EP1401437A1 - Immune response modifiers for the treatment of periodontal disease - Google Patents
Immune response modifiers for the treatment of periodontal diseaseInfo
- Publication number
- EP1401437A1 EP1401437A1 EP02742096A EP02742096A EP1401437A1 EP 1401437 A1 EP1401437 A1 EP 1401437A1 EP 02742096 A EP02742096 A EP 02742096A EP 02742096 A EP02742096 A EP 02742096A EP 1401437 A1 EP1401437 A1 EP 1401437A1
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- European Patent Office
- Prior art keywords
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- amines
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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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
Definitions
- the invention is directed to methods for the treatment or prevention of periodontal conditions.
- the invention includes the novel use of immune response modifier compounds to treat or prevent periodontal disease.
- Preferred immune response modifiers are selected from the group of immune response modifiers comprising imidazoquinoline amines, imidazopyridine amines, 6,7 -fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.
- Periodontal disease or periodontitis is an inflammatory disease that results in the destruction of both the hard and soft tissues supporting the teeth and has recently been hypothesized as a risk factor for cardiovascular disease. Beck et al. "Dental Infections and atherosclerosis, "American Heart Journal, JL3:S528-533 (1999). It is estimated that over 10 million people in the United States are currently being treated for the more serious forms of this disease, with approximately 8 billion dollars spent for treatment each year. Clinically, periodontitis is an inflammation of the periodontium and results in inflammation of the gingiva and may result in resorption of alveolar bone and recession of the gingiva. Recession of the gingiva can lead to exposure of the periodontal ligament allowing microorganisms to invade and destroy the ligament.
- Periodontitis include early onset periodontitis (EOP), chronic adult periodontitis (AP), and refractory periodontitis (RP).
- EOP early onset periodontitis
- AP chronic adult periodontitis
- RP refractory periodontitis
- Localized juvenile periodontitis is a form of EOP which occurs in otherwise seemingly healthy adolescents and is associated with infection by A. actinomycetemcomitans.
- "Chronic adult periodontitis” is commonly associated with the presence of B. forsythus, P. gingivalis, many gram-negative asaccharolytic rods, and oral spirochetes. It typically occurs in patients over 35 years of age. Clinically, it resembles acute necrotizing ulcerative gingivitis imposed on rapidly progressive periodontitis. Patients may lose 9 to 12 mm of gingival attachment in as little as six months.
- the present invention provides methods for treating or preventing a periodontal condition comprising administering a therapeutically effective amount of an immune response modifier (IRM) compound directly to periodontal tissue in a patient affected by the periodontal condition.
- IRM immune response modifier
- the IRM compound is selected from the group comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.
- FIG. 1 is a diagram illustrating periodontal anatomy
- FIG. 2 is a graph showing the proportion of Porphyromonas gingivalis in the plaque of infected mice ;
- FIG. 3 is a graph showing bone loss in infected mice
- FIG. 4a is a graph of bleeding index, gingival index and probing depth of a dog pre-treatment.
- FIG. 4b is a graph of bleeding index, gingival index and probing depth of a dog at two weeks post-treatment.
- immune response modifier means a compound which induces the production of one or more cytokines, e.g., Interferon ( ), Tumor
- Necrosis Factor and Interleukin-12, from hematopoietec cells including dendritic cells and/or monocyte/macrophages.
- Examples of such compounds include the CpG oligonucleotides, lipopolysaccharides, polyinosic:polycytidylic acid complexes, and polypeptides and proteins know to induce cytokine production from dendritic cells and/or monocyte/macrophages .
- the JJRM compound is selected from the group comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.
- Methods for preparing such JJ Ms and pharmaceutical compositions containing them are disclosed in, for example, U.S. Patent Nos.
- each tooth consists of three parts, a crown 1, neck 2 and root 3.
- the crown 1 is the part of the tooth that projects above the gingiva 4 and occludes with one or more other teeth in the opposite jaw.
- the neck 2 is the part of the tooth between the crown 1 and the root 3.
- the cemento-enamel junction (CEJ) 5 is the location where the cementum 6 of the root 3 and enamel 7 of the crown 1 meet.
- the root 3 is fixed in the tooth socket 8, or "alveolus”.
