WO2000023071A1 - Pharmaceutical formulations useful to treat inflammatory and immune disorders - Google Patents
Pharmaceutical formulations useful to treat inflammatory and immune disorders Download PDFInfo
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- WO2000023071A1 WO2000023071A1 PCT/US1999/024361 US9924361W WO0023071A1 WO 2000023071 A1 WO2000023071 A1 WO 2000023071A1 US 9924361 W US9924361 W US 9924361W WO 0023071 A1 WO0023071 A1 WO 0023071A1
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- WSRLSVWUOBPWAE-IKOFQBKESA-N COc(cc([C@@H](CC1)OC1c(cc1OC)cc(OC)c1OC)cc1CN)c1OCCCSc(cc1)ccc1Cl Chemical compound COc(cc([C@@H](CC1)OC1c(cc1OC)cc(OC)c1OC)cc1CN)c1OCCCSc(cc1)ccc1Cl WSRLSVWUOBPWAE-IKOFQBKESA-N 0.000 description 1
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
Definitions
- the present invention relates generally to drug delivery, and more particularly relates to pharmaceutical formulations and methods for treating inflammatory and immune disorders using the novel formulations.
- the compounds are 2,5-diaryl tetrahydrothiophenes, tetrahydrofurans, and pyrrolidines, 1,3-diaryl cyclopentanes, and 2,4-diaryl tetrahydrothiophenes, tetrahydrofurans and pyrrolidines.
- An exemplary compound is ( ) tr ⁇ «5-2-[5-(N'-methyl-N'-hydroxyureidylmethyl)-3-methoxy-4-/7- chlorophenylthioethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydro furan, sometimes referred to herein as "CMI-392" and shown in the following structural formula:
- CMI-392 a compound that, uniquely, is both a 5-LO inhibitor and a PAF receptor antagonist, has proved to be an extremely effective agent for treating inflammatory and immune disorders, as have the other compounds set forth in the Cai et al. patent.
- the compounds have been found to be particularly useful in treating psoriasis and atopic dermatitis, both chronic inflammatory skin disorders affecting millions of people.
- a number of pharmaceutical compositions containing these drugs have been proposed and prepared. However, there remains a need for a formulation which allows for enhanced penetration of the drug into the skin or mucosal tissue, is stable under typical storage conditions for at least several months, and can be prepared as a cream or other composition containing water, alcohol, or other hydrophilic components.
- SUBSTTTUTE SHEET (RULE 26) to ambient temperature, light, and the like, results in degradation to a discolored melt.
- the instability of the drug has limited its potential for manufacturing and scale-up; in addition, the waxy nature of the material has precluded purification on a large scale.
- Preparation of alcohol-containing or water-containing gels, lotions and creams has not, until now, been possible, as the original form of the drug was unstable in water and other protic solvents.
- many skin permeation enhancers are hydrophilic compounds, e.g., lower alkanols or the like, has prevented the combination of such compounds with CMI-392 in a topical formulation.
- CMI-392 and/or other structurally similar antunflammatory agents as described in the Cai et al. patent, comprising an ointment that is stable to heat, light and moisture, in which the active agent is itself stabilized, and which provides for efficient and effective penetration of the drug into the epidermal and dermal skin layers.
- a new, crystalline form of CMI-392 has been prepared that is stable in a variety of different environments, i.e., is far more stable to heat, light and moisture than the original form of the compound.
- the crystalline form of the drug allows for the preparation of a number of different types of compositions, including ointments, creams, oils, solutions and gels, and the incorporation therein of a variety of components which can serve as vehicles and stabilization enhancers.
- It is another object of the invention to provide a novel pharmaceutical formulation comprising an ointment containing CMI-392 or a structurally similar diaryl- substituted cyclic or heterocyclic compound, in combination with an enhancer
- SUBSTT ⁇ jTE SHEET (RULE 26) composition effective to increase formulation stability and enhance the penetration of the drug into the skin.
- a pharmaceutical formulation in the form of an ointment containing an active agent selected from the group consisting of 2,5-diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines.
- an active agent selected from the group consisting of 2,5-diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl
- Preferred active agents are 2,5-diaryl tetrahydrofurans (exemplary compounds are shown in Formula (I), below, wherein X is O), and a particularly preferred active agent is CMI-392.
- the ointment also contains an enhancer composition comprising an ester, typically an ester that is liquid at room temperature and has a molecular weight of less than about 250. It has been found that such ester-containing enhancer compositions stabilize CMI-392 and other analogous active agents as disclosed herein, and also provide for increased penetration of the drug into and/or through the skin, mucosal tissue or eye.
- Oil-based formulations of the invention also are preferred, particularly oil formulations that contain an alcohol component, especially a branched . ⁇ alcohol such as isopropyl alcohol.
- a novel crystalline form of the active agent is provided.
- the new form of the drug which may be CMI-392 or an alternative active agent as described herein, has enhanced stability and increased compatibility with water, alcohol-containing solutions, and other protic materials.
- this form of the active agent enables preparation of a variety of pharmaceutical formulations such as gels, creams, lotions, solutions, oils, suppositories and the like.
- Methods of using the novel formulations to treat individuals with inflammatory and/or immune disorders are also provided.
- active agents herein are PAF receptor antagonists and 5-lipoxygenase inhibitors
- the methods of use involve treatment of disorders mediated by PAF or leukotrienes.
- Leukotrienes as is known in the art, are produced by the oxidation of arachidonic acid by lipoxygenases, including 5- lipoxygenase, and play a major role in inflammatory and allergic responses.
- FIGS 2a-2c schematically illustrate synthesis of CMI-392 in crystalline form from 3,4,5-trimethoxy benzoic acid, as described in Example 2.
- Figures 3a-3c schematically illustrate an alternative method for synthesizing crystalline CMI-392 using acetovanillone as a starting material, as described in Example 3.
