolved in the gel formulation.
4. A gel formulation according to any one of claims 1 to 3, wherein the colloidal silicon dioxide is present in an amount of about 8 to about 10 percent by weight based on the total weight of the formulation.
5. A gel formulation according to any one of claims 1 to 4, wherein the triacetin is present in an amount of about 88 to about 93 percent by weight based on the total weight of the formulation.
6. A gel formulation for the topical administration of 4-amino-2-ethoxymethyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, which formulation comprises:
(a) a therapeutically effective amount of 4-amino-2-ethoxy-methyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, (b) colloidal silicon dioxide present in an amount of about 7 percent to about 12 percent by weight based on the total weight of the formulation;
(c) propylene glycol present in an amount of about 1 percent to about 30 percent by weight based on the total weight of the formulation; and (d) triacetin present in an amount of about 58 percent to about 92 percent by weight based on the total weight of the formulation.
(a) a therapeutically effective amount of 4-amino-2-ethoxy-methyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, (b) colloidal silicon dioxide present in an amount of about 7 percent to about 12 percent by weight based on the total weight of the formulation;
(c) propylene glycol present in an amount of about 1 percent to about 30 percent by weight based on the total weight of the formulation; and (d) triacetin present in an amount of about 58 percent to about 92 percent by weight based on the total weight of the formulation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/759,992 US5939090A (en) | 1996-12-03 | 1996-12-03 | Gel formulations for topical drug delivery |
| US08/759,992 | 1996-12-03 | ||
| PCT/US1997/021995 WO1998024436A2 (en) | 1996-12-03 | 1997-12-01 | Gel formulations for topical drug delivery |
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| CA2273094A1 CA2273094A1 (en) | 1998-06-11 |
| CA2273094C true CA2273094C (en) | 2005-08-16 |
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| CA002273094A Expired - Fee Related CA2273094C (en) | 1996-12-03 | 1997-12-01 | Gel formulations for topical drug delivery |
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| US (2) | US5939090A (en) |
| EP (1) | EP0942724B1 (en) |
| JP (1) | JP4615633B2 (en) |
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| AT (1) | ATE245422T1 (en) |
| AU (1) | AU723897B2 (en) |
| BR (1) | BR9713677B1 (en) |
| CA (1) | CA2273094C (en) |
| CZ (1) | CZ301713B6 (en) |
| DE (1) | DE69723721T2 (en) |
| DK (1) | DK0942724T3 (en) |
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| HU (1) | HU229599B1 (en) |
| IL (1) | IL130065A (en) |
| NO (1) | NO325684B1 (en) |
| NZ (1) | NZ335821A (en) |
| PT (1) | PT942724E (en) |
| WO (1) | WO1998024436A2 (en) |
Families Citing this family (162)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5741908A (en) | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
| UA67760C2 (en) | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines |
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| CA2419379C (en) | 2000-08-15 | 2011-10-11 | Surmodics, Inc. | Medicament incorporation matrix |
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| JP2008531580A (en) * | 2000-12-08 | 2008-08-14 | スリーエム イノベイティブ プロパティズ カンパニー | Compositions and methods for targeted delivery of immune response modifiers |
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| US7163947B2 (en) * | 2003-03-07 | 2007-01-16 | 3M Innovative Properties Company | 1-Amino 1H-imidazoquinolines |
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| US7699057B2 (en) * | 2003-03-13 | 2010-04-20 | 3M Innovative Properties Company | Methods for treating skin lesions |
| JP4891066B2 (en) * | 2003-03-13 | 2012-03-07 | スリーエム イノベイティブ プロパティズ カンパニー | How to improve skin quality |
| EP1603476A4 (en) * | 2003-03-13 | 2010-01-13 | 3M Innovative Properties Co | Method of tattoo removal |
| US20040192585A1 (en) * | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