- tooth Most of the tooth is composed of dentin 10 that is covered by enamel 7 over the crown 1 and cementum 6 over the root 3.
- the cementum 6 over the root 3 is attached to the alveolar bone 11 by periodontal ligament 13 to form a fibrous joint between the tooth and its alveolus 8.
- peripheral tissues are the tissues surrounding and supporting a tooth and include the periodontal ligament, alveolar bone and gingiva.
- periodontal pocket is a pathologically induced space extending below the cemento- enamel junction (CEJ) and resulting from break down of the alveolar bone and/or periodontal ligament.
- cytokines that are secreted by TH2 cells can activate inappropriate host tissue remodeling enzymes that contribute to the destruction of the connective tissue that holds the teeth to the jaw, and enzymes that cause the resorption of the alveolar bone around the teeth.
- imidazoquinoline amine imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amine compounds have demonstrated potent immunomodulating, antiviral and antitumor (including anticancer) activity, and have also been shown to be useful as vaccine adjuvants to enhance protective immune system response to vaccines. Recently, it has been found that many of these IRM compounds can inhibit TH2 immune responses, as well as enhance
- treatment with IRM compounds can reduce the destruction of the alveolar bone or periodontal ligament. If treatment is administered at an appropriate time before destruction of periodontal tissues begins, the invention can also be used to modulate the patient's immune response to effectively prevent clinical signs of periodontal disease.
- the IRM compositions can have both therapeutic and prophylactic value.
- a "patient” includes humans and animals
- a pharmaceutical composition useful in the method of the invention includes an immune response modifier (IRM) compound.
- IRM immune response modifier
- Preferred compositions include compounds selected from the group of immune response modifiers comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and
- Preferred immune response modifier compounds include lH-imidazo[4,5- c]quinolin-4-amines defined by one of Formulas I-V below:
- R ⁇ is selected from the group consisting of alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, 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, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl 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, alkoxy of one to four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than six carbon atoms;
- R 21 is selected from the group consisting of hydrogen, alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl 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, alkoxy of one to four carbon atoms and halogen, with the proviso that when the benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; and each R ⁇ 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 R ⁇ groups together contain no more than six carbon atoms;
- R 12 is selected from the group consisting of straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of straight chain or branched chain alkyl containing one to four carbon atoms and cycloalkyl containing three to six carbon atoms; and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; and
- R 22 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of straight chain or branched chain alkyl containing one to four carbon atoms, straight chain or branched chain alkoxy containing 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 carbon atoms; and each R 2 is independently selected from the group consisting of straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, and n is an integer from zero to
- R 23 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two 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 carbon atoms; and each R 3 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 branched chain alkyl of one to four carbon atoms, and n is an integer from zero to 2, with the provis
- R 14 is -CHR x R y wherein R y 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 moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when 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 hydroxy alkyl 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 consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and
- R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms; V wherein
- R 15 is selected from the group consisting of: hydrogen; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxy
- Rs and Rx are independently 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 consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
- 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 four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1- pyrrolidino, alkylthio of one to four carbon atoms; and R 5 is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms; and a pharmaceutically acceptable salt of any of the foregoing.
- Preferred 6,7 fused cycloalkylimidazopyridine amine IRM compounds are defined by Formula VI below:
- R 16 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 atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; fluoro- or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloal
- R y 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 moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when 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 26 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 hydroxyalkyl containing one to six carbon atoms, morpholinoalkyl, benzyl, (phenyl)ethyl and phenyl, the 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 halogen; and
- R s and R ⁇ are independently 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 consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
- 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, 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 morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms, and 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 branched chain fluoro- or chloroalkyl containing one to four carbon atoms and at least one fluorine or chlorine atom; and pharmaceutically acceptable salts
- R 27 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 hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, the 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 halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms;
- R 67 and R 77 are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms, with the proviso that R 67 and R 77 taken together contain no more than six carbon atoms, and with the further proviso that when R 77 is hydrogen then R 67 is other than hydrogen and R 27 is other than hydrogen or morpholinoalkyl, and with the further proviso that when R 67 is hydrogen then R 77 and R 27 are other than hydrogen; and pharmaceutically acceptable salts thereof.
