Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • 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
• • 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
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• Glaucoma is an eye condition characterized, among other symptoms, by a slow or rapid increase in pressure
• Glaucoma leads to the destruction of the optic nerve fibers and can lead to loss of vision.
• glaucoma One of the major treatments for glaucoma is to reduce intraocular pressure.
• the drugs currently known for the treatment of glaucoma present difficulties of use.
• pilocarpine has local side effects, while active principles such as epinephrine or an adrenergic beta-blocker: timolol, are difficult to use for certain patients suffering from cardiovascular disease or who cannot withstand the effects.
• the present invention relates to the use of a potassium agonist for the preparation of a medicament intended to reduce and / or control the abnormally high intraocular pressure.
• the invention also relates to the use of a potassium agonist in combination with another active ingredient for the treatment of glaucoma.
• the active ingredient used in combination with the potassium agonist compound may be either a beta-adrenergic blocking agent, itself useful for lowering intraocular pressure, or an anti-inflammatory drug, in particular a steroidal anti-inflammatory drug or corticosteroid for the treatment of glaucoma, a side effect of which is an intraocular increase.
• the potassium agonist can be used in combination with a beta-adrenergic blocking agent and a steroidal anti-inflammatory.
• the invention also relates to a set or kit comprising on the one hand a potassium agonist in a topical ophthalmic excipient and on the other hand an anti-inflammatory in an ophthalmic excipient, preferably topical for the treatment of glaucoma.
• the present invention also relates to pharmaceutical compositions containing a potassium agonist and a steroid or a potassium agonist and a beta-adrenergic compound.
• a potassium agonist is called a potassium channel agonist.
• the pharmacological properties of potassium channel agonists are described in Trends in Pharmacological Sciences, 1988, 9, 21-28. Some of these compounds are described in J. Med. Chem., 1986, 29, 2194-2201.
• Potassium agonists are compounds that facilitate the opening of cellular potassium channels. This is reflected, in particular, by a relaxing effect on the smooth muscles.
• the potassium agonist effect of a compound can, for example, be measured by its inhibitory power of spontaneous contractile activities of the isolated portal vein of the rat.
• the potassium agonists whose use is the subject of the present invention are derivatives of chroman, quinoline or
• each of the substituents R 1 to R 10 of each of the indices m, n, p, of each of the groups A, A 1 , A 2 , A 3 , D, E, G, L, M, Q, X , Y, Z relate only to the general formula of the compound in which these substituents, indices or groups are used.
• R 1 and R 2 together form an alkylene group of 3 to 6 carbon atoms - R 3 is OH or OAc
• R 4 is H - or R 3 and R 4 together form a double bond
• R 5 is 1H-pyridone-2 yl-1, 1H- ⁇ yridazinone-6 yl-1, 1H pyrimidinone-2 yl-1, 1H-pyrazinone-2 yl-1, 1H-thiopyridone-2 yl-1, these heterocycles may be partially hydrogenated and may be unsubstituted or substituted 1 or 2 times with A, F, C1, Br, I, OH, OA, OAc, NO 2 , NH 2 , NHAc, COOH or COOA;
• R 6 and R 7 each represent H, A, HO, AO, CHO, ACO, ACS, COOH, C00A, CSOA, ACOO, ACSO, 1-6 C hydroxyalkyl or mercaptoalkyl, N0 2 , NH 2 , NHA, NA 2 , CN, F, C1, Br, I, CF 3 , ASO, ASO 2 , AOSO, AOSO 2 , Ac NH, AO-CO-NH, NH 2 SO, HNA-SO, A 2 , NSO, NH 2 , SO 2 , HNASO 2 , A 2 NSO 2 , NH 2 CO, HNACO, A 2 NCO,
• alk is an alkylene group of 1 to 6 C
• Ac is an alkanoyl of 1 to 8 C or an aroyl of 7 to 11 C; as well as their salts. (C: carbon atom (s))
• Patent applications EP 277611 and EP 277612 describe compounds of formula:
• - R 1 is CN, NO 2 , (C 1 -C 6 ) alkyl -S (O) n or Ar S (O) n
• - Ar is an unsubstituted aromatic or heterocyclic system
• alkyl C 1 -C 2) alkoxy (C 1 -C 2), halogen, CF 3, CN, NO 2, carbonyl (C 1 -C 2) alkyl or
• R 2 H, OH, (C 1 -C 2 ) alkyl, alkoxy (C 1 -C 2 ), halogen or NR 5 R 6
• R 5 and Eg are H, alkyl (C 1 -C 2) alkylcarbonyl or (C 1 -C 2)
• R 3 and I ⁇ are each a C 1 -C 4 alkyl
• - X is (CH 2 ) m unsubstituted or substituted by an alkyl (C 1 -C 2 )
• R 7 is H or C 1 -C 4 alkyl.