| US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
| WO2004108072A2 (en) * | 2003-04-10 | 2004-12-16 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
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| US8211906B1 (en) | 2003-08-05 | 2012-07-03 | Scherrer Lawrence C | Method of inhibiting growth of neoplastic cells and inhibiting infection by administering an immune enhancer drug |
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| WO2005020912A2 (en) | 2003-08-25 | 2005-03-10 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
| CA2551075A1 (en) * | 2003-08-25 | 2005-03-03 | 3M Innovative Properties Company | Immunostimulatory combinations and treatments |
| RU2006105101A (en) | 2003-08-27 | 2007-10-10 | 3М Инновейтив Пропертиз Компани (US) | Aryloxy and arylalkylene-substituted substituted imidazoquinolines |
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| KR101154101B1 (en) | 2003-10-03 | 2012-06-11 | 쓰리엠 이노베이티브 프로퍼티즈 컴파니 | Alkoxy substituted imidazoquinolines |
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| JP2007511527A (en) * | 2003-11-14 | 2007-05-10 | スリーエム イノベイティブ プロパティズ カンパニー | Oxime-substituted imidazo ring compounds |
| CN1906192A (en) | 2003-11-14 | 2007-01-31 | 3M创新有限公司 | Hydroxylamine substituted imidazo ring compounds |
| NZ547467A (en) | 2003-11-25 | 2010-06-25 | 3M Innovative Properties Co | Substituted imidazo ring system and methods |
| AU2004293096A1 (en) * | 2003-11-25 | 2005-06-09 | 3M Innovative Properties Company | Hydroxylamine and oxime substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
| US6943470B2 (en) * | 2003-12-02 | 2005-09-13 | Siemens Westinghouse Power Corporation | Air gap baffle assembly for gas-cooled turbine generator and method of installing |
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| EP1689361A4 (en) * | 2003-12-02 | 2009-06-17 | 3M Innovative Properties Co | Therapeutic combinations and methods including irm compounds |
| AR048289A1 (en) * | 2003-12-04 | 2006-04-19 | 3M Innovative Properties Co | ETERES OF RING IMIDAZO SULFONA REPLACED. |
| AU2004312510A1 (en) * | 2003-12-29 | 2005-07-21 | 3M Innovative Properties Company | Piperazine, [1,4]diazepane, [1,4]diazocane, and [1,5]diazocane fused imidazo ring compounds |
| EP1701955A1 (en) | 2003-12-29 | 2006-09-20 | 3M Innovative Properties Company | Arylalkenyl and arylalkynyl substituted imidazoquinolines |
| EP1699398A4 (en) * | 2003-12-30 | 2007-10-17 | 3M Innovative Properties Co | Enhancement of immune responses |
| EP1699788A2 (en) | 2003-12-30 | 2006-09-13 | 3M Innovative Properties Company | Imidazoquinolinyl, imidazopyridinyl and imidazonaphthyridinyl sulfonamides |
| JP4991520B2 (en) | 2004-03-15 | 2012-08-01 | スリーエム イノベイティブ プロパティズ カンパニー | Immune response modulator formulation and method |
| US8697873B2 (en) | 2004-03-24 | 2014-04-15 | 3M Innovative Properties Company | Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines |
| JP2007532572A (en) * | 2004-04-09 | 2007-11-15 | スリーエム イノベイティブ プロパティズ カンパニー | Methods, compositions and preparations for delivering immune response modifiers |
| EP1755665A4 (en) * | 2004-04-28 | 2010-03-03 | 3M Innovative Properties Co | Compositions and methods for mucosal vaccination |
| US20050267145A1 (en) * | 2004-05-28 | 2005-12-01 | Merrill Bryon A | Treatment for lung cancer |
| US20080015184A1 (en) * | 2004-06-14 | 2008-01-17 | 3M Innovative Properties Company | Urea Substituted Imidazopyridines, Imidazoquinolines, and Imidazonaphthyridines |
| US8017779B2 (en) | 2004-06-15 | 2011-09-13 | 3M Innovative Properties Company | Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines |
| US7884207B2 (en) * | 2004-06-18 | 2011-02-08 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
| WO2006009826A1 (en) | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines |
| US7915281B2 (en) | 2004-06-18 | 2011-03-29 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method |
| WO2006009832A1 (en) * | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Substituted imidazo ring systems and methods |