- Preferred 1,2-bridged imidazoquinoline amine IRM compounds are defined by Formula Vffl below:
- Z is selected from the group consisting of: -(CH 2 ) P - wherein p is 1 to 4;
- R D is hydrogen or alkyl of one to four carbon atoms
- R E is selected from the group consisting of alkyl of one to four carbon atoms, hydroxy, -OR F wherein Rp is alkyl of one to four carbon atoms, and -NR G R G wherein R G and R' G are independently hydrogen or alkyl of one to four carbon atoms;
- Suitable thiazolo- and oxazolo- quinolinamine and pyridinamine compounds include compounds of Formula LX:
- 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 are each independently: -hydrogen; -X-alkyl; -halo; -haloalkyl;
- R 39 and R 9 form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
- X is selected from the group consisting of -O-, -S-, -NR 59 -, -C(O)-, -C(O)O-
- each R 59 is independently H or C 1-8 alkyl; and pharmaceutically acceptable salts thereof.
- Suitable imidazonaphthyridine and tetrahydroimidazonaphthyridine IRM compounds are those of Formulae X and XI below:
- R110 is selected from the group consisting of:
- R 410 is
- each R310 s independently selected from the group consisting of hydrogen and C ⁇ . 10 alkyl; and each R is independently selected from the group consisting of hydrogen, ⁇ o alkyl, C 1-10 alkoxy, halogen and trifluoromethyl, and pharmaceutically acceptable salts thereof.
- R 111 is selected from the group consisting of: - hydrogen;
- Y is -N- or -CR-;
- R 211 is selected from the group consisting of: -hydrogen; -d.io alkyl;
- each R 311 is independently selected from the group consisting of hydrogen and Q. 10 alkyl; and each R is independently selected from the group consisting of hydrogen, C MO alkyl, Ci-io alkoxy, halogen and trifluoromethyl, and pharmaceutically acceptable salts thereof.
- Additional preferred lH-imidazo[4,5-c]quinolin-4-amines and tetrahydro- 1H- imidazo[4,5-c]quinolin-4-amines include compounds defined by Formulas XII, XIII and XrV below:
- R112 is -al yl-NRs ⁇ -CO-R ⁇ or -alkenyl-NR 312 -CO- R 1 wherein R 4 ⁇ 2 is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: -alkyl;
- R 512 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
- R 212 is selected from the group consisting of: -hydrogen; -alkyl;
- each R 3 i 2 is independently selected from the group consisting of hydrogen; C 1-10 alkyl-heteroaryl; C 1-10 alkyl-(substituted heteroaryl); C 1-10 alkyl-aryl; C 1-10 alkyl- (substituted aryl) and C ⁇ _ ⁇ o alkyl; v is 0 to 4; and each R i2 present is independently selected from the group consisting of C 1-10 alkyl, C ⁇ -10 alkoxy, halogen and trifluoromethyl;
- R ⁇ i3 is -alkyl-NR 313 - SO 2 -X-R 413 or -alkenyl-NR 313 - SO 2 -X-R413 ;
- X is a bond or -NR 513 -;
- R 413 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
- R 213 is selected from the group consisting of:
- each R31 3 is independently selected from the group consisting of hydrogen and . 1 0 alkyl;
- R 513 is selected from the group consisting of hydrogen and - 10 alkyl, or R 413 and R 513 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; v is 0 to 4 and each R 13 present is independently selected from the group consisting of Ci-io alkyl, C 1-10 alkoxy, halogen and trifluoromethyl;
- R ⁇ i4 is -alkyl-NR 314 -CY-NR 514 -X-R4 1 or -alkenyl-NR 3 ⁇ -CY- NR 514 -X- R 414 wherein
- X is a bond, -CO- or -SO 2 -;
- R t ⁇ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
- R 414 can additionally be hydrogen;
- R 214 is selected from the group consisting of:
- each R 314 is independently selected from the group consisting of hydrogen and . 10 alkyl;
- R 514 is selected from the group consisting of hydrogen and C 1-10 alkyl, or R 414 and R 514 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; v is 0 to 4 and each R 14 present is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, halogen and trifluoromethyl, and a pharmaceutically acceptable salts thereof.