• Z represents a halogen or a cyano, acetyl, trifluoroacetyl, nitro, alkylthio, carboxy, phosphono, dialkoxyphosphoryl group,
• - G represents hydrogen, a methyl group or a hydroxyl group
• L and M each independently represent hydrogen or a methyl group, only one of the substituents G, L, M possibly being methyl;
• - Q represents a hydrogen atom, a halogen atom, a methyl group or a hydroxyl group
• one of the substituents R 3 or R 2 is hydrogen, the other is chosen from: an alkylcarbonyl, an alkoxycarbonyl, alkylcarbonyloxy, an alkylhydroxymethyl, a nitro, a cyano, a trifluoromethyl, an alkylsulfinyl, an alkoxysulfonyl, an alkylcarbonylamino , an alkoxycarbonylamino or an aminosulfinyl, an aminosulfonyl or an aminocarbonyl, the amino part being optionally substituted by one or two alkyl or alkysulfinylamino or alkylsulfonylamino, alkoxysulfinylamino or alkoxysulfonylamino or ethylenyl substituted on its terminal part, an alkylcar, or a -C (akyl) NOH or a C (alkyl) NNH 2 , the alkyl radicals
• R 3 and R 4 is hydrogen or an alkyl having 1 to 4 carbon atoms, the other is an alkyl having 1 to 4 carbon atoms or R 3 and R 1 together constitute with the carbon atom to which they are attached a spiroalkyl having 3 to 6 carbon atoms;
• R 5 is hydrogen, an alkyl having from 1 to 3 carbon atoms or an acyl having from 1 to 8 carbon atoms;
• n 1 or 2; the lactarae group being in the trans position relative to the substituent OR 5 .
• a preferred compound is trans cyano-6 dihydro-3,4 dimethyl-2,2 (2-oxo pyrrolidinyl-1) 2 H-benzo (b) pyran-3 ol, which bears the international common name : cromakalime.
• Patent application EP 274 821 describes compounds similar to those of formula (III) above in which the oxo-2 pyrrolidinyl or oxo-2 piperidinyl ring is substituted by a hydroxyl group.
• Patent application EP 91748 describes compounds close to those described in EP 76075.
• alkylcarbonyl alkoxycarbonyl, alkylcarbonyloxy,
• CZ NNH 2 , all alkyl groups containing from 1 to 6 carbon atoms;
• R 1 and R 2 are a nitro, a cyano, an alkanoyl (C 1 -C 3 ) and the other is a methoxy or an amino optionally substituted by 1 or 2 alkyls (C 1 -C 6 ) or by an alkanoyl (C 2 -C 7 )
• - Z is a C 1 to C 6 alkyl
• - X is an oxygen atom, a sulfur atom or a nitrogen atom
• - R is a hydrogen atom, a (C 1 -C 7 ) alkyl, an alkanoyl (C 2 -C 7 ), a phenylalkyl (C 6 -C 10 ), a naphthylcarbonyl, a benzoyl, a benzylcarbonyl, all rings which may be unsubstituted or substituted once or twice by a (C 1 -C 6 ) alkyl, a (C 1 -C 6 ) alkoxy or a halogen atom, or a mono- or bi-cyclic heteroarylcarbonyl.
• Application EP 93535 describes analogous compounds of formula:
• - X can be an oxygen atom or a sulfur atom
• Patent application EP 126 350 describes analogous compounds of formula: in which :
• - X represents an oxygen atom or a sulfur atom
• R 6 represents hydrogen or a C 1 -C 6 alkyl
• R 5 represents hydrogen, an alkyl (C 1 -C 6 ) optionally substituted by a hydroxyl, an alkoxy (C 1 -C 6 ), an alkoxycarbonyl (C 2 -C 7 ) or COOH, or an alkyl (C 1 -C 2 ) optionally substituted with a halogen or alkenyl atom (C 2 -C 7 )
• R 5 + R 6 together form a polymethylene containing 3 or 4 carbon atoms.
