CA1207236A - Isosorbide dinitrate solution - Google Patents
Isosorbide dinitrate solutionInfo
- Publication number
- CA1207236A CA1207236A CA000447580A CA447580A CA1207236A CA 1207236 A CA1207236 A CA 1207236A CA 000447580 A CA000447580 A CA 000447580A CA 447580 A CA447580 A CA 447580A CA 1207236 A CA1207236 A CA 1207236A
- Authority
- CA
- Canada
- Prior art keywords
- isosorbide dinitrate
- liquid
- weight
- percent
- formulation according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 title claims abstract description 22
- 229960000201 isosorbide dinitrate Drugs 0.000 title claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000002459 sustained effect Effects 0.000 claims abstract description 9
- 230000000699 topical effect Effects 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 23
- 238000009472 formulation Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- -1 polyhydroxyethylene Polymers 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 claims description 5
- 229940031578 diisopropyl adipate Drugs 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- FCGXLCNBWYIEAA-UHFFFAOYSA-N 1,3-benzothiazol-6-ylmethanamine Chemical compound NCC1=CC=C2N=CSC2=C1 FCGXLCNBWYIEAA-UHFFFAOYSA-N 0.000 claims description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims 1
- 229940074928 isopropyl myristate Drugs 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229960002479 isosorbide Drugs 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical class CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical class CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- OJIBJRXMHVZPLV-UHFFFAOYSA-N 2-methylpropyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(C)C OJIBJRXMHVZPLV-UHFFFAOYSA-N 0.000 description 1
- 208000031968 Cadaver Diseases 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical class CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001517310 Eria Species 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 241000271915 Hydrophis Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical class CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical class [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/335—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
SUSTAINED ACTION PHARMACEUTICAL FORMULATION
Abstract The invention relates to a sustained action pharmaceutical formulation for topical use containing isosorbide dinitrate, characterised in that it contains a) a liquid lipophilic solvent for isosorbide dinitrate and b) a liquid hydrophilic solvent for isosorbide dinitrate in a weight ratio of a:b of between about 0.8 and 0.2, preferably of between about 0.5 and about 0.3.
Abstract The invention relates to a sustained action pharmaceutical formulation for topical use containing isosorbide dinitrate, characterised in that it contains a) a liquid lipophilic solvent for isosorbide dinitrate and b) a liquid hydrophilic solvent for isosorbide dinitrate in a weight ratio of a:b of between about 0.8 and 0.2, preferably of between about 0.5 and about 0.3.
Description
~Z~7Z36 P.C. ~539 SUSTAINED ACTION PEIARMAC~UTICAL_FORMULA'~ION
The invention relates to a sustained action pharmaceu-tical formulation for topical use containing isosorbid~
dinitrate as the active ingredient.
Isosorbide dinltrate is a known active ingredient for the treatment of disturbances of coronary blood supply Attempts have been made over many years to fina methods of administration of this active ingredient such that the active ingredient it gradually absorbed by the organism so that the preparations are suitable for long-term therapy.
In a known commercial preparation, continuous release ox tne active substance is achieved by a particular typo of pelleting. On oral administration of this type of preparatlon in the form of a capsule, uniform high ievels lS of the active ingredienk in the blood are achieved which are maintained for at ]east 8 hours, and the active ingredient is still detectable in tne plasma 12 hours afteL- oral administration.
preparation for topical use for allevlatiny spasms 2a in flexor and extensor muscles is known from U.S Patent Specification 4,112,115, in which the nitrate active ingredient is in khe form of a solution in a pnarmaceu-tically acceptable vehicle. The vehicles recommended art aqueous ethanol and aqueous isopropanol, but skirl creams and hydrophilic ointments are also sail to be possihie vehicles.
'I'
The invention relates to a sustained action pharmaceu-tical formulation for topical use containing isosorbid~
dinitrate as the active ingredient.
Isosorbide dinltrate is a known active ingredient for the treatment of disturbances of coronary blood supply Attempts have been made over many years to fina methods of administration of this active ingredient such that the active ingredient it gradually absorbed by the organism so that the preparations are suitable for long-term therapy.