- Particularly preferred compounds include l-(2-methylpropyl)-lH-imidazo[4,5- c]quinolin-4-amine (imiquimod), 4-amino-2-ethoxymethyl- ⁇ , ⁇ -dimethyl-lH-imidazo[4,5- c]quinoline-l-ethanol (resiquimod), 2-propyl[l,3]thiazolo[4,5-c]quinolin-4-amine, N-[4- (4-amino-2-butyl- lH-imidazo[4,5-c] [ 1 ,5]naphthyridin- l-yl)butyl]-N' -cyclohexylurea; 2- methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin-4-amine, and l-(2- methylpropyl)- lH-imidazo[4,5-c] [ 1 ,5]naphthy
- the pharmaceutical compositions can be provided in a form suitable for systemic application or in a form suitable for local delivery to the affected site. The latter mode is presently preferred.
- the pharmaceutical compositions can be formulated to provide for delivery of the IRM compound to the treatment site at a predetermined rate, for a predetermined duration, alone, or in combination with other therapeutic or prophylactic agents, for example antibiotics, fluoride sources etc.
- Excipients commonly used to formulate drugs into a suitable vehicle can be incorporated as necessary provided that the excipient does not substantially interfere with the function or stability of the composition.
- Non-limiting examples of forms suitable for the pharmaceutical compositions include enhanced viscosity formulations such as disclosed in U.S. Patent Nos.
- transmucosal patches such as disclosed in U.S. Patent Nos. 5,780,045 and 5,750,134 and PCT Publication WO 00/19987
- microcapsules such as disclosed in U.S. Patent No. 5,500,228
- biodegradable cross-linked hydrolyzed gelatin matrices such as those used in the PerioChipTM (available from Perio Products Ltd., Jerusalem, Israel); dental rinses and dentifrices.
- Excipients such as flavorings, colorants, surfactants, binders can be employed as needed.
- a “treatment site” means the site where the pharmaceutical composition is delivered to the patient.
- Treatment sites are typically local sites proximate to a lesion and generally include the gingival surfaces, periodontal pockets, or any other site that the drug could be delivered to the maxillary or mandibular tissue.
- the composition is typically delivered topically or by placing the composition in the subgingival space (periodontal pocket).
- therapeutically effective amount means an amount of an
- IRM compound sufficient to prevent, reduce or reverse periodontal disease.
- the therapeutically effective amount of an IRM compound for periodontitis will vary depending on such things as the activity of the particular compound, the particular composition administered, the duration of delivery, the frequency of administration, the treatment site, and any other therapeutic agents being coadministered.
- a pharmaceutical composition useful for practicing the methods of the invention can contain from about 0.001% to 5.0% of an IRM compound based on total weight of the pharmaceutical composition. Typically the composition will contain from about 0.01% to 1% of an IRM compound.
- the IRM compound may be present in the pharmaceutical composition as the sole therapeutically active ingredient or in combination with other therapeutic agents such as antibiotics, e.g., penicillins, tetracycline; antiseptics, e.g., chlorhexidine; corticosteroids, e.g., hydrocortisone, betamethasone; nonsteroidal antiinflammatories, e.g., flurbiprofen, ibuprofen, naproxen.
- antibiotics e.g., penicillins, tetracycline
- antiseptics e.g., chlorhexidine
- corticosteroids e.g., hydrocortisone, betamethasone
- nonsteroidal antiinflammatories e.g.,
- Treatment regimens may include administration at least one time per week, typically two to three times per week, or even daily for at least one week, typically two weeks and in some cases three to four weeks.
- the patient can be rechecked according to the common standards of care. Thus recalls can be monthly, every two months and typically every three months. Repeated administration can be provided as needed.
- the IRM compound can be applied to a treatment site in some type of sustained release formulation, such as gels, capsules, patches, biodegradable matrices, etc. for delivery of the IRM compound to the treatment site over a period of about 1-24 hours, typically about 1-8 hours, and in some embodiments, about 1-3 hours. It is also foreseen that in certain situations, a burst of IRM compound can be provided by direct administration, such as by subgingival placement, use of a dentifrice or mouth wash, etc. at the discretion of the clinician.
- the following Examples are provided to further explain the invention through specific description of some embodiments of the invention. The Examples, however, are not intended to limit the scope of the invention.
- Example 1 Treatment of Mice with an IRM
- mice All mice were kept in an animal colony, where they were caged away from other animals. All mice were kept on a 12-hour light/dark cycle and received distilled water ad libitum. Mice within experiments were sex- and age-matched (12-18 weeks at the start of various experiments).