• Patent application EP 139 992 discloses similar compounds wherein the substituent in position 3 of the chroman is a group OR 5 wherein R 5 is hydrogen, alkyl (C 1 -C 4 alkyl) or acyl (C 1 -C 8 ).
• Patent application EP 214818 describes neighboring compounds of formula:
• Patent application WO80869 describes compounds of formula
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 have meanings similar to those described above for (III) and (IV).
• Patent application EP 250 077 describes compounds of formula:
• - Y represents a nitrogen atom or if R 3 is a hydroxyl, an alkoxy or an acyloxy, Y represents CH;
• R 1 and R 2 are a hydrogen atom or a C 1 -C 4 alkyl, the other is a C 1 -C 4 alkyl, or R 1 + R 2 represent a polymethylene group in C 2 -C 5
• R 3 represents a hydrogen atom, a hydroxyl, a C 1 -C 6 alkoxy or an acyloxy in CC- - R 4 represents a C 3 -C 8 cycloalkyl or a C 1 -C 6 alkyl,
• R 7 represents a hydroxyl, a C 1 -C 6 alkoxy, an amino, a mono or di-alkyl (C 1 -C 6 ) amino, an alkanoylamino (C 1 -C 7 ), a cycloalkyloxy (C 3 - C 8 ), a cycloalkylamino or a 1,3-dioxo-2-isoindolinyl;
• an alkyl optionally substituted by a halogen, a hydroxyl, an alkoxy (C 1 -C 6 ), an alkoxycarbonyl (C 2 -C 7 ), a carboxy, an amino mono or di-substituted by an alkylamino (C 1 -C 6 ),
• R 6 represents hydrogen or a C 1 -C 6 alkyl
• R 5 + R 6 represent CH 2 (CH 2 ) n Z (CH 2 ) n
• - Z represents CH 2 , O, S or NR
• R is hydrogen, C 1 -C 6 alkyl, (C 2 -C 7 ) alkanoyl,
• phenylalkyl C 1 -C 4
• naphthoyl benzoyl or phenylacetyl (optionally substituted on the phenyl or naphthyl ring, with one or two C 1 -C 6 alkoxy C 1 -C 6 alkyl or halogen ) or a mono or bi-cyclic heteroarylcarbonyl;
• R 5 and R 6 form, with the atoms to which they are linked, a tetrahydroisoquinoline or tetrahydroisoquinol.nethionc group,
• R 3 is hydroxyl, alkoxy or acyloxy
• R 5 is NR 8 R 9 or CH 2 R 10
• R 8 is hydrogen or a C 1 -C 6 alkyl
• R 9 is an alkyl (C 1 - C 6 )
• R 8 + R 9 constitute a C 4 -C 5 polymethylene
• R 6 + R 9 represent (CH 2 ) 2 or (CH 2 ) 3
• R 10 is hydrogen or a (C 1 -C 5 ) alkyl or R 6 + R 10 represent
• Patent EP 120 426 describes compounds of formula:
• one of the substituents R 1 or R 2 represents hydrogen, a
• alkylthiocarbonyl (C 1 -C 6), an alkylthiocarbonyloxy (C 1 -C 6) a mercapto (C 2 -C 7) or a formyl
• R 3 or R 4 is hydrogen or a C 1 -C 4 alkyl, the other is a C 1 -C 4 alkyl or CR 3 R 4 is a spiroalkyl (C 3 -C 8 ) - R 5 is hydrogen, (C 1 -C 3 ) alkyl or acyl (C 1 -C 8 )
• a 1 represents a (C 4 -C 8 ) alkyl
• a 2 represents hydrogen, an OA 4 or OCOA 4 group
• a 3 represents a bicyclic group, a heterocyclic group or a substituted phenyl
• a 4 represents a (C 1 -C 6 ) alkyl optionally substituted by an amino or mono- or di-alkylamino (C 1 -C 6 ) group
• R 3 and R 4 are hydrogen or a C 1 -C 4 alkyl, the other is an alkyl (CPC 4 ) or R 3 and R 4 represent a polymethylene (C 2 -C 5 )
• R 5 represents a hydroxyl, an alkoxy (C 1 -C 3 ) or an alkyloxy (C 1 -C 8 ) - R 2 is hydrogen
• Patent application EP 205 292 describes compounds of formula:
• R 1 or R 2 is hydrogen or a C 1 -C 4 alkyl, the other is a C 1 -C 4 alkyl or R 1 and R 2 together form a polymethylene ( C 2 -C 5 )
• R 3 is hydrogen, a hydroxyl group, a (C 1 -C 6 ) alkoxy or an acyloxy
• R 5 is hydrogen, a (C 1 -C 6 ) alkyl, / optionally substituted 1 to 3 times by a halogen atom, by a hydroxyl, by an alkoxy
• polymethylene C 4 -C 5 ) /, an alkenyl (C 2 -C 6 ), an amino / optionally mono substituted by an alkyl (C 1 -C 6 ), an alkenyl (C 2 -C 6 ) or an alkanoyl ( C 1 -C 6 ) optionally substituted 1 to 3 times with a halogen or a phenyl optionally substituted with an alkyl (C 1 -C 6 ), an alkoxy (C 1 -C 6 ) or a halogen /, an aryl or a heteroaryl both optionally substituted one or more times by an alkyl
• R 5 is a carboxy, an alkoxycarbonyl (C 1 -C 6 ), an aminocarbonyl
• R 6 is hydrogen or C 1 -C 6 alkyl
• Z CH 2 , O, S, or NR
• R represents hydrogen, a C 1 -C 9 alkyl, an alkanoyl (C 2 -C 7 ), a phenylalkyl (C 1 -C 4 ), a naphthylcarbonyl, a phenylcarbonyl or a benzylcarbonyl optionally substituted on the part phenyl or naphthyl with one or two alkyl (C 1 -C 6) alkoxy (C 1 -C 6) alkyl or halogen; - or else R is a heteroarylcarbonyl;
• - - X is oxygen or sulfur
• R 5 , R 6 , X and N together form a tetrahydroisoquinoline, or a tetrahydroisoquinolinethione optionally substituted on the phenyl ring by R;
• Patent application EP 344747 describes compounds of formula:
• R 1 and R 2 each represent a lower alkyl
• R 3 is a hydroxyl or an acyloxy
• Y represents -S -, - O- or a group of formula -N (R 7 ) - in which R 7 is hydrogen, acyl or lower alkyl which may be suitably substituted and R 5 and R 6 are each hydrogen or lower alkyl,
• Y is as defined above and R 5 and R 6 together form a
• YR 5 is a suitably substituted heterocyclic group and R 6 is hydrogen or lower alkyl; and their pharmaceutically acceptable salts.
• Z represents a halogen atom, a cyano, nitro, acetyl, phosphono or dialkoxyphosphoryl group, the alkoxy group containing from 1 to 3 carbon atoms;
• All potassium agonists have the property of being usable for the preparation of medicaments intended for the treatment of glaucoma.
• the compounds (I) described in patent application EP 273262, as well as the compounds (XVI) described in patent application EP 312432, the compounds (III) described in patent application EP 296 975 are favorite. Cyano-6 (1,2-dihydro-2-oxo-pyridyl-1) -4 dimethyl-2,2 chromene described in EP 296 975 is particularly preferred.
• trans-cyano-6 (1,2-chloro-1,2-dihydro-2-oxo-pyridyl-1) -4 dimethyl-2,2 chromannol-3
• trans-cyano-6 (dihydro-1,6 hydroxy- 3-methyl-5 oxo-6 pyridazinyl-1) -4 dimethyl-2,2 chromannol-3
• trans-cyano-6 (dihydro-1,6 hydroxy-3 methyl-4 oxo-6 pyridazinyl-1) -4 dimethyl- 2,2 chromannol-3
• diethylphosphono-6 (1,2-dihydro-1,2-oxo-pyridyl-1) -4 dimethyl-2,2 chromene
• IC 50 inhibitory concentration
• the potassium agonists known in the prior art are prepared by known and described methods, in particular in the aforementioned patents, or by similar methods, derived therefrom.
• the pharmaceutically acceptable salts of the potassium agonists described also form part of the present invention for their use in the treatment of glaucoma.
