Classifications

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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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  • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • 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
  • A61K47/06—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
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  • 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
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • 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
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
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  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • 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
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to pharmaceutical formulations and methods for
• the invention provides formulations and methods which are particularly advantageous for
• cervical dysplasias including dysplasia associated with human papillomavirus (HPV).
• HPV human papillomavirus
• cycloalkylimidazopyridine amine 1 ,2-bridged imidazoquinoline amine, thiazolo- and oxazolo- quinolinamines and pyridinamines, imidazonaphthyridine and
• IRM immune response modifier
• IRM compounds known as imiquimod, has been commercialized in a topical formulation
• AldaraTM for the treatment of anogenital warts associated with human papillomavirus.
• cytokines e.g., interferons, interleukins, tumor necrosis factor, etc.
• Such compounds have been shown to stimulate a rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating B cells to
• cytokines such as, for example, tumor necrosis factor (TNF), IL-1 and IL-6 also have TNF, tumor necrosis factor (TNF), IL-1 and IL-6 also have TNF, tumor necrosis factor (TNF), IL-1 and IL-6 also have TNF, tumor necrosis factor (TNF), IL-1 and IL-6 also have TNF, tumor necrosis factor (TNF), IL-1 and IL-6 also have TNF, tumor necrosis factor (TNF), IL-1 and IL-6.
• TNF tumor necrosis factor
• IL-1 interleukin-6
• tissue irritation at a particular location may be hindered due to tissue irritation, formulation wash away,
• the present disclosure provides pharmaceutical formulations containing immune
• IRM immune response modifier
• cervical conditions such as cervical dysplasias including cervical intraepithelial neoplasia.
• formulations of the invention include 4-amino-2-ethoxymethyl- , ⁇ -dimethyl-lH-
• the IRMs can be formulated for application to a mucosal membrane, particularly
• FIG. 1 is a graph comparing imiquimod transport across hairless mouse skin from
• FIG. 2 is a graph comparing imiquimod transport across hairless mouse skin from
• FIG. 3 is a graph comparing mean serum imiquimod concentration in rats after a
• FIG. 4 provides bar graphs of the pharmacokinetic comparison of imiquimod in rats after vaginal dosing of Formulation A or Formulation B.
• a mucosal associated condition means an inflammatory, infectious, neoplastic or other condition that involves a mucosal surface or that is in sufficient proximity to a mucosal surface to be affected by a therapeutic or prophylactic agent topically applied to the
• the invention provides new methods for using immune
• IRM immune response modifier
• cervical dysplasias such as cervical intraepithelial neoplasia.
• novel formulations are particularly useful.
• the formulations can enhance therapeutic efficiency of the IRM by
• the invention also provides pharmaceutical formulations containing a
• preservative system that renders the formulations suitable for packaging in multiple-use
• modifier compounds of the invention include lH-imidazo[4,5-c]quinolin-4-amines defined
• R ⁇ is selected from the group consisting of alkyl of one to ten carbon atoms
• substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms,
• R 2 ⁇ is selected from the group consisting of hydrogen, alkyl of one to eight carbon
• alkyl of one to four carbon atoms selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to
• each Ri is independently selected from the group consisting of alkoxy of one to four carbon atoms, halogen, and alkyl of one to four carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said Ri groups together contain no more than six
• R ⁇ 2 is selected from the group consisting of straight chain or branched chain
• R is selected from the group consisting of hydrogen, straight chain or branched
• each R 2 is independently selected from the group consisting of straight chain or
• n is an integer from zero to
• R 23 is selected from the group consisting of hydrogen, straight chain or branched
• moieties independently selected from the group consisting of straight chain or branched chain alkyl of one to four carbon atoms, straight chain or branched chain alkoxy of one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six
• each R is independently selected from the group consisting of straight chain or branched chain alkoxy of one to four carbon atoms, halogen, and straight chain or
• n is an integer from zero to 2, with the proviso that if n is 2, then said R 3 groups together contain no more than six carbon
• R 14 is -CHR x R y wherein R y is hydrogen or a carbon-carbon bond, with the proviso