- Figure 4a-4c schematically illustrate an alternative method for synthesizing crystalline CMI-392 using acetyl salicylic acid (aspirin) as a starting material.
- Figure 5 is a DSC of crystalline CMI-392, taken over a temperature range of 25 to 350°C (heating rate 10°C/min.).
- topical administration is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders.
- skin is used herein, as in administration of a topical formulation to "the skin,” it is to be understood that administration to mucosal tissue is intended as a possibility as well.
- Topical delivery is additionally intended to include administration to the eye. Colonic delivery, e.s., by way of an enema solution or suppository is also encompassed herein.
- active agent drug
- drug pharmaceutically active agent
- the terms include derivatives, analogs and prodrugs of such compounds, as well as pharmaceutically acceptable salts, esters, amides, and the like.
- effective amount of a drug is meant a nontoxic but sufficient amount of a compound, to provide the desired effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
- vehicle and “carrier” as used herein refer to pharmaceutically acceptable vehicles and carriers.
- topical vehicle or “topical carrier” as used herein specifically refer to a vehicle suitable for topical application of a drug.
- PAF receptor antagonist refers to a compound that binds to a PAF receptor with a binding constant of 30 :M or lower.
- 5-lipoxygenase inhibitor refers to a compound that inhibits the enzyme at 30 ⁇ M or lower, as may be evaluated in a broken cell system.
- enantiomerically enriched composition refers to a composition that includes at least 95% by weight of a single enantiomer of the compound.
- alkyl refers to a saturated straight chain, branched or cyclic hydrocarbon group of 1 to 10 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, M-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
- lower alkyl intends an alkyl group of one to six carbon atoms, and includes, for example, methyl, ethyl, /z-propyl, isopropyl, w-butyl, isobutyl, t- butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
- alkenyl refers to a branched, unbranched or cyclic (in the case of C 5 and C 6 ) hydrocarbon group of 2 to 10 carbon atoms containing at least one double bond, such as ethenyl, vinyl, allyl, octenyl, decenyl, and the like.
- lower alkenyl intends an alkenyl group of two to six carbon atoms, and specifically includes vinyl and allyl.
- alkynyl refers to a branched or unbranched hydrocarbon group of 2 to 10 carbon atoms containing at least one triple bond, such as acetylenyl, ethynyl, ..-propynyl, isopropynyl, n-butynyl, isobutynyl, t-butynyl, octynyl, decynyl and the like.
- lower alkynyl intends an alkynyl group of two to six carbon atoms, and includes, for example, acetylenyl and propynyl.
- lower alkylamino refers to an amino group that has one or two lower alkyl substituents.
- aryl refers to phenyl or substituted phenyl, wherein the substituent is halo or lower alkyl.
- halo is used in its conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
- haloalkyl refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
- heterocycle or “heteroaromatic,” as used herein, and unless otherwise specified, refer to an aromatic moiety that includes at least one sulfur, oxygen or nitrogen atom in the aromatic ring.
- moieties include, but are not limited to, pyrryl, furyl, pyridyl, 2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl and isoxazolyl.
- aralkyl refers to an aryl group with an alkyl substituent.
- alkaryl refers to an alkyl group that has an aryl substituent.
- Optional or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
- the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
- the topical pharmaceutical formulations of the invention contain, as the active agent suitable for treating inflammatory and/or immune disorders, a diaryl-substituted cyclic or heterocyclic compound as described in U.S. Patent No. 5,434,151 to Cai et al,
- SUBSTTTUTE SHEET (RULE 26) cited earlier herein.
- Such compounds are 2,5-diaryl tetrahydrothiophenes, tetrahydrofurans, and pyrrolidines, 1,3-diaryl cyclopentanes, and 2,4-diaryl tetrahydrothiophenes, tetrahydrofurans and pyrrolidines.
- the compounds have the structural formulae (I), (II) or (III):
- R 1 and R 2 are independently selected from the group consisting of: hydrogen; lower alkyl, e.g., methyl, cyclopropylmethyl, ethyl, isopropyl, butyl, pentyl and hexyl;
- R 3 and R 4 are independently alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, hydrogen, alkyl, C,. 6 alkylthio-C,. 10 alkyl; and C,. 10 substituted alkyl (wherein the substituent is independently hydroxyl or carbonyl, located on any one of C,.
- Ar 3 and Ar 4 are independently
- W is independently:
- R 3 , R 4 and R 5 are as defined above, R 6 is lower alkyl, lower alkenyl, lower alkynyl, aralkyl, halogenated lower alkyl, halogenated lower alkenyl, halogenated lower alkynyl or aryl, R 7 is an organic or inorganic anion, R 19 is hydrogen, lower alkyl or lower alkenyl, R 20 is hydrogen, halogen, lower alkoxy or lower alkyl, "M” is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group, and "A" is alkyl, alkenyl, alkynyl, alkaryl, aralkyl, halogenated lower alkyl, halogenated lower alkenyl, halogenated lower alkynyl, ., 0 alkyl(oxy)-C 1 .
- a heterocycle including but not limited to, pyrryl, furyl, pyridyl; 1,2,4- thiadiazolyl; pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl and isoxazolyl, optionally substituted with a group described in preceding paragraph, (2);
- X' is halo such as F, Cl, Br and I; -C(0)aryl; CF 3 ; -OR 3 ; -OC(O)NH 2 ; -CR 3 R 3 R 4 ; -C(O)R 3 ; -CH 2 OR 3 ; -CH 2 CO 2 R 3 ; -CH 2 OC(O)R 3 ; R 3 CH(R 3 )CH 2 SO 3 -; -NHCH 2 COOR 3 ; -NR 3 R 3 R 4 R 7' ; -NR 3 SO 2 R 3 ; -COR 3 ; -NO : ; -CN;
- R 13 , R 14 and R' 3 independently represent:
- B is -CH 2 -oxacyclopropyl, -CH 2 OR 3 , -CH 2 C(O)R 3 , - CH 2 CH(R 3 )R 3 , -CH 2 .aryl, -CH 2 CH(OH)-CH 2 OH; R 3 C(R 3 ) 2 CH 2 SO 2 ; or R ,3 -R 14 or R 14 -R 15 are joined together to form a bridge such as -OCHR 2 CHR 2 -S(0) n , wherein n is 0 to 3.