• compositions according to the present invention are administered in the form of ophthalmic pharmaceutical compositions suitable for topical administration to the eye, such as solutions, suspensions or ointments.
• the formulations according to the invention may contain from 0.000001 to 1% by weight of a potassium agonist, more particularly from 0.00001 to 0.1%.
• Each dosage unit comprises a quantity of potassium agonist between 1 ng and 0.1 mg, preferably between 5 ng and 50 ng.
• control of elevated intraocular pressure means the regulation, the reduction and the modulation of elevated intraocular pressure which is the first symptom allowing the diagnosis of glaucoma.
• the expression also means that the decrease in intraocular pressure obtained according to the invention by the use of a potassium agonist is maintained for a sufficient period of time, for example between the administration of two consecutive doses.
• Potassium agonists can be used in pharmaceutical compositions, either as the only active ingredient intended to reduce intraocular pressure, or in combination with other active ingredients also intended to lower pressure
• a separate mechanism such as a beta-adrenergic blocking agent, timolol, in the form of maleate, for example.
• Timolol is therefore prescribed in the topical treatment of glaucoma at the rate of one or two drops per day of a 0.25 mg / 100 ml or 0.5 mg / 100 ml solution. It is known, however, that this product should be used with caution due to its activity on the cardiovascular system and its side effects.
• the beta-blocker and the potassium agonist are preferably administered together in the form of a composition in a pharmaceutical formulation.
• the unit dosage form preferably contains:
• each of the active ingredients may vary depending on the severity of the disease and the individual response of the patients.
• concentrations of each of the active principles of the composition which make it possible to reduce the intraocular pressure are variable, they have a lower limit below which the composition is inactive. This lower limit is approximately 5% of the effective dose and depends on the potency of the potassium agonist and, possibly, that of the beta-blocker used, the age and size of the patient, as well as the severity of disease.
• Steroidal anti-inflammatory drugs include hydrocortisone, cortisone, flunisolide, beclomethasone, alclomethasone, flunisolide, chlorocortolone, diflorasone, alkinolide, fluocinonide, fluocinolone, deoximethasone, medrysone, parametone dichloro-9,21 / (furanylcarbonyl-2) oxy-17 / hydroxy-11 methyl-16 ⁇ pregnadiene-1,4 dione-3,20 and the
• fluorometholone and their pharmaceutically acceptable salts and esters.
• the rise in intraocular pressure can occur following any mode of administration of these drugs: systemic administration, generally oral, local injection, for example the injection of a delayed form and particularly during an ophthalmic injection. topical or intravitrous.
• a potassium agonist may be administered after steroid therapy to lower the elevated intraocular pressure or it may be co-administered with the steroid to suppress the effect of increasing the intraocular pressure of the steroid, without interfering with its anti-inflammatory activity.
• any combination of dosage forms can be used to administer the combination of the anti-inflammatory steroid and the potassium agonist: both drugs in oral form, or both in topical form, or one in form oral, the other in topical form, or the steroid in the form of a local injection and 1 potassium agonist in topical form; a preferred combination is topical administration of the steroid and potassium agonist. Particularly preferred is a topical ophthalmic composition comprising both the steroid and the potassium agonist.
• the method of reducing and controlling elevated intraocular pressure, associated with the use of a steroidal anti-inflammatory drug systemically or ophthalmically also includes separate administration of this agent and a potassium agonist.
• a kit comprising two separate units: a pharmaceutical composition comprising a potassium agonist and a pharmaceutical composition comprising a steroid.
• a kit comprises a topical ophthalmic composition of potassium agonist and a pharmaceutical steroid composition.
• the kit comprises two topical ophthalmic compositions, one comprising the potassium agonist, the other the steroid.
• a particular advantage of this presentation is that it provides a composition based on potassium agonist which can be administered once or twice a day and a composition based on a steroid which can be administered more often: hourly for example.
• topical formulation can contain
• the potassium agonist represents from 0.000 001% to approximately 1% by weight of the drug, more particularly from 0.000 01 to 0.1%.
• a unit dosage form comprises from 1 ng to 0.1 mg, preferably between 5 ng and 50 ng to be applied to the eye. In each individual case, the amount to be administered and the frequency of administration depend on the potency of the potassium agonist used, the severity of the increase in intraocular pressure to be treated and the response of the patient.