• R x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains
• R y is a carbon-carbon bond
• R y and R x together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to four carbon atoms;
• R 24 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group
• R 4 is selected from the group consisting of hydrogen, straight chain or branched
• R ⁇ 5 is selected from the group consisting of: hydrogen; straight chain or branched
• the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to
• acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four
• Rx are independently selected from the group consisting of hydrogen, alkyl
• X is selected from the group consisting of alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the
• alkyl moiety contains one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to
• R 5 is selected from the group consisting of hydrogen, straight chain or branched
• R ⁇ 6 is selected from the group consisting of hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to ten carbon
• acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, with the proviso that
• acyloxyalkyl group does not have a fully carbon substituted carbon atom bonded
• moieties independently selected from the group consisting of alkyl of one to four carbon
• R v is hydrogen or a carbon-carbon bond, with the proviso that when R y is hydrogen R x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1- alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy
• R y is a carbon-carbon
• R y and R x together form a tetrahydrofuranyl group optionally substituted with one or
• R is selected from the group consisting of hydrogen, straight chain or branched
• benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and
• substituent is selected from the group consisting of alkyl of one to four carbon
• X is selected from the group consisting of alkoxy containing one to four carbon
• alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the
• alkyl moiety contains one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms, and mo ⁇ holinoalkyl wherein the alkyl moiety
• R 6 is selected from the group consisting of hydrogen, fluoro, chloro, straight chain or branched chain alkyl containing one to four carbon atoms, and straight chain or
• Preferred imidazopyridine amine IRM compounds are defined by Formula VII
• R ⁇ is selected from the group consisting of hydrogen; -CH 2 Rw wherein R is selected from the group consisting of straight chain, branched chain, or cyclic alkyl containing one to ten carbon atoms, straight chain or branched chain alkenyl containing
• CH CR z Rz wherein each Rz is independently straight chain, branched chain, or cyclic alkyl of one to six carbon atoms;
• R 7 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, straight chain or branched chain
• R 7 and R 77 are independently selected from the group consisting of hydrogen and
• R 67 is other than hydrogen and R 27 is other than hydrogen or mo ⁇ holinoalkyl, and with the further proviso that when R 67 is hydrogen then R 77 and R 27 are other than
• Preferred 1 ,2-bridged imidazoquinoline amine IRM compounds are defined by
• Z is selected from the group consisting of:
• R D is hydrogen or alkyl of one to four carbon atoms
• R E is selected from the group
• R G and R' G are independently hydrogen or
• alkyl of one to four carbon atoms and -(CH 2 ) a -(Y)-(CH 2 ) b - wherein a and b are integers and a+b is 0 to 3, and Y is O, S, or -NRj- wherein Rj is hydrogen or alkyl of one to four carbon atoms; and wherein q is 0 or 1 and R 8 is selected from the group consisting of alkyl of one
• R 19 is selected from the group consisting of oxygen, sulfur and selenium
• R 29 is selected from the group consisting of
• R 39 and R 49 form a fused
• X is selected from the group consisting of -O-, -S-, -NR 59 -, -C(O)-, -C(O)O-,
• each R 59 is independently H or -salkyl
• Rno is selected from the group consisting of: - hydrogen
• alkenyl-NR 310 -Q-X-R 410 wherein Q is -CO- or -SO 2 -; X is a bond, -O- or -NR 3 ⁇ o- and uo is aryl; heteroaryl; heterocyclyl; or -C ⁇ -20 alkyl or C 2- 0 alkenyl that is unsubstituted or substituted by one or more substituents
• Y is -N- or -CR-;
• R 210 is selected from the group consisting of: -hydrogen
• each R 310 is independently selected from the group consisting of hydrogen and -
• each R is independently selected from the group consisting of hydrogen
• B is -NR-C(R) 2 -C(R) 2 -C(R) 2 -; -C(R) 2 -NR-C(R) 2 -C(R) 2 -;
• R 111 is selected from the group consisting of:
• X is a bond, -O- or -NR 3 ⁇ - and Rm is aryl; heteroaryl; heterocyclyl; or - - 20
• alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents
• Y is -N- or -CR-;
• R 2 ⁇ is selected from the group consisting of: -hydrogen
• each R 3 ⁇ is independently selected from the group consisting of hydrogen and C ⁇ .
• each R is independently selected from the group consisting of hydrogen
• Ci-io alkyl, Cj.io alkoxy, halogen and trifluoromethyl, and pharmaceutically acceptable salts thereof are disclosed in the patents and applications noted
• the preferred 1 -substituents are alkyl containing one to six carbon atoms and hydroxyalkyl
• the 1- substituent is 2-methylpropyl
• the substituents R 2 ⁇ - R 211 above are generally designated "2-substituents" herein.