| US7897609B2 (en) | 2004-06-18 | 2011-03-01 | 3M Innovative Properties Company | Aryl substituted imidazonaphthyridines |
| US8541438B2 (en) | 2004-06-18 | 2013-09-24 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
| US20060045886A1 (en) * | 2004-08-27 | 2006-03-02 | Kedl Ross M | HIV immunostimulatory compositions |
| WO2006028962A2 (en) * | 2004-09-02 | 2006-03-16 | 3M Innovative Properties Company | 1-alkoxy 1h-imidazo ring systems and methods |
| WO2006029115A2 (en) | 2004-09-02 | 2006-03-16 | 3M Innovative Properties Company | 2-amino 1h imidazo ring systems and methods |
| US20090270443A1 (en) * | 2004-09-02 | 2009-10-29 | Doris Stoermer | 1-amino imidazo-containing compounds and methods |
| US20080193468A1 (en) * | 2004-09-08 | 2008-08-14 | Children's Medical Center Corporation | Method for Stimulating the Immune Response of Newborns |
| WO2006042254A2 (en) * | 2004-10-08 | 2006-04-20 | 3M Innovative Properties Company | Adjuvant for dna vaccines |
| EP1819364A4 (en) * | 2004-12-08 | 2010-12-29 | 3M Innovative Properties Co | Immunomodulatory compositions, combinations and methods |
| US8080560B2 (en) * | 2004-12-17 | 2011-12-20 | 3M Innovative Properties Company | Immune response modifier formulations containing oleic acid and methods |
| AU2005326708C1 (en) | 2004-12-30 | 2012-08-30 | 3M Innovative Properties Company | Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds |
| AR052447A1 (en) * | 2004-12-30 | 2007-03-21 | 3M Innovative Properties Co | 1- (2-METIPROPIL) ETANSULFONATE -1H-IMIDAZO [4,5-C] [1,5] NAFTIRIDIN-4- AMINA AND 1- (2- METIPROPIL) -1H-IMIDAZO [4,5-C ] [1,5] NAFTIRIDIN-4-AMINA |
| JP5543068B2 (en) | 2004-12-30 | 2014-07-09 | スリーエム イノベイティブ プロパティズ カンパニー | Chiral fused [1,2] imidazo [4,5-c] cyclic compound |
| US8436176B2 (en) * | 2004-12-30 | 2013-05-07 | Medicis Pharmaceutical Corporation | Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine |
| EP1830876B1 (en) | 2004-12-30 | 2015-04-08 | Meda AB | Use of imiquimod for the treatment of cutaneous metastases derived from a breast cancer tumor |
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| AU2006338521A1 (en) | 2005-02-09 | 2007-10-11 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted thiazolo(4,5-c) ring compounds and methods |
| WO2006086449A2 (en) * | 2005-02-09 | 2006-08-17 | Coley Pharmaceutical Group, Inc. | Alkyloxy substituted thiazoloquinolines and thiazolonaphthyridines |
| US7968563B2 (en) | 2005-02-11 | 2011-06-28 | 3M Innovative Properties Company | Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods |
| WO2006091394A2 (en) | 2005-02-11 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Substituted imidazoquinolines and imidazonaphthyridines |
| AU2006223634A1 (en) | 2005-02-23 | 2006-09-21 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinolines |
| US8846710B2 (en) | 2005-02-23 | 2014-09-30 | 3M Innovative Properties Company | Method of preferentially inducing the biosynthesis of interferon |
| CA2598639A1 (en) | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazonaphthyridines |
| AU2006216798A1 (en) | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinoline compounds and methods |
| WO2006099275A2 (en) | 2005-03-14 | 2006-09-21 | 3M Innovative Properties Company | Method of treating actinic keratosis |
| WO2006107853A2 (en) | 2005-04-01 | 2006-10-12 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridine-1,4-diamines and analogs thereof |
| EP1863814A1 (en) | 2005-04-01 | 2007-12-12 | Coley Pharmaceutical Group, Inc. | 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases |
| AU2006241166A1 (en) * | 2005-04-25 | 2006-11-02 | 3M Innovative Properties Company | Immunostimulatory compositions |
| ZA200803029B (en) * | 2005-09-09 | 2009-02-25 | Coley Pharm Group Inc | Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods |
| AU2006287270A1 (en) | 2005-09-09 | 2007-03-15 | Coley Pharmaceutical Group, Inc. | Amide and carbamate derivatives of N-{2-[4-amino-2- (ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide and methods |