- R 1 through R 8 and R'° are as defined above;
- R" is phenyl-S(0) g -lower alkyl-; (RO) d -phenyl-S(0) admir-lower alkyl-; (R 3 R 3 N) d - phenyl-S(O) g -lower alkyl-; (CN) d -phenyl-S(0)_-lower alkyl-; (halo) d -phenyl-S(O) g -lower alkyl-; (R 3 COO) d -phenyl-S(0) g -lower alkyl-; (ROCO) d -phenyl-S(0) g -lower alkyl-; (R 3 CO) d -phenyl-S(0) g -lower alkyl-; (R 3 CO) d -phenyl-S(0) g -lower alkyl-; (R 3 CO) d -phenyl-S(0) g -lower alkyl-;
- R 12 is alkyl; substituted alkyl wherein the substituent is selected from the group consisting of hydroxyl- and amino; -lower alkyl-O-R 18 , wherein R 18 is -PO 2 (OH) " M " or - PO 3 (M “r ) 2 wherein M” is a pharmaceutically acceptable cation; -C(0)(CH 2 ) 2 CO 2 " M * or -
- Q is selected from the group consisting of substituted C, to C 12 alkyl wherein the substituent is selected from the group consisting of hydroxy and amino, alkylcarbonylalkyl, alkyl; lower alkyl S(O) m -lower alkyl in which m is 1 or 2; imidazolyl lower alkyl, morpholinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, imidazolylcarbonyl, morpholinyl carbonyl, amorpholinyl (lower alkyl) aminocarbonyl, N-pyrrylpyridinyl-lower alkyl; pyridylthio-lower alkyl; morpholinyl-lower alkyl; hydroxyphenylthio-lower alkyl; cyanophenylthio-lower alkyl; imidazolylthio-lower alkyl; triazolylthio-lower alkyl;
- M + is a pharmaceutically acceptable cation; -C(O)(CH 2 ) 2 CO 2 " M + , or - SO 3 " M + ; -lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl, -lower alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl, wherein the amine substituents each independently represent lower alkyl; pyridyl-lower alkyl; imidazolyl-lower alkyl; imidazolyl-Y -lower alkyl wherein Y is thio or amino; morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl, piperidinyl-lower alkyl; morpholinyl- lower hydroxyalkyl; N-pyrryl; piperazinyl-low
- m is 1, 2 or 3, n is 1 or 2, p is 0 or 1; in Formula (II) compounds, m is as just defined, and t is 1, 2, 3 or 4. In Formula (HI) compounds, m and n are as just defined, and v is 0, 1 or 2.
- R 21 is H or OH
- R 22 is H or OH
- R 23 is lower alkyl, preferably C, to C 4 alkyl
- R 24 is S or SO 2
- R 25 is lower alkyl, lower alkoxy or halide.
- a particularly preferred compound is ( ⁇ ) tran_;-2-[5-( ⁇ '-methyl- ⁇ '- hydroxyureidyl-methyl)-3-methoxy-4-jr.-chlorophenylthioethoxyphenyl]-5-(3,4,5- trimethoxyphenyl)tetrahydro furan, CMI-392 :
- Additional particularly preferred compounds, structural variants of CMI-392 are ( ⁇ ) tran_--2-[5-(N'-methyl-N'-hydroxyureidylmethyl)-3-methoxy-4-/.- chlorophenylthiopropoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, ( ⁇ ) trans-2- [5-(N'-methyl-N'-hydroxyureidylmethyl)-3-methoxy-4-/.- fluorophenylthioethoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, and ( ⁇ ) trans- 2-[5 -(N' -methyl-N' -hydroxyureidylmethyl)-3 -methoxy-4-/. -fluorophenylthiopropoxy- phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, shown structurally as follows:
- the active agent may be in the form of a pharmaceutically acceptable salt, ester, amide, prodrug, or other derivative or analog, or it may be modified by appending one or more appropriate functionalities to enhance selected biological properties. Such modifications are known in the art and include those which increase the rate of penetration into the skin or mucosal tissue, increase bioavailability, increase solubility, and the like.
- the active agent may be in enantiomerically pure or enantiomerically enriched form, or it may be incorporated into the formulations herein as a racemic mixture of enantiomers.
- the active agent may be converted into a pharmaceutically acceptable salt using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).
- Acid addition salts are prepared from the free base using conventional means, involving reaction with a suitable acid.
- the base form of the compound is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added at a temperature of about 0°C to about 100°C, preferably at ambient temperature.
- the resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent.
- Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- organic acids e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
- An acid addition salt may be reconverted to the free base by treatment with a suitable base.
- Basic salts of acid moieties which may be present on the active agent can be prepared in a similar manner using pharmaceutically acceptable inorganic or organic bases.
- inorganic bases include ammonia and carbonates, hydroxides and hydrogen carbonates of group I and group II metals such as sodium, potassium, magnesium and calcium.
- organic bases include aliphatic and aromatic amines such as methylamine, trimethylamine, triethylamine, benzylamine, dibenzylamine or ⁇ - or ⁇ -phenylethylamine, and heterocyclic bases such as piperidine, 1-methylpiperidine and morpholine.
- the active agent may also be converted into a pharmaceutically acceptable ester. Suitable esters include branched or unbranched, saturated or unsaturated C, to C 6 alkyl esters, for example, methyl, ethyl and vinyl esters.
- esters involves functionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure.
- Esters are typically acyl- substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl.