In a known commercial preparation, continuous release ox tne active substance is achieved by a particular typo of pelleting. On oral administration of this type of preparatlon in the form of a capsule, uniform high ievels lS of the active ingredienk in the blood are achieved which are maintained for at ]east 8 hours, and the active ingredient is still detectable in tne plasma 12 hours afteL- oral administration.
preparation for topical use for allevlatiny spasms 2a in flexor and extensor muscles is known from U.S Patent Specification 4,112,115, in which the nitrate active ingredient is in khe form of a solution in a pnarmaceu-tically acceptable vehicle. The vehicles recommended art aqueous ethanol and aqueous isopropanol, but skirl creams and hydrophilic ointments are also sail to be possihie vehicles.
'I'
-2~ 7~3~
ph~r~ceutical formulation containing isosorbide dini-trat~ is known from the German Offenlegungsschrift ~,924,005, which formulation contains, apart from the active ingredient, a solvent for iso~orbide dinitr~te, an ointment-bodying agent,~ater, optionally an emùlsifier and optionally further customary add.itives, such as pry-serva~ives, antioxidants, pH-regulators and/or perfuminy agents. Those known pharmaceutical Eormulations contain a consider2ble amount o water; the weight ratio of water: -bodying agent: solvent is said to be 30-80: 3 to 35~ 3-35.
In this known pharmaceutical formulation, the isosorbide I dinitrate is present partially in a dissolved state and partially in an undissolved state; a long duration of action is said to be achieved by having a sufficiently ¦ large proportion of undissolved isosorbide dinit~ate.
however, there is the danger with this type of formulation that the crystals of active ingredient, which remain on the skin and have not ye dissolved, are~iped off on the clothing and then are no longer available for gradual ¦ dissolution and absorption. In contrast, the present invention provides a liquid ormulation in which the active ingredient is completely dissolved and which immediately penetrates the skin, and thus can Jo longer be inadvertently removed after administrationr but never-theless gives an outstanding sustained action.
The pharmaceutical formulation according to the invention containing isosorbide dinitrate as the active ¦ ingredient is characterised in that is contains a a liquid lipophilic solvent for isosorbide dinitrate and b) a liquid hydrophilic solvent for isosorbide dinitrate in a weight ratio of a:b of between about 0.8 and about 0.2, preferably of between about 0.5 and about 0.3.
~3- ~2~3~
The liquid lipophilic and hydrophilic solvents suit-able for use in -tne present i,^nvention are those in which isosorbide dinitrate is soluble to an extent of at least about 5% by weight prererably àt least about 8% by weight, and especially at least ab~u~ 10 QO by weight. The pharma~
ceutical formulation accordiny to the invention should contain isosorbide dinitrate in an arnount of about 5 to - about 25~ by weigh! preferably of about 8 to about 15 by sleight.
Suitable liquid lipophilic solvents art alcohols, e.g.
those containing 8-12 carbon atoms such as n-decyl alcohol;
ethers, e.g. those containing 6~10 carbon atoms such as isosorhide dimethyl ether; esters of lower fatty acidst c those containing 4-10 carbon atoms like glycexol triac~-tate; liquid iriglycerides, e.g. those OL fatty acids containing S-18 carbon atoms such as saturated plant atty acids of medium chain length, liquid lipophilic esters of higher fatty acids for example those containing lO-l~ carbon atoms and monohydric aliphatic alcohols, for example, whose containing 2-4 carbon atoms, such as isopropyl myrista~-e, isobutyl steara~e, isobutyl palmitate, isoprop~1 st~arate or isopropyl palmitate; liquid esters of dicarboxylic acids7 for example, those containing 6-lO
carbon atoms and of monohydric alconols for example those containing 2-4 carbon atoms, such as diisopropyl adipate, diethyl sebacate or dibutyl sebacate; liquid esters of aromatic dicarboxylic acids containing 8 carbon atoms and oE monohydric alcohols, for example those containing 2-4 carbon atGmS, such as diethyl phthalate or dibutyl phthalate; liquid esters of tricarboxylic acids, for example, those containing 6 carbon atoms and monohydric alcohols, for example those contai-ning 2-4 carbon atoms, sucn as esters of citric acid, for example tributyl citrate or triethyl acetylcitrate. The preferred lipophilic solvents are diisopropyl adipate, isopropyl myristace and isosorbide dirnethyl etll2r.