| US8889154B2 (en) | 2005-09-15 | 2014-11-18 | Medicis Pharmaceutical Corporation | Packaging for 1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-4-amine-containing formulation |
| KR20080083270A (en) | 2005-11-04 | 2008-09-17 | 콜레이 파마시티컬 그룹, 인코포레이티드 | Hydroxy and alkoxy substituted 1h-imidazoquinolines and methods |
| WO2007079203A2 (en) * | 2005-12-28 | 2007-07-12 | 3M Innovative Properties Company | Treatment for cutaneous t cell lymphoma |
| EP3085373A1 (en) | 2006-02-22 | 2016-10-26 | 3M Innovative Properties Company | Immune response modifier conjugates |
| WO2007106854A2 (en) | 2006-03-15 | 2007-09-20 | Coley Pharmaceutical Group, Inc. | Hydroxy and alkoxy substituted 1h-imidazonaphthyridines and methods |
| WO2008008432A2 (en) | 2006-07-12 | 2008-01-17 | Coley Pharmaceutical Group, Inc. | Substituted chiral fused( 1,2) imidazo (4,5-c) ring compounds and methods |
| AU2007275815A1 (en) * | 2006-07-18 | 2008-01-24 | Wirra Ip Pty. Ltd. | Immune response modifier formulations |
| AU2007279376B2 (en) * | 2006-07-31 | 2012-09-06 | Wirra Ip Pty Ltd | Immune response modifier compositions and methods |
| US8178539B2 (en) | 2006-09-06 | 2012-05-15 | 3M Innovative Properties Company | Substituted 3,4,6,7-tetrahydro-5H-1,2a,4a,8-tetraazacyclopenta[cd]phenalenes and methods |
| US20080149123A1 (en) | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
| DK3150586T3 (en) | 2007-02-23 | 2020-02-17 | Gilead Sciences Inc | MODULATORS OF PHARMACOKINETIC PROPERTIES OF THERAPEUTICS |
| PL2296633T3 (en) * | 2008-05-02 | 2016-03-31 | Gilead Sciences Inc | The use of solid carrier particles to improve the processability of a pharmaceutical agent |
| US20110033515A1 (en) * | 2009-08-04 | 2011-02-10 | Rst Implanted Cell Technology | Tissue contacting material |
| WO2011084725A1 (en) * | 2009-12-21 | 2011-07-14 | 3M Innovative Properties Company | 4-AMINO-2-(ETHOXYMETHYL)-1-(2-HYDROXY-2-METHYLPROPYL)-1H-IMIDAZO[4,5-c]QUINOLIN-5-IUM 1-HYDROXYNAPHTHALENE-2-CARBOXYLATE COMPOSITIONS AND METHODS |
| EP3222621B1 (en) | 2010-08-17 | 2023-03-08 | 3M Innovative Properties Company | Lipidated immune response modifier compound and its medical use |
| AU2012261959B2 (en) | 2011-06-03 | 2015-12-03 | Solventum Intellectual Properties Company | Hydrazino 1H-imidazoquinolin-4-amines and conjugates made therefrom |
| WO2012167088A1 (en) | 2011-06-03 | 2012-12-06 | 3M Innovative Properties Company | Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom |
| US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
| CA2871490C (en) | 2012-04-27 | 2022-10-04 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of cpg oligonucleotides co-formulated with an antibiotic to accelerate wound healing |
| SI2844282T1 (en) | 2012-05-04 | 2019-08-30 | Pfizer Inc. | Prostate-associated antigens and vaccine-based immunotherapy regimens |
| HUE051406T2 (en) | 2012-11-14 | 2021-03-01 | Grace W R & Co | Compositions containing a biologically active material and a non-ordered inorganic oxide |
| CA2954446A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
| EP3188723B1 (en) | 2014-09-02 | 2021-05-26 | Epien Medical Inc. | Formulation for treating chronic wounds |
| EP3210619A2 (en) * | 2014-10-24 | 2017-08-30 | HPRD-Health Products Research and Development LDA | Topical formulation for treating skin or mucosal infections, preparation method and uses thereof |
| AU2018207283B2 (en) | 2017-01-10 | 2024-02-15 | Nektar Therapeutics | Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods |
| EP3728255B1 (en) | 2017-12-20 | 2022-01-26 | 3M Innovative Properties Company | Amide substituted imidazo[4,5-c]quinoline compounds with a branched chain linking group for use as an immune response modifier |
| WO2020226889A1 (en) * | 2019-05-07 | 2020-11-12 | Wellstat Therapeutics Corporation | Formulations of uridine triacetate in triacetin |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA831186B (en) * | 1982-03-22 | 1983-11-30 | Upjohn Ltd | Gelled pge2/triacetin solutions |
| IL73534A (en) * | 1983-11-18 | 1990-12-23 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds |
| CA1272953A (en) * | 1984-10-08 | 1990-08-21 | Yuji Makino | Pharmaceutical composition for external use containing active-type vitamin d.sub.3 |