- Pharmacologically acceptable esters may be prepared using methods known to those skilled in the art and/or described in the pertinent literature. Esters can be reconverted to the free acids, if desired, by using conventional hydrogeno lysis or hydrolysis procedures. Preparation of amides and prodrugs can be carried out in an analogous manner.
- C 3 and C 4 atoms are also chiral, and can also exist as a diastereomeric pair, that is, also as a mixture of four enantiomers.
- the R groups in the active compounds described herein can likewise include chiral carbon atoms and thus, optically active centers. It is sometimes found that one or more enantiomers of a biologically active compound is more active, and perhaps less toxic, than other enantiomers of the same compound. Such enantiomerically enriched compounds are often preferred for pharmaceutical administration to humans. For example, it has been discovered that tr «5-2,5-diaryl tetrahydrothiophene and trans-2,5- diaryl tetrahydrofuran are often more active PAF receptor antagonists than their cis counterparts. Synthesis of the pure trans isomer of CMI-392 is described in the examples herein.
- Recrystallization can be performed at any stage in the preparation of the compound or the final enantiomeric product. If successful, this simple approach represents a method of choice. When recrystallization fails to provide material of acceptable optical purity, other methods can be evaluated. If the compound is basic, one can use chiral acids that form diastereomeric derivatives that may possess significantly different solubility properties.
- Nonlimiting examples of chiral acids include malic acid, mandelic acid, dibenzoyl tartaric acid, 3-bromocamphor-8-sulfonic acid, 10- camphorsulfonic acid and di-p-toluoyltartaric acid.
- acylation of a free hydroxyl group with a chiral acid also results in the formation of diastereomeric derivatives whose physical properties may differ sufficiently to permit separation.
- Example 1 A first method for synthesizing CMI-392 is described in detail in Example 1. Briefly, the method involves synthesis of 3,4,5-trimethoxyphenylvinylketone from 3,4,5- trimethoxy-acetophenone, reaction of the vinyl ketone with an appropriately substituted iodobenzaldehyde, reduction of the dione so produced with sodium borohydride, and successive synthesis of the two side chains, (1) the para-chlorophenylthioethoxy group, followed by (2) the N'-methyl-N'-hydroxy-ureidylmethyl moiety.
- the method readily lends itself to scale-up, as demonstrated in Example 4.
- a preferred form of the active agent is a novel crystalline form now provided using the synthetic methods, purification techniques and reagents described infra.
- One method for synthesizing and purifying this novel crystalline form of the active agent herein is set forth in Example 2.
- Alternative methods of preparing pure crystalline CMI-392 using acetovanillone or aspirin as starting materials are described in the Examples and Drawings which follow.
- CMI-392 analogs and derivatives particularly those compounds having Formula (I), (II) or (III), may also be synthesized using the methods described in the present examples, by making minor modifications to the starting compound(s) and/or reactants used.
- a pharmaceutical formulation is provided as an ointment containing an active agent having the structural formula (I), (II) or (III) as defined in the preceding section.
- the ointment contains approximately .01 to 10 wt.%, preferably 0.5 to 8 wt.%, more preferably 4 wt.% to 8 wt.%, and optimally 4 wt.% to 6 wt.%, active agent, which may or may not be in crystalline form.
- the ointment also contains a skin penetration enhancer or a combination of enhancers for increasing the rate at which the active agent permeates into and/or through the skin or mucosal tissue.
- the enhancer also stabilizes the drug, i.e., renders it less sensitive to heat and/or moisture.
- the active agent in the ointment composition in a form other than the novel crystalline structure described in the preceding section, the ointment will contain less than about 5 wt.%, preferably less than about 1 wt.%, most preferably less than about 0.5 wt.%, protic solvents that are liquids at temperatures of less than about 30°C, e.g., water, lower alkanols, and the like.
- the active agent is not in crystalline form, then, it is necessary that the ointment be essentially anhydrous.
- a preferred ointment contains an enhancer composition comprising at least one component which is a saturated mono functional or polyfunctional ester which may be either open-chain or cyclic.
- an enhancer composition comprising at least one component which is a saturated mono functional or polyfunctional ester which may be either open-chain or cyclic.
- Such compounds have been found to enhance the stability of the active agent herein. That is, such esters not only result in a formulation which is chemically and physically stable, but, surprisingly, provide a formulation having greater stability than exhibited by the active agent alone.
- saturated monofunctional or polyfunctional esters serve as delivery aids with the potential to increase the permeation of the active agent into and/or through the skin or mucosal tissue.
- Suitable ester components for incorporation into the enhancer composition are nontoxic organic compounds that are physically and chemically compatible with the active agent and in which the active agent has at least some solubility.
- Preferred esters are liquid at room temperature and have a molecular weight of less than about 250.
- Typical esters contain 3-18 carbon atoms and one to three ester functionalities, and are generally lower alkyl esters or cyclic esters. Particularly preferred esters are diethyl succinate, propylene carbonate (PC), diisopropyl adipate (DIA) and triacetin (also known as glyceryl triacetate). In fact, it has been found that these latter four esters work exceptionally well in combinations, to provide optimal enhancement of stability.
- the pharmaceutical formulations herein contain on the order of 0.02 wt % to 50 wt.%, preferably on the order of 0.02 wt.% to 20 wt.%, of the enhancer composition.
- the agent should be at least about 15% (w/w) soluble in the ester component.
- the active agent and enhancer composition are present in an ointment base.
- ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
- ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency.
- an ointment base should be inert, stable, nonirritating and nonsensitizing.
- ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
- Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
- Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
- Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, lanolin and stearic acid.
- Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy for further information. Any of the aforementioned ointment bases may be used herein, although white petrolatum is preferred.
- the formulation may contain various additives, known to those skilled in the art.
- additives include emulsifiers, solubilizing agents, opacifiers, anti-oxidants, anti-microbial agents, gelling agents, thickening agents, stabilizers, and the like.