-4~ 2~
Suit~le liquid hycruphilic solvents are ~onohydric alcohols, c those cor.t2inin~2-3 carbon ~toms,l~uch a5 ethanol, isopropanol and n-p~dpanol, polyhydric a~ohols~
e.g., those containing 3-6 carbon ztoms, such as propan2diol~
ylycerol, diethylene glycol and triethylene glycol; poly-ethylene glycols, e.g., those having a molecular weight of 200-600; polyhydro~yethylene/polyhydroxyp~opylene condensates, e.g. those having a molecular weight of lsO0-3000, such as the various commercially a~ailahle I liquid Pluronic~ types of Wyandotte Chemicals Corps The preferred hydrophi~ic solvents are said polyethylene glycol and polyhydroxyethylene/polyhydroxypropylene condensatec.
lS Since the pharmaceutical formulation acccrdin~ to the invention should have a low viscosity, only those ¦ liq;lid polyilydroxyethylene/polyhydroxypropylene con-densates are employed which have an appropriateiy low viscositv, e.s. in the range of 250-700 Cp4 A proportion Or one hyd~ophilic solvent advantageously ists of ethanol, preferably about ~0 to about 70~ my ' weight.
The pharmaceutical for,~ula~ions according to the invention should contain eiiher no water or only a very small amount of water. A content of water as is produced by using normal ethanol does not interfere. In general, however r the waxer content ox the formulatior according to the invention should not be greater than about 4~ by w2ight, preferably not greater than about 2~ by weight.
A particularly preferrer formulation according to the invention consis,s of about 10~ by rleight ox isosorb~de dinitrate, about 27% by weight of diisopropyl a~ipate, about 27% by weight of polyethylene glycol 400 and about 36% by rJeight ox ethanol.
The phar~aceuiical formulations according to the invention car. ye used as spraying agents. whey are pre-erabl~ atomised my mea.~s ox â mechanical metering pump
ph~r~ceutical formulation containing isosorbide dini-trat~ is known from the German Offenlegungsschrift ~,924,005, which formulation contains, apart from the active ingredient, a solvent for iso~orbide dinitr~te, an ointment-bodying agent,~ater, optionally an emùlsifier and optionally further customary add.itives, such as pry-serva~ives, antioxidants, pH-regulators and/or perfuminy agents. Those known pharmaceutical Eormulations contain a consider2ble amount o water; the weight ratio of water: -bodying agent: solvent is said to be 30-80: 3 to 35~ 3-35.
In this known pharmaceutical formulation, the isosorbide I dinitrate is present partially in a dissolved state and partially in an undissolved state; a long duration of action is said to be achieved by having a sufficiently ¦ large proportion of undissolved isosorbide dinit~ate.
however, there is the danger with this type of formulation that the crystals of active ingredient, which remain on the skin and have not ye dissolved, are~iped off on the clothing and then are no longer available for gradual ¦ dissolution and absorption. In contrast, the present invention provides a liquid ormulation in which the active ingredient is completely dissolved and which immediately penetrates the skin, and thus can Jo longer be inadvertently removed after administrationr but never-theless gives an outstanding sustained action.
The pharmaceutical formulation according to the invention containing isosorbide dinitrate as the active ¦ ingredient is characterised in that is contains a a liquid lipophilic solvent for isosorbide dinitrate and b) a liquid hydrophilic solvent for isosorbide dinitrate in a weight ratio of a:b of between about 0.8 and about 0.2, preferably of between about 0.5 and about 0.3.
~3- ~2~3~
The liquid lipophilic and hydrophilic solvents suit-able for use in -tne present i,^nvention are those in which isosorbide dinitrate is soluble to an extent of at least about 5% by weight prererably àt least about 8% by weight, and especially at least ab~u~ 10 QO by weight. The pharma~
ceutical formulation accordiny to the invention should contain isosorbide dinitrate in an arnount of about 5 to - about 25~ by weigh! preferably of about 8 to about 15 by sleight.
Suitable liquid lipophilic solvents art alcohols, e.g.