• the preferred 2-substituents are hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl
• the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and hydroxyalkyl of one to four carbon atoms. More preferably the 2-substituent is hydrogen, methyl, butyl, propyl hydroxymethyl, ethoxymethyl or methoxyethyl.
• n can be zero, one, or two, n is preferably zero or one.
• a therapeutically effective amount means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine
• the formulations can affect the pharmacokinetics of the IRM such that reduced concentrations
• a pharmaceutical formulation of the invention includes an ERM, a fatty acid, a preservative system and a viscosity enhancing agent such as a carbomer.
• the IRMs include an ERM, a fatty acid, a preservative system and a viscosity enhancing agent such as a carbomer.
• the amount of IRM is preferably
• IRM amount does not exceed about 5% by weight and most preferably is about 0.1 to
• a pharmaceutical formulation of the invention is an oil in water
• the oil component of the formulation includes an IRM and a fatty acid.
• fatty acid is present in the formulation in an amount sufficient to solubilize the IRM. This is generally about 2 % to about 45 %, typically about 10 % to about 30 %, and preferably about 15% to about 18% based on the total weight of the formulation. Fatty acids such as isostearic acid are suitable for the formulations. Alternatively, the IRM can be solubilized
• a pharmaceutical formulation of the invention can also include an emulsifier such
• Suitable surfactants include, for example, polysorbate 60,
• surfactants such as Poloxamers (e.g., Pluronic F68 available from Pluronic F68 available from Pluronic F68).
• sorbitan trioleate e.g., Span 85 available from Sigma Chemical Co., St. Louis, MO
• the non- ionic surfactant is typically present in an amount of about 0.5% to about 10% of total
• the total emulsifier content does not exceed about 5% of total formulation weight, and is more preferably about 3.5% of total formulation weight.
• a formulation of the invention can also include a viscosity enhancing agent such as a carbomer, preferably having mucoadhesive properties.
• a viscosity enhancing agent such as a carbomer, preferably having mucoadhesive properties.
• the carbomer can be present in
• Suitable carbomers include polyacrylic acids such as Carbopol 934P, Carbopol
• carbomer is Carbopol 974P.
• the formulation can also include a chelating agent.
• chelating agent functions to chelate metal ions. If present, unchelated metal ions can
• a preferred chelating agent is disodium ethylenediaminetetraacetate (EDTA) in a concentration of about .0001 to about 0.5%, typically about .0005 to about 0.1% per total formulation weight.
• EDTA disodium ethylenediaminetetraacetate
• a preservative such as methylparaben, sorbic acid, propylene glycol, etc. can also be used as a preservative.
• methylparaben and sorbic acid are each provided
• formulation weight and propylene glycol is present in amounts up to about 30%, preferably
• the methylparaben and sorbic acid can be solubilized in propylene glycol prior to adding to the formulation.
• the remainder of the pharmaceutical formulation can be comprised of water to
• the carbomer In addition to providing mucoadhesive properties to the formulation, the carbomer also increases viscosity by forming a stabilizing gel. Many factors, such as the amount of
• Suitable inorganic bases include, for example, KOH, NaOH, etc.
• the pH for a pharmaceutical formulation of the invention is typically about pH 3.0 to
• pH 7.0 preferably about pH 4.0 to about pH 6.0.
• compositions can be applied topically, particularly
• Mucosal surfaces include
• mucosal membranes such as buccal, gingival, nasal, tracheal, bronchial, gastrointestinal,
• IRM may extend only to the superficial layers of the mucosal surface or to tissues deep to the surface.
• the disclosed IRMs can be topically applied to the vaginal or supravaginal region of the cervix for treatment of dysplastic conditions such as cervical
• the above described formulations are particularly advantageous for cervical application of an IRM for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic abso ⁇ tion of the IRM.
• Papanicoulaou Test (Pap smear) is the screening test which has been accepted since the 1950s as the method to detect abnormal cells of the cervix, including inflammation and dysplasia, which includes cervical cancer. This screening test has been
• the etiologic agent for cervical cancer was originally thought to be the he ⁇ es
• HPV human papillomavirus
• Th-1-Type Response the cell- mediated immune response
• the inventors foresee the topical application of IRMs
• cervical intraepithelial for the non-invasive treatment of cervical conditions including cervical intraepithelial
• IRM intravaginal application of a herein disclosed IRM is preferred.