- Preparation of ointments will employ conventional techniques of drug formulation, particularly topical drug formulation, which are within the skill of the art. Such techniques are fully explained in the literature. See Remington: The Science and Practice of Pharmacy, cited supra, as well as Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. (New York: McGraw-Hill, 1996).
- the ointment base e.g., petrolatum or the like, is warmed, combined with all
- SUBSTT ⁇ JTE SHEET (RULE 26) components to be incorporated into the final formulation, and mixed thoroughly.
- the active agent is typically, although not necessarily, dissolved in the ester penetration enhancer and added last. After sufficient homogeneity has been achieved, the ointment is cooled. It may be desirable to perform the process under an inert atmosphere, e.g., under argon.
- compositions are provided that may or may not be ointments, and that contain the crystalline form of the active agent.
- the active agent is less sensitive to moisture and chemical attack by protic solvents or reagents. Accordingly, in this embodiment, a variety of formulation types are provided containing any number of carriers, vehicles, enhancers, and the like.
- compositions containing the active agent in crystalline form may be in the form of a lotion, cream, paste, gel, solution, oil, powder, suppository, ointment or the like.
- the formulations contain carriers, excipients and the like which are generally suited to topical drug administration, including any such materials known in the art. It is essential, clearly, that the selected carrier not adversely affect the active agent or other components of the formulation.
- suitable topical carriers for use in combination with the crystalline form of the active agent include, but are not limited to, water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, and waxes.
- Lotions are preparations to be applied to the skin or muscosal surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base.
- Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type.
- Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds
- SUBSTT ⁇ JTE SHEET RULE 26 useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethylcellulose, or the like.
- Creams are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
- Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
- the oil phase also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
- the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
- oil formulations of the invention are preferred.
- oil formulations that contain an alcohol component especially a C 2 alcohol, or more preferably a C,. 8 or C, .6 alcohol are preferred.
- Branched alkyl alcohols such as alcohols that have one, two, three or more secondary and/or tertiary carbon and/or alcohol groups, also are preferred for use in oil compositions of the invention.
- Use of isopropyl alcohol in oil compositions of the invention can provide unexpected storage stability. See, for instance, the results of Example 15 which follows.
- Preferred oil formulations contain from 1 to about 30 weight percent of isopropyl alcohol or other branched alkyl alcohol based on total weight of the formulation, more preferably from about 5 to about 15 weight percent of isopropyl alcohol or other branched alkyl alcohol based on total weight of the formulation, still more preferably about 10 weight percent of isopropyl alcohol or other branched alkyl alcohol based on total weight of the formulation.
- oil compositions of the invention include e.g., propylene glycol dicaprylate/dicaprate (available under tradename of Miglyol 840), ethyl oleate, triacetin, and diisopropyl adipate caprylic/capric triglyceride (available under tradename of Miglyol 812).
- the formulation may also be in the form of a gel.
- gels are semisolid, suspension-type systems.
- Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
- compositions of the invention are typically sprayed on to the skin using conventional means, as will be appreciated by those skilled in the art.
- the pharmaceutical compositions of the invention may also be in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
- Compositions for administration to the colon may also be in the form of enema solutions, comprising standard vehicles used for such solutions, typically aqueous vehicles.
- the active agent is present in an amount representing 0.01 to 10 wt.%, preferably 0.5 to 8 wt.%, more preferably 4 wt.% to 8 wt.%, and optimally 4 wt.% to 6 wt.%, of the composition. Also, it is desirable that an enhancer composition be incorporated as described in part (A) of this section, containing one or more esters.
- the composition contain some isopropyl alcohol, generally up to about 10 wt.%, preferably in the range of 0.1 wt.% to 10 wt.%, more preferably in the range of 0.5 wt.% to 7.5 wt.%, as this has been found to enhance the stability of the formulation.
- the active agent used to prepare the formulation is in crystalline form
- other components may be incorporated into the formulations as well, i.e., vehicles and additives which could react with or otherwise destabilize the "original" form of the drug (i.e., the waxy solid discussed earlier herein).
- standard permeation enhancers can be included, such as, for example, dimethylsulfoxide (“DMSO”), dimethyl formamide (“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide (“C I0 MSO”), polyethylene glycol monolaurate (“PEGML”), glycerol monolaurate, lecithin, the 1 -substituted azacycloheptan-2-ones, particularly ⁇ -n- dodecylcyclazacycloheptan-2-one (available under the trademark Azone from Durham Pharmaceuticals, Durham, NC), ethanol, and the like.
- Other types of additives can be included as well, as discussed in the preceding section, i.e., solubilizing agents, opacifiers, anti-oxidants, etc.
- the present pharmaceutical formulations may also be delivered to the skin using conventional "transdermal" patches, wherein the formulation is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin.
- the drug composition is contained in a layer, or "reservoir," underlying an upper backing layer.
- the laminated structure may contain a single reservoir, or it may contain multiple reservoirs.
- the reservoir comprises a polymeric matrix of a pharmaceutically acceptable adhesive material that serves to affix the system to the skin during drug delivery.
- suitable adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
- the adhesive selected will depend on the particular drug, vehicle, etc., i.e., the adhesive must be compatible with all components of the drug-containing composition.
- the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.
- the backing layer in these laminates serves as the upper surface of the device.
- the material selected for the backing material should be substantially impermeable to the drug and any other components of the drug-containing composition, thus preventing loss of any components through the upper surface of the device.
- the backing layer may be either occlusive or nonocclusive, depending on whether it is desired that the skin become hydrated during drug delivery.
- the backing is preferably made of flexible elastomeric material, e.g., polyethylene, polypropylene, polyesters, or the like.
- the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device so that the system may be affixed to the skin.
- the release liner should be made from a drug/vehicle impermeable material.
- compositions of the invention are useful for treating humans and animals suffering from inflammatory and/or immune disorders, and, in particular, disorders mediated by PAF or products of 5-lipoxygenase.