• the steroid represents from 0.05% to about 1.5% by weight of the drug.
• a unit dosage form comprises from 20 ug to 600 ⁇ g to be applied to the eye. In each individual case, the amount to be administered and the frequency of administration depend on the potency of the steroid chosen, the severity of the disease and the response of the patient. For each particular steroid, one can determine which potassium agonist to use and at what concentration.
• the two active principles namely the potassium agonist and the steroid
• the two active principles are administered simultaneously and contained in the same pharmaceutical form, each being present in the pharmaceutical form at its preferred concentration.
• the steroid is administered by systemic or topical route, other than ophthalmic, its dosage may vary depending on the criteria
• kits or pharmaceutical compositions of the invention which contain a potassium agonist in combination with an anti-inflammatory; said potassium agonist can also be associated with a beta-adrenergic blocking compound.
• kits or pharmaceutical compositions which contain the three active principles - potassium agonist, anti-inflammatory, beta-adrenergic blocker - are part of the invention.
• the dosage of said three active ingredients is carried out according to the indications provided above for the formulations with two active ingredients.
• the effect of lowering the intraocular pressure of a pharmaceutical composition according to the invention can be measured according to the method described in J. Ocul. Pharmacol., 1985, / (2), 161-168.
• cyano-6 (1,2-dihydro-2 oxo-2 pyridyl-1) -4 dimethyl-2,2 chromene allows rapid restoration of intraocular pressure to its normal value after said pressure has been increased by iv injection of a 5% glucose solution.
• the pharmaceutical compositions can be mixed with a suitable vehicle for topical ophthalmic administration.
• a suitable vehicle for topical ophthalmic administration As pharmaceutical vehicles acceptable in this case, mention may be made of water, a mixture of water and water-miscible solvents such as lower alkanols, vegetable oils, mineral oils and comprising from 0.5 to 5% by weight. weight of hydroxyethylcellulose, ethyl oleate,
• carboxymethylcellulose polyvinylpyrrolidone and other water-soluble polymers, non-toxic and compatible with ophthalmic use, for example cellulose derivatives such as methylcellulose, an alkali metal derivative of
• acrylates such as salts of polyacrylic acids
• ethylcrylates polyacrylamides, natural products such as gelatin, alginates, pectins, tragacanth, karaya, xanthan, carrageenan, agar, acacia, starch derivatives such as acetate starch, hydroxyethyl starch ethers,
• hydroxypropyl starch as well as other synthetic derivatives such as polyvinyl alcohol, polyvinylpyrrolidone., polyvinyl methyl ether, polyethylene oxide, neutral carbopol or mixtures of these polymers.
• the pharmaceutical preparation can also contain non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, texturing agents and others such as, for example, polyethylene glycols 200, 300, 400, 600, carbowax 1000, 1500, 4000, 6000, 10000, antibacterial products such as quaternary ammonium, phenylmercuric salts known to have cold sterilizing properties without being aggressive, timerosal, propylparaben, benzyl alcohol, phenyl ethanol, isotonic agents such as chloride of alkali metal, borate, acetate or gluconate buffers, antioxidants such as sodium metabisulfite, butylated hydroxyanisol, butylated hydroxytoluene or similar agents and other agents
• the pharmaceutical preparation can also be a suspension in which the particles are polymers soluble in water or insoluble in water.
• a suspension can contain microforms such as microparticles or nanoparticles.
• compositions according to the invention may contain additional therapeutic agents in addition to the potassium agonist.
• antibiotics, anesthetics or other agents that lower the intraocular pressure may be present.
• the constituents of the solution are mixed under the usual conditions to obtain an ophthalmic solution.
• the constituents of the solution are mixed under the usual conditions to obtain an ophthalmic solution.

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• 1989
  • 1989-03-30 FR FR8904180A patent/FR2645021A1/fr active Pending
• 1990
  • 1990-03-30 WO PCT/FR1990/000223 patent/WO1990011758A2/fr not_active Application Discontinuation
  • 1990-03-30 JP JP2506339A patent/JPH04506208A/ja active Pending
  • 1990-03-30 EP EP90906254A patent/EP0465583A1/de not_active Withdrawn

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