• the IRM can be applied
• an IRM can be formulated as a suppository and administered intravaginally using a suppository applicator.
• a suitable suppository applicator includes
• Formulations according to the invention can also be administered using a barrel type applicator.
• An example of a suitable barrel type applicator can be found in U.S. Patent No. 5,282,789, the disclosure of which is inco ⁇ orated herein by reference.
• an IRM can be administered directly to the cervical mucosa.
• the IRM can be topically applied to the cervical mucosa by using a direct cervical applicator, such as a cervical cap.
• a direct cervical applicator such as a cervical cap.
• the cervical cap which is then applied directly over the cervix.
• the IRM is
• a viscosity agent such as a carbomer
• PK was determined by measuring imiquimod and metabolites through 48 hours post- dose and the PD response was determined by serum analysis for the cytokines: tumor
• necrosis factor- ⁇ TNF- ⁇
• IFN- ⁇ interferon-
• IL-1RA interleukin- 1 receptor agonist
• interleukin-6 IL-6
• NPT neopterin
• IL-6 interleukin-6
• NPT neopterin
• This example describes a novel formulation for a vaginal application, that is a stable formulation, with a high viscosity, and well preserved to pass the EP preservative effectiveness test (PET) criteria.
• PET EP preservative effectiveness test
• Imiquimod was dissolved in isostearic acid with Span 85.
• Carbopol 974P, propylene glycol, sorbic acid, and methylparaben were dissolved in water.
• Formulations A and B both at 5% w/w imiquimod.
• FIG. 1 is a graph of the results of imiquimod penetration studies of Formulations A and B, of Examples 1 and 2, using hairless mouse skin according to the procedure described in U.S. Patent No. 5,238,944, the entire disclosure of which is inco ⁇ orated
• hairless mouse skin was removed from female hairless mice that were 5 to
• the mouse skin was mounted on a diffusion cell of the type shown in U.S. Patent
• the receptor fluid was HCl receptor fluid such that the receptor fluid contacted the skin.
• the receptor fluid was
• the cell was then placed in a constant temperature (31°C) chamber. To maintain
• the chamber utilized a heat exchanger coupled to a constant temperature
• the receptor fluid was stirred by means of a magnetic stirring bar throughout the experiment to ensure a uniform sample and a reduced
• the entire volume of receptor fluid was removed and immediately replaced with fresh receptor fluid.
• the withdrawn receptor fluid was analyzed for imiquimod content by conventional high pressure chromatography as follows:
• Example 5 Imiquimod transport across nude mouse skin from Formulations C-F at 1% w/w and 3% w/w imiquimod with varied concentrations of isostearic acid (ISA).
• Table 4 below provides the imiquimod concentration, isostearic acid concentration,
• Serum imiquimod concentration versus time profiles were compared in ovariectomized rats after single intravaginal doses of Formulation A or Formulation B.
• the two 5 % w/w formulations were dosed to provide a dose level of 35 mg/kg. After dosing, each rat was collared to prevent removal of the formulation by licking. After about
• Serum was analyzed by HPLC for imiquimod. Mean serum imiquimod
• C max the maximum imiquimod concentration for Formulation B was approximately 1.6 times greater than for Formulation A and the respective area under the curve versus time (AUC) was 3.3 times greater (FIG. 4). Based upon these data, the rate and extent of abso ⁇ tion of imiquimod was greater from Formulation B than from Formulation A.
• Example 7 Preparation of Pharmaceutical Formulation G The w/w% of the ingredients for Formulation G are shown in Table 5.
• the oil phase was then allowed to cool to a temperature of less than 30°C.
• An aqueous phase was prepared as follows. Sorbic acid (30.0 g) and methylparaben (40.0g) were added with stirring to propylene glycol (1000 g). The
• a sodium hydroxide solution was prepared by dissolving sodium hydroxide pellets
• the oil phase was added to the aqueous phase and then the sodium hydroxide
• Carbomer 974 1.00 1.00 1.00 1.00 1.00 1.00
• imidazoquinoline amines imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, and 1,2-bridged imidazoquinoline amines of the present invention can be
• compositions can be particularly advantageous for the disclosed pharmaceutical formulations.

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