- mice in Groups I-III were given sulphamethoxazole/trimethoprim, 10 ml per pint in deionized water, ad libitum for 10 days before experimentation, followed by 4 days without antibiotics.
- the mice of Groups II-HI were then infected by gavage with 10 9 colony-forming units of live P. gingivalis, in 100 ⁇ l of phosphate buffered saline (PBS) with 2% carboxymethylcellulose, three times at 2 to 4 day intervals as described in Klausen et al, "Two complementary methods of assessing periodontal bone level in rats", Scandinavian Journal of Dental Research, 97, 494-9 (1989).
- PBS phosphate buffered saline
- Subgingival plaque samples were obtained from the molars of mice from all three groups using sterile fine paper points (Johnson and Johnson Dental Products Co. East Windsor, NJ). The points were placed in 1 ml of water that was then tested for total bacteria and P. gingivalis levels by quantitative PCR similar to that described for Bacteroides forsythus in Shelburne et al, "Quantitation of Bacteroides forsythus in subgingival plaque: comparison of immunoassay and quantitative polymerase chain reaction", J. Microbial. Methods, 39:97-107 (2000).
- mice of Groups I and II were dosed by oral gavage twice weekly for seven weeks with either 1 mg/kg or 0.1 mg/kg of resiquimod (4-amino-2-ethoxymethyl- ⁇ , -
- Bone loss around the maxillary molars was assessed by a morphometric method developed for studies of bone loss in mice.
- Baker P.J., et al. "Oral infection with Porphyromonas gingivalis and induced alveolar bone loss in immunocompetent and severe combined immunodeficient mice," Arch. Oral Biol., 39(12): 1035-40 (December
- the sides of the mixing bowl and the mixing blades were scraped.
- the formulation was mixed under vacuum (about 17 in Hg; 4.3 X 10 4 Pa) for about 10 minutes at 36 rpm.
- the resulting gel contained 0.05% resiquimod, 5.0% propylene glycol, 9.5% colloidal silicon dioxide, and 85.45% triacetin.
- Treatment with an IRM gel composition
- the animal was sedated with xylazine at a dose of about 1 mg/kg and its teeth cleaned of supragingival and subgingival plaque.
- the teeth affected by periodontitis were scaled and root planed to remove plaque and calculus from both supragingival (enamel) and subgingival (root) tooth surfaces using an ultrasonic Cavitron® (Dentsply, York, PA) and curets.
- the Cavitron was used to remove gross debris and the curets were used to smooth the root surface. A clean, smooth root surface resulting from the root planing allows epithelial and connective tissue attachment to the root surface during the healing process.
- Root planing was performed to remove residual embedded calculus and portions of cementum from the roots of the teeth to produce a smooth, hard, clean surface.
- the primary objective of scaling and root planing is to restore gingival health by completely removing material from the tooth surface that provokes gingival inflammation; that is, plaque, calculus and altered cementum.
- Scaling and root planing were not done as separate procedures in this Example. The difference between scaling and root planing is only a matter of degree. The nature of the tooth surface determines the degree to which the root surface is scaled or planed.
- gel composition prepared as described above was applied to sites affected by periodontitis.
- composition was placed in the periodontal pocket adjacent to each site using a blunt 27 ga. needle and syringe filled with the composition. In this example a single application of the gel was used.
- the animal was treated with yohimbine at about 0.1 mg/kg to reverse the sedation and the animal was returned to its cage.
- the pockets were examined at weekly intervals for the indicies measured at the time of treatment. Measurement of attachment loss was performed using a standard North Carolina Periodontal probe marked at 1 mm intervals. The probe, which is about 1mm in diameter was inserted into the periodontal pocket to the base. The depth of the pocket
- FIGs. 4a and 4b there was an over all improvement in PD, Bl and GI as a result of the mechanical cleaning of the teeth (compare left hand panels of Baseline graph (FIG. 4a) and 2 Week Post-Treatment graph (FIG. 4b). There was improvement in the Bl and GI of the treated sites compared to untreated sites that is statistically significant (p ⁇ 0.01). (Compare left and right panels of the 2 Week Post-Treatment graph, FIG. 4b). This is due to the IRM treatment.