- the compositions find utility in the treatment in inflammatory skin disorders, including, but not limited to, psoriasis, contact dermatitis, atopic dermatitis (also known as allergic eczema), exfoliative dermatitis, seborrheic dermatitis, erythemas (including erythema multiforme and erythema nodosum), discoid lupus erythematosus and dermatomyositis.
- the compounds and compositions of the invention are particularly effective in treating psoriasis and atopic dermatitis.
- the formulations are administered topically, to the skin, mucosal tissue or eye, as ointments, creams, gels, solutions, oils, or the like, as described in the preceding section, within the context of a dosing regimen effective to bring about the desired result.
- the formulations may also be administered to the colon, typically as an ointment, enema solution, or suppository, to treat inflammation of the gastrointestinal tract.
- the preferred dose of active agent is in the range of about 0.01 to 300 mg/kg/day, preferably 0.1 to 100 mg/kg/day, more typically about 0.5 to 25 mg/kg/day.
- a dosing regimen involves administration of the selected topical formulation at least once daily, and preferably one to four times daily, until symptoms have subsided.
- reaction mixture was cooled and quenched with water and extracted with ethyl acetate.
- organic layer was washed with water and saturated NaCl solution, dried over MgSO 4 , filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (1.79 g, 90.0%).
- reaction mixture was refluxed for 1 hour, cooled, and then treated with a few drops of 10%> HCl.
- the reaction mixture was poured into 10%> K 2 CO 3 and extracted with ethyl acetate.
- the organic layer was washed with water and saturated NaCl solution, dried over MgSO 4 , filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 93:7 CH 2 Cl 2 /MeOH) (64 mg, 21.2%).
- Quaternary ammonium salt 207 In a 50 L all glass assembly, compound 206 (3.5 kg) was stirred with 6 L of 10% aqueous NaH. The free base thus liberated was extracted with ethyl acetate (2 x 7.5 L). The organic layer was collected and cooled to 0- 5°C. To this cold solution, Mel (1.045 L) was added and stirred for two hours at 0-10°C and then at room temperature for an additional four hours. The solid that separated was filtered and dried under reduced pressure. Quantity obtained, compound 207: 4.1 kg (87.8%). M.p.: 165-170°C.
- the solid, iodovanillin was collected and centrifuged, and washed with water, followed by sodium dithionite (1.0 kg dissolved in 10 L water).
- the dark brown compound was dried in an oven (heated by dry air at 80°C) for 3 hr.
- the crude dark colored iodovanillin (8.50 kg) was taken in a 50 L glass assembly along with isopropanol (17 L) and heated to reflux for 30 min. Half of the material went into solution. The contents were then cooled and the yellow product was collected by centrifuge.
- the pure iodovanillin was dried (90°C for 6 hr). Quantity obtained: 6.5 kg. M.p.: 180-181°C. HPLC: >98% pure.
- the phosphoric acid layer was extracted with benzene (1.0 L), and the benzene layer was washed with water (500 mL), NaHCO 3 solution (2 x 250 mL) and finally with water (500 mL).
- the combined benzene extracts were concentrated to obtain 1.0 kg of crude product.
- the residue was filtered through a silica gel column and eluted with ethyl acetate/ «-hexane (40:60). Fractions containing compound were collected and concentrated to give an oily compound containing a cis - trans mixture of compound 217. Yield: 800 g (c ⁇ s:trans ratio, 40:60).
- the benzene solution containing compound 310 (2 L), prepared in the preceding step, and orthophosphoric acid (130 mL) were placed in a 3 L round bottom flask and refluxed for 2 hours. The contents were cooled to room temperature and the upper benzene layer was decanted. The benzene layer was washed with water (500 mL), 20% sodium bicarbonate (2 x 500 mL) and finally with brine (2 x 500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give an oily compound. Yield: 370 g (94%).
- the solution was seeded with pure trans compound, and left standing at -10°C for 12-14 hours.
- the solid was collected by filtration, washed four times with 20% ethyl acetate in w-hexane, and dried under vacuum for 2 hours.
- the solid thus obtained was thoroughly mixed with the first solid, the mixture suspended in hexane (150 mL), filtered, and dried. Yield: 105 g (45.6%), purity: 97% trans, 1.2% cis, m.p.: 85-86°C.
- the reaction mixture was cooled to room temperature, water (500 mL) was then added, and the organic layer was separated and washed with 10% potassium hydrogen sulfate (1 x 300 mL, 2 x 150 mL), IN NaOH solution (800 mL), brine (4 x 250 mL), 10% potassium hydrogen sulfate solution (200 mL) and finally with brine (500 mL).
- the organic layer was dried over sodium sulfate and concentrated to give an oil. Yield: 105g (98%).
- trimethoxybenzoyl chloride 101 kg dissolved in hot toluene (250 L, 100-110°C) and the remaining aqueous NaOH (32%, 100L) were simultaneously added while maintaining the temperature of the reaction solution below 5°C and pH between 10-11. The contents were stirred for an additional 2 hours at room temperature. The stirring was then stopped and the two layers separated. The aqueous layer was then heated with NH 4 C1 (24 kg) and stirred for 12-14 hours. The solid was then collected by filteration, washed and dried at room temperature. Yield: 62 kg (50.4%), m.p.: 92°C.
- Quaternary ammonium salt 207 In a 100 L all glass assembly, compound 206 (20 kg) was stirred with 40 L of 10% aqueous NaOH. The free base thus liberated was extracted with ethyl acetate (100 L). The organic layer was collected and cooled to 0-5°C. To this cold solution, methyl iodide (12.2 kg) was added in three equal portions and stirred at room temperature for 8-10 hours. The solid that separated was filtered, washed with ethyl acetate (20 L), and dried under reduced pressure. Yield: 22.5 kg (83.5%), m.p.: 180°C.