those containing 8-12 carbon atoms such as n-decyl alcohol;
ethers, e.g. those containing 6~10 carbon atoms such as isosorhide dimethyl ether; esters of lower fatty acidst c those containing 4-10 carbon atoms like glycexol triac~-tate; liquid iriglycerides, e.g. those OL fatty acids containing S-18 carbon atoms such as saturated plant atty acids of medium chain length, liquid lipophilic esters of higher fatty acids for example those containing lO-l~ carbon atoms and monohydric aliphatic alcohols, for example, whose containing 2-4 carbon atoms, such as isopropyl myrista~-e, isobutyl steara~e, isobutyl palmitate, isoprop~1 st~arate or isopropyl palmitate; liquid esters of dicarboxylic acids7 for example, those containing 6-lO
carbon atoms and of monohydric alconols for example those containing 2-4 carbon atoms, such as diisopropyl adipate, diethyl sebacate or dibutyl sebacate; liquid esters of aromatic dicarboxylic acids containing 8 carbon atoms and oE monohydric alcohols, for example those containing 2-4 carbon atGmS, such as diethyl phthalate or dibutyl phthalate; liquid esters of tricarboxylic acids, for example, those containing 6 carbon atoms and monohydric alcohols, for example those contai-ning 2-4 carbon atoms, sucn as esters of citric acid, for example tributyl citrate or triethyl acetylcitrate. The preferred lipophilic solvents are diisopropyl adipate, isopropyl myristace and isosorbide dirnethyl etll2r.
-4~ 2~
Suit~le liquid hycruphilic solvents are ~onohydric alcohols, c those cor.t2inin~2-3 carbon ~toms,l~uch a5 ethanol, isopropanol and n-p~dpanol, polyhydric a~ohols~
e.g., those containing 3-6 carbon ztoms, such as propan2diol~
ylycerol, diethylene glycol and triethylene glycol; poly-ethylene glycols, e.g., those having a molecular weight of 200-600; polyhydro~yethylene/polyhydroxyp~opylene condensates, e.g. those having a molecular weight of lsO0-3000, such as the various commercially a~ailahle I liquid Pluronic~ types of Wyandotte Chemicals Corps The preferred hydrophi~ic solvents are said polyethylene glycol and polyhydroxyethylene/polyhydroxypropylene condensatec.
lS Since the pharmaceutical formulation acccrdin~ to the invention should have a low viscosity, only those ¦ liq;lid polyilydroxyethylene/polyhydroxypropylene con-densates are employed which have an appropriateiy low viscositv, e.s. in the range of 250-700 Cp4 A proportion Or one hyd~ophilic solvent advantageously ists of ethanol, preferably about ~0 to about 70~ my ' weight.
The pharmaceutical for,~ula~ions according to the invention should contain eiiher no water or only a very small amount of water. A content of water as is produced by using normal ethanol does not interfere. In general, however r the waxer content ox the formulatior according to the invention should not be greater than about 4~ by w2ight, preferably not greater than about 2~ by weight.
A particularly preferrer formulation according to the invention consis,s of about 10~ by rleight ox isosorb~de dinitrate, about 27% by weight of diisopropyl a~ipate, about 27% by weight of polyethylene glycol 400 and about 36% by rJeight ox ethanol.
The phar~aceuiical formulations according to the invention car. ye used as spraying agents. whey are pre-erabl~ atomised my mea.~s ox â mechanical metering pump
3~
ar.d sprayed onto the skin, and may be rubbed into the skin after spraying. Very exact dozing results and thy solution can be distributed over an exàctly defined zrea Of skin my maintaining a specified spraying distance. The urea of sprayed skin determines the level of active ingredient in the bloom. Other suitzble forms of application known to those in the art may also be employed.
A good proportloned absorption of the active insredient could in fact be achieved hitherto from solvents, as described, fGr example, in the above mentioned ~OS. Patent
ar.d sprayed onto the skin, and may be rubbed into the skin after spraying. Very exact dozing results and thy solution can be distributed over an exàctly defined zrea Of skin my maintaining a specified spraying distance. The urea of sprayed skin determines the level of active ingredient in the bloom. Other suitzble forms of application known to those in the art may also be employed.
A good proportloned absorption of the active insredient could in fact be achieved hitherto from solvents, as described, fGr example, in the above mentioned ~OS. Patent
4,112,115, jut no long-term action could be ashieved.
The finding according to the present inventlon is thus surprisins. While the high proportion of liquid lipophilic solvent in t'ne formulations of the present invention would, if present alone, permit a high and brie-ly persistent isosorbide dinitrate level in the blood, altering the lipophllic ratio by the addition of hydrophilic solvents results in a sustained release formulation lasting more than 12 hours. At the same time, tne levels in the blood ~0 are higher than those which can be achieved with the ointment formulation according to German Offenlegungsschrift ~,92., oas .
The pharmaceutical formulations according to the present invention can also contain relatively small amounts of customary additives, such as, or example, preservative, antioxidants or per-umi~g agents.