- a human patient affected with chronic adult periodontal disease can be identified by clinical signs typically including Bl, GI, Probing Depth.
- the human can be treated with a transmucosal patch containing an IRM, prepared as described in Example 4 below, in addition to the standard treatment of scaling and root planing.
- the patient's teeth can be cleaned of supragingival plaque.
- the teeth affected by periodontitis can be scaled and root planed to remove plaque and calculus from both supragingival and subgingival tooth surfaces using known instruments, such as, for example, an ultrasonic Cavitron and curets.
- the Cavitron is used to remove gross debris and the curets are used to smooth the root surface
- transmucosal patch containing about 0.05 -1.0 % of IRM per patch, and prepared, for example, as described in Example
- the transmucosal patches can remain adhered to the gingiva for about 1-24 hours. In a typical situation the patch will remain adhered for about 1-3 hours.
- the patches can be applied two times a week for three weeks. The patient can be reexamined at 1 month after completion of treatment and at three month intervals thereafter. Treatment can be repeated as necessary.
- IRM compound 4-amino-2-ethoxymethyl- , -dimethyl- 1 H-imidazo [4,5-c]quinoline- 1 -
- polyoxyethylene 10 oleyl ether (21.78 g of Brij® 97), propylene glycol (10.00), water (2.89 g), resiquimod (0.10 g) and 2-hydroxy-l-(4-(2-hydroxyethoxy)phenyl)-2-methyl-l-
- propanone (0.55 g of Irgacure® 2959) were combined in a glass jar and then mixed on a platform shaker until a clear liquid composition was obtained.
- the composition contained 0.10% by weight of resiquimod.
- the liquid was knife coated at a wet thickness of 25 mil (635 ⁇ M) onto the non- woven polypropylene side of a trilaminate backing and the exposed surface was covered with a clear polyester ( 1.5 mil, 38 ⁇ M) silicone coated release liner.
- the coated composition was then exposed to UVA light for 8 minutes so that the composition was exposed to a total energy of 2677 mJ/cm 2 .
- the release liner was removed and the exposed surface of the cured composition was laminated to a silicone coated polyester release liner ( 5mil, 127 ⁇ M). Patches (2.05 cm 2 ) were cut from the laminate.
Abstract
Description
Claims
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US29876801P | 2001-06-15 | 2001-06-15 | |
US298768P | 2001-06-15 | ||
PCT/US2002/018944 WO2002102377A1 (en) | 2001-06-15 | 2002-06-14 | Immune response modifiers for the treatment of periodontal disease |
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EP1401437A1 true EP1401437A1 (en) | 2004-03-31 |
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EP02742096A Withdrawn EP1401437A1 (en) | 2001-06-15 | 2002-06-14 | Immune response modifiers for the treatment of periodontal disease |
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EP (1) | EP1401437A1 (en) |
JP (1) | JP2005519849A (en) |
CN (1) | CN1523987A (en) |
CA (1) | CA2449754A1 (en) |
WO (1) | WO2002102377A1 (en) |
Families Citing this family (40)
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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 |
US6541485B1 (en) | 1999-06-10 | 2003-04-01 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6573273B1 (en) | 1999-06-10 | 2003-06-03 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6756382B2 (en) | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6916925B1 (en) | 1999-11-05 | 2005-07-12 | 3M Innovative Properties Co. | Dye labeled imidazoquinoline compounds |
US6664265B2 (en) | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6660735B2 (en) | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Urea substituted imidazoquinoline ethers |
US6525064B1 (en) | 2000-12-08 | 2003-02-25 | 3M Innovative Properties Company | Sulfonamido substituted imidazopyridines |
US6545016B1 (en) | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Amide substituted imidazopyridines |
US6667312B2 (en) | 2000-12-08 | 2003-12-23 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6545017B1 (en) | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Urea substituted imidazopyridines |
US6677348B2 (en) | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Aryl ether substituted imidazoquinolines |
US6664264B2 (en) | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