- the solid, iodovanillin was washed with sodium dithionite (5.0 kg dissolved in 50 L water). The dark brown compound was dried in an oven (heated by dry air at 80°C) for 10-12 hours. The crude dark colored iodovanillin (38.8 kg) was taken in isopropanol (80 L) and heated to 78-82°C for 3 hours. The contents were then cooled to room temperature, the solid collected by filteration, washed with isopropanol (10 L) and dried in the oven (70-75°C for 10-2 hours). Yield: 30 kg (82%), m.p.: 179-180 C.
- the reaction mixture was then quenched with water (1 L) and stirred for 2 hours.
- the organic solvents were removed under reduced pressure and the residue dissolved in benzene (10 L) and washed with water (5 L).
- the aqueous layer was extracted with benzene (2 x 1 L) and the combined organic layers were washed with brine solution (2 x 4 L).
- the organic layer was dried over sodium sulfate (2 kg) and the inorganic salts were collected by filtration. The compound in the filtrate was used without further purification in the next step.
- the upper benzene layer was taken in a separating funnel and washed with water (3 x 2 L), 20% NaHCO 3 solution (2 x 5 L) and finally with bromine (2 x 4 L).
- the benzene solution was then passed through a short bed of silica gel and the solvent removed under reduced pressure to give an oily compound that was used without further purification in the next step.
- reaction mixture was kept undisturbed for another 24 hours and the upper clear solution (8 L) was decanted under nitrogen atmosphere.
- compound 218 1.2 kg
- THF 6 L
- the N,N-dimethylethyl-amine complex prepared in the preceding step is then added slowly during a 1 hour period, and the solution refluxed for 1.5-2 hours.
- the reaction was momtored using TLC (silica gel, solvent system: ethyl acetate and acetone 1:1 ). The contents were then cooled to 0°C, stirred for an additional hour, and quenched with saturated sodium sulfate solution (250 ml).
- n-Hexane (3.9 L) was added to the chilled solution of CMI-392, seeded with pure CMI-392, and left below 0°C for another 12-14 hours.
- the solid was collected by filtration, washed with 5% isopropyl alcohol in n-hexane (1 L) and dried in vacuo for 2 hours.
- the product was recrystallized again from isopropyl alcohol and «-hexane, and washed with 10% isopropyl alcohol in n-hexane (3 x 2 L). Yield: 1.02 kg (75%), HPLC > 98% pure, m.p.: 55-56°C.
- composition no. 28 The effect of isopropanol on drug substance stability was evaluated by preparing a composition containing crystalline CMI-392 and 5 wt.%> isopropanol (composition no. 28) and evaluating stability over time relative to the same composition containing no isopropanol (composition no. 27). Results are set forth in Table 1 :
- the samples were filled into amber vials under an argon headspace.
- composition no. 1 herein containing 6 wt.% crystalline CMI-392 was prepared containing the following components:
- Glyceryl monostearate EP 3.5 wt.%
- the white petrolatum, microcrystalline wax, and glyceryl monostearate were weighed into a stainless steel vessel. The components were warmed until complete melt was achieved (70 °C to 75°C). The mixture was then cooled to approximately 55°C to 60°C, while stirring at low speed. Diisopropyl adipate and propylene carbonate were weighed out in a stainless steel vessel, butylated hydroxytoluene was added, and the mixture was stirred until solution was achieved. CMI-392 was added to the solution, and the mixture was warmed to between approximately 35°C and 45°C to ensure complete dissolution. The CMI-392 solution was then combined with the petrolatum mixture, heated to approximately 60°C and mixed for at least about five minutes. The mixture was then cooled, with continued mixing, to between about 25°C and 30°C.
- the ointment formulation so prepared has a shelf life on the order of eighteen months at room temperature.
- composition No. 2
- Glyceryl monostearate 3.5 wt. %
- Microcrystalline wax 5.0 wt. %
- composition No. 4
- Microcrystalline wax 5.0 wt. %
- Microcrystalline wax 5.0 wt. %
- Microcrystalline wax 5.0 wt. %
- Microcrystalline wax 5.0 wt. %
- composition No. 8
- Triacetin 5.0 wt. %
- Glyceryl monostearate 3.5 wt. %
- Skin penetration was evaluated as follows. Formulations were tested on freshly excised skin obtained from a single pig. The formulations were spiked with C l4 -CMI-392 and penetration was assessed by liquid scintillation counting (LSC). Following euthanasia, skin was harvested from the upper back of Buffalo pigs approximately 40 kg in weight. Excised pig skin was cut with a dermatome to yield a thickness of 0.7 mm, with a range of 0.5-0.9 mm. This "split-thickness" skin was composed of the epidermis and the outer most portion of the dermis containing the papillary dermis. Samples of split thickness skin were attached to penetration cells. The visceral side of the skin sample
- SUBST ⁇ JTE SHEET (RULE 26) was bathed by tissue culture medium which served as a sink for radiolabel that penetrated the skin.
- Different formulations containing the radiolabeled test compound CMI-392 were topically applied in order to obtain three replicates for each of the formulations.
- receptor fluid was replaced.
- the skin surface was decontaminated with a dry cotton ball.
- the stratum corneum was harvested by tape stripping. Tape strips 1 and 2 were combined in one LSC vial and represented a portion of the skin surface residue of the CMI-392 formulations. Strips 3-22 were counted as the stratum corneum.
- the remaining epidermis was separated from the dermis.
- the cotton ball, tape strips, epidermis, dermis and receptor fluid were analyzed for radioactivity.
- Skin penetration results for acetone (reference; 2) and ointment compositions 3 through 7, above, are set forth in Table 3 :
- Results are indicated as the percentage of CMI-392 remaining, i.e., the % of the original quantity of 6.0 wt. %.
- composition no. 9 herein comprising a 5 wt.%) crystalline CMI-392 cream was prepared containing the following components:
- the cream formulation prepared by mixing the above components has a shelf life on the order of two months at room temperature.