| DE3777919D1 (en) | 1986-07-14 | 1992-05-07 | Sandoz Ag | 5-HETERO- OR -ARYL-SUBSTITUTED IMIDAZO (2,1-A) ISOCHINOLINE. |
| US4788064A (en) * | 1987-07-31 | 1988-11-29 | Warner-Lambert Company | Transdermal delivery system |
| US4814173A (en) * | 1987-09-08 | 1989-03-21 | Warner-Lambert Company | Silicone elastomer transdermal matrix system |
| US5238944A (en) * | 1988-12-15 | 1993-08-24 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
| IL92537A (en) * | 1988-12-15 | 1994-04-12 | Riker Laboratories Inc | Topical formulations and transdermal delivery systems containing- isobutyl-1H-imidazo [4,5-c] quinolin-4-amine |
| DK0385630T3 (en) * | 1989-02-27 | 1997-05-12 | Riker Laboratories Inc | 1H-imidazo (4,5-c) quinoline-4-amines as antivirals |
| HU222247B1 (en) * | 1991-03-01 | 2003-05-28 | Minnesota Mining And Manufacturing Company | 1h-imidazo[4,5-c]quinolin-5n-oxide derivatives for producing 1- and 2-substituted 1h-imidazo[4,5-c]-quinolin-4-amine derivatives |
| US5389640A (en) * | 1991-03-01 | 1995-02-14 | Minnesota Mining And Manufacturing Company | 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
| DE4117249C2 (en) * | 1991-05-27 | 1998-05-14 | Christian Dr Stief | Linsidomine used to treat erectile dysfunction |
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1996
- 1996-12-03 US US08/759,992 patent/US5939090A/en not_active Expired - Lifetime
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1997
- 1997-12-01 CA CA002273094A patent/CA2273094C/en not_active Expired - Fee Related
- 1997-12-01 KR KR10-1999-7004821A patent/KR100503716B1/en not_active IP Right Cessation
- 1997-12-01 CZ CZ0195599A patent/CZ301713B6/en not_active IP Right Cessation
- 1997-12-01 DK DK97950772T patent/DK0942724T3/en active
- 1997-12-01 IL IL13006597A patent/IL130065A/en not_active IP Right Cessation
- 1997-12-01 NZ NZ335821A patent/NZ335821A/en not_active IP Right Cessation
- 1997-12-01 AT AT97950772T patent/ATE245422T1/en active
- 1997-12-01 AU AU53686/98A patent/AU723897B2/en not_active Ceased
- 1997-12-01 DE DE69723721T patent/DE69723721T2/en not_active Expired - Lifetime
- 1997-12-01 BR BRPI9713677-8A patent/BR9713677B1/en not_active IP Right Cessation
- 1997-12-01 JP JP52574098A patent/JP4615633B2/en not_active Expired - Fee Related
- 1997-12-01 PT PT97950772T patent/PT942724E/en unknown
- 1997-12-01 WO PCT/US1997/021995 patent/WO1998024436A2/en active IP Right Grant
- 1997-12-01 EP EP97950772A patent/EP0942724B1/en not_active Expired - Lifetime
- 1997-12-01 ES ES97950772T patent/ES2200206T3/en not_active Expired - Lifetime
- 1997-12-01 HU HU0000568A patent/HU229599B1/en not_active IP Right Cessation
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1999
- 1999-06-01 NO NO19992638A patent/NO325684B1/en not_active IP Right Cessation
- 1999-06-04 US US09/325,369 patent/US6365166B2/en not_active Expired - Lifetime
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| WO1998024436A3 (en) | 1998-08-06 |
| KR20000069233A (en) | 2000-11-25 |
| HU229599B1 (en) | 2014-02-28 |
| ES2200206T3 (en) | 2004-03-01 |
| DK0942724T3 (en) | 2003-11-17 |
| CZ301713B6 (en) | 2010-06-02 |
| CA2273094A1 (en) | 1998-06-11 |
| NZ335821A (en) | 2001-04-27 |
| EP0942724A2 (en) | 1999-09-22 |
| BR9713677B1 (en) | 2009-05-05 |
| NO992638L (en) | 1999-07-16 |
| DE69723721D1 (en) | 2003-08-28 |
| US6365166B2 (en) | 2002-04-02 |
| WO1998024436A2 (en) | 1998-06-11 |
| NO325684B1 (en) | 2008-07-07 |
| EP0942724B1 (en) | 2003-07-23 |
| IL130065A0 (en) | 2000-02-29 |
| PT942724E (en) | 2003-12-31 |
| ATE245422T1 (en) | 2003-08-15 |
| HUP0000568A2 (en) | 2000-10-28 |
| NO992638D0 (en) | 1999-06-01 |
| US20020015715A1 (en) | 2002-02-07 |
| CZ195599A3 (en) | 1999-09-15 |
| AU723897B2 (en) | 2000-09-07 |
| BR9713677A (en) | 2000-03-28 |
| HUP0000568A3 (en) | 2001-01-29 |
| AU5368698A (en) | 1998-06-29 |
| KR100503716B1 (en) | 2005-07-26 |
| IL130065A (en) | 2004-06-20 |
| US5939090A (en) | 1999-08-17 |
| JP4615633B2 (en) | 2011-01-19 |
| JP2001501968A (en) | 2001-02-13 |
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