UA74852C2 (en) | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
WO2003045391A1 (en) | 2001-11-29 | 2003-06-05 | 3M Innovative Properties Company | Pharmaceutical formulations comprising an immune response modifier |
CA2365732A1 (en) | 2001-12-20 | 2003-06-20 | Ibm Canada Limited-Ibm Canada Limitee | Testing measurements |
US6677349B1 (en) | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
US6797718B2 (en) | 2002-06-07 | 2004-09-28 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
US7427629B2 (en) | 2002-08-15 | 2008-09-23 | 3M Innovative Properties Company | Immunostimulatory compositions and methods of stimulating an immune response |
AU2003299082A1 (en) | 2002-09-26 | 2004-04-19 | 3M Innovative Properties Company | 1h-imidazo dimers |
MXPA05006740A (en) | 2002-12-20 | 2005-10-05 | 3M Innovative Properties Co | Aryl / hetaryl substituted imidazoquinolines. |
EP2572715A1 (en) | 2002-12-30 | 2013-03-27 | 3M Innovative Properties Company | Immunostimulatory Combinations |
WO2004078138A2 (en) | 2003-03-04 | 2004-09-16 | 3M Innovative Properties Company | Prophylactic treatment of uv-induced epidermal neoplasia |
EP1603510B1 (en) | 2003-03-13 | 2012-05-09 | 3M Innovative Properties Company | Methods of improving skin quality |
US20040192585A1 (en) | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
EP1617871A4 (en) | 2003-04-10 | 2010-10-06 | 3M Innovative Properties Co | Delivery of immune response modifier compounds using metal-containing particulate support materials |
US7176214B2 (en) | 2003-05-21 | 2007-02-13 | Bristol-Myers Squibb Company | Imidazo-fused oxazolo[4,5-β]pyridine and imidazo-fused thiazolo[4,5-β]pyridine based tricyclic compounds and pharmaceutical compositions comprising same |
CA2536249A1 (en) | 2003-08-25 | 2005-03-10 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
WO2005020995A1 (en) * | 2003-09-02 | 2005-03-10 | 3M Innovative Properties Company | Methods related to the treatment of mucosal associated conditions |
US8871782B2 (en) | 2003-10-03 | 2014-10-28 | 3M Innovative Properties Company | Alkoxy substituted imidazoquinolines |
MXPA06005910A (en) | 2003-11-25 | 2006-08-23 | 3M Innovative Properties Co | Substituted imidazo ring systems and methods. |
WO2005055932A2 (en) | 2003-12-02 | 2005-06-23 | 3M Innovative Properties Company | Therapeutic combinations and methods including irm compounds |
CA2597092A1 (en) | 2005-02-04 | 2006-08-10 | Coley Pharmaceutical Group, Inc. | Aqueous gel formulations containing immune reponse modifiers |
US20100160368A1 (en) | 2008-08-18 | 2010-06-24 | Gregory Jefferson J | Methods of Treating Dermatological Disorders and Inducing Interferon Biosynthesis With Shorter Durations of Imiquimod Therapy |
RS58566B1 (en) | 2008-12-19 | 2019-05-31 | Medicis Pharmaceutical Corp | Lower dosage strength imiquimod formulations and short dosing regimens for treating actinic keratosis |
EP2453747B1 (en) | 2009-07-13 | 2017-08-30 | Medicis Pharmaceutical Corporation | Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts |
US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
WO2019216438A1 (en) * | 2018-05-11 | 2019-11-14 | 株式会社セルテクノロジー | Therapeutic agent for periodontal disease which contains culture supernatant of mesenchymal cell |
EP3921322A4 (en) * | 2019-02-07 | 2022-07-20 | Canwell Biotech Limited | Phosphorus imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof |
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GB9420168D0 (en) * | 1994-10-06 | 1994-11-23 | Boots Co Plc | Therapeutic agents |
US6541485B1 (en) * | 1999-06-10 | 2003-04-01 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
AU2001280546B2 (en) * | 2000-07-13 | 2005-10-20 | Alteon, Inc. | Cyanomethyl substituted thiazoliums and imidazoliums and treatments of disorders associated with protein aging |
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- 2002-06-14 JP JP2003504964A patent/JP2005519849A/en active Pending
- 2002-06-14 EP EP02742096A patent/EP1401437A1/en not_active Withdrawn
- 2002-06-14 CA CA002449754A patent/CA2449754A1/en not_active Abandoned
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CA2449754A1 (en) | 2002-12-27 |
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WO2002102377A1 (en) | 2002-12-27 |
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