- Example 9 Concentrations of the various components were optimized to provide stable formulations, and optimal composition ranges are set forth in Table 6: TABLE 6
- Method of preparation of cream formula Add CMI-392 to Diisopropyl Adipate and warm to about 40°C with stirring to dissolve. Combine remainder of oil phase components as present (Stearyl Alcohol, Brij 72, Brij 721, White Petrolatum, BHT) in separate vessel and warm to melt completely. In a separate vessel warm the Purified
- Isopropyl Alcohol as present and stir well. Cool emulsion to room temperature with stirring.
- CMI-392 oil compositions were prepared containing the following components.
- the ability of the CMI-392 ointment to inhibit ocular inflammation in an allergy model also was assessed.
- Groups of guinea pigs were immunized with ovalbumin and then an ocular challenge was given 14 days later.
- Ointment containing 0.2%o or 2% CMI- 392, or a positive control agent (0.05% levoptha) were administered to the eyes four times per day for the two days prior to challenge, and five times in the three hours immediately prior to the challenge.
- the inflammation was measured by assessing the amount of Evans Blues dye extracted from the eyelids and eyeballs 20 minutes after challenge. As shown in Figure 6b, there was a reduction in the amount of inflammation at both dose levels.
- PAF Platelet activating factor
- leukotrienes are observed in various inflammatory bowel disease, including Crohn's disease, and ulcerative colitis.
- administration of either a PAF receptor antagonist, an inhibitor of leukotriene synthesis, or leukotriene receptor antagonist is effective in reducing the severity of the disease. This effect was observed in both animal models and in clinical studies.
- CMI-392 is a dual-acting compound designed to inhibit both LT production and antagonize PAF binding: when administered topically or intravenously, CMI-392 exerts significantly higher anti-inflammatory activity than single-acting 5-LO inhibitors or PAF receptor antagonists in a number of animal models.
- CMI-392 is an inhibitor of topical arachidonic acid-induced ear edema in the mouse. Arachidonic acid was applied to the mouse ears following i.v. or topical administration of CMI-392, and edema was measured by comparing the average wet weight of the ear punch biopsies obtained from treated and untreated animals. CMI-392 was shown to inhibit arachidonic acid-induced ear edema dose-dependently with an i.v. ED 50 of 1.7 mg/kg and a topical ED 50 of 0.28 mg/ear.
- Topical CMI-392 also resulted in a significant decrease in overall ear mass and inflammatory cell infiltration following both acute and chronic 12-o-tetradecanoyl- phorbol- 13 -acetate (TPA) application: the ED 50 for the acute model was 0.117-0.233 mg/ear, and the ED 50 for the chronic model was 0.552 mg/ear.
- CMI-392 also inhibited UVB irradiation induced erythema in guinea pigs with an ED 50 of 0.92 mg/area.
- the effects of CMI-392 on the prevention of colitis has been assessed experimentally using DSS-induced colitis in the mouse. Groups of animals were fed ad libitum with drinking water containing 5% DSS for six days.
- CMI-392 (at a dose level of 50, 100, 150 or 200 mg/kg/day) in corn oil containing 1% Span 20 was given daily, either by oral gavage or intra-rectally, to groups of mice, starting one day prior to DSS exposure. After four days, signs of acute disease occur with weight loss, diarrhea, and bloody stools. Histological changes include initial shortening of the crypts, then areas of separation of the crypts and muscular is mucosae in the absence of inflammatory infiltrate. After five days the pathological changes become confluent with the appearance of erosions and early hyperplastic epithelium. Inflammation scores are high with neutrophils, lymphocytes, and plasma cells in the lamina limbalium.
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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AU11223/00A AU1122300A (en) | 1998-10-16 | 1999-10-15 | Pharmaceutical formulations useful to treat inflammatory and immune disorders |
EP99955021A EP1123095A1 (en) | 1998-10-16 | 1999-10-15 | Pharmaceutical formulations useful to treat inflammatory and immune disorders |
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US17390398A | 1998-10-16 | 1998-10-16 | |
US09/173,903 | 1998-10-16 |
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WO2000023071A9 WO2000023071A9 (en) | 2000-09-14 |
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PCT/US1999/024361 WO2000023071A1 (en) | 1998-10-16 | 1999-10-15 | Pharmaceutical formulations useful to treat inflammatory and immune disorders |
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EP (1) | EP1123095A1 (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2002089791A2 (en) * | 2001-04-30 | 2002-11-14 | Zouboulis Christos C | Acne treatment with lipooxigenase inhibitors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5434151A (en) * | 1992-08-24 | 1995-07-18 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
US5648486A (en) * | 1992-07-13 | 1997-07-15 | Cytomed, Inc. | Compounds and methods for the treatment of inflammatory and immune disorders |
US5741809A (en) * | 1992-08-24 | 1998-04-21 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular inflammatory and immune disorders |
-
1999
- 1999-10-15 AU AU11223/00A patent/AU1122300A/en not_active Abandoned
- 1999-10-15 EP EP99955021A patent/EP1123095A1/en not_active Withdrawn
- 1999-10-15 WO PCT/US1999/024361 patent/WO2000023071A1/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5648486A (en) * | 1992-07-13 | 1997-07-15 | Cytomed, Inc. | Compounds and methods for the treatment of inflammatory and immune disorders |
US5434151A (en) * | 1992-08-24 | 1995-07-18 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
US5741809A (en) * | 1992-08-24 | 1998-04-21 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular inflammatory and immune disorders |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002089791A2 (en) * | 2001-04-30 | 2002-11-14 | Zouboulis Christos C | Acne treatment with lipooxigenase inhibitors |
WO2002089791A3 (en) * | 2001-04-30 | 2003-12-11 | Christos C Zouboulis | Acne treatment with lipooxigenase inhibitors |
Also Published As
Publication number | Publication date |
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EP1123095A1 (en) | 2001-08-16 |
AU1122300A (en) | 2000-05-08 |
WO2000023071A9 (en) | 2000-09-14 |
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