Toe formulation according to the invention is applied such that a daily dosage of about 0.5 - 6 mg, preCerably G.75 - 2 mg isosorhide dinitrate per ~g bOQy weight results.
the dosage Jay, however, also be higher or less and will be de.ermined by 'he physician in each individual case .
In the following eY.amples all preparation steps are performed at room temperature, if not stated otherwise.
_5_ ~2~723~
EXP~lPLE 1 S~artinr~ materials:
1. 10 kg of isosorbide dinitrate 2. 27 kg of diisopropyl adioate 3. 27 kg of polyethylene glycol 400 4. 3~ ks o, ethanbl Starving materials 2 and 3 are carefully mixed and starting material 1 i5 dissolved in the mixture with thorough stirring.
After completion of solution, starting material 4 is added and the mixture is again homogenized by stirring.
The solution is filtered.
The filtered solution in 50 g portions is willed into glass mottles, on top of which is affixed a pump atomizer 5 hazing a stroke capacity of 300 mg.
E~MPLE 2 Starting materials:
1. iO kg of isosorbide dinitrate 2. 25 kg of diisopropyl adipate 3- 29 kg of Pluronic L 31 (a commercial product Gf Wyandotte C;~emicals Coy.
- consisting of polyhydroxy-ethylene/polyhydroxy-propylene condensate, 2~ molecular weight 1050) 4. 36 kg of etnanol Starting rnaterials 2 and 3 are carefully mixed by stir-ring and, in this mixture, starting material 1 is dissolved with fuxther stirring.
After completion of solution, starting material 4 is added an mixed with the solution. The resulting solution is then filtered and filled into 5 ml glass bottles, on to?
of ~7hich a pump ato.rizer i5 afflxed.
_7~ 723~
Startinq materials:
1. 10 kg of isosorbide dinitrate 2. 26 kg of isosorbide dimethyl ether 3~ 64 kg of polyF~thylene glyc:ol 400 Starting material 1 is dissolved in starting ma~eria:l 2 with stirring. After completa solution, starting material 3 is added with further stirring.
The solution is then filtered and filled into 10 5Q ml glass bottles, on top of which pump atomizers are af f ixed .
The finding according to the present inventlon is thus surprisins. While the high proportion of liquid lipophilic solvent in t'ne formulations of the present invention would, if present alone, permit a high and brie-ly persistent isosorbide dinitrate level in the blood, altering the lipophllic ratio by the addition of hydrophilic solvents results in a sustained release formulation lasting more than 12 hours. At the same time, tne levels in the blood ~0 are higher than those which can be achieved with the ointment formulation according to German Offenlegungsschrift ~,92., oas .
The pharmaceutical formulations according to the present invention can also contain relatively small amounts of customary additives, such as, or example, preservative, antioxidants or per-umi~g agents.
Toe formulation according to the invention is applied such that a daily dosage of about 0.5 - 6 mg, preCerably G.75 - 2 mg isosorhide dinitrate per ~g bOQy weight results.
the dosage Jay, however, also be higher or less and will be de.ermined by 'he physician in each individual case .
In the following eY.amples all preparation steps are performed at room temperature, if not stated otherwise.
_5_ ~2~723~
EXP~lPLE 1 S~artinr~ materials:
1. 10 kg of isosorbide dinitrate 2. 27 kg of diisopropyl adioate 3. 27 kg of polyethylene glycol 400 4. 3~ ks o, ethanbl Starving materials 2 and 3 are carefully mixed and starting material 1 i5 dissolved in the mixture with thorough stirring.
After completion of solution, starting material 4 is added and the mixture is again homogenized by stirring.
The solution is filtered.
The filtered solution in 50 g portions is willed into glass mottles, on top of which is affixed a pump atomizer 5 hazing a stroke capacity of 300 mg.
E~MPLE 2 Starting materials:
1. iO kg of isosorbide dinitrate 2. 25 kg of diisopropyl adipate 3- 29 kg of Pluronic L 31 (a commercial product Gf Wyandotte C;~emicals Coy.
- consisting of polyhydroxy-ethylene/polyhydroxy-propylene condensate, 2~ molecular weight 1050) 4. 36 kg of etnanol Starting rnaterials 2 and 3 are carefully mixed by stir-ring and, in this mixture, starting material 1 is dissolved with fuxther stirring.
After completion of solution, starting material 4 is added an mixed with the solution. The resulting solution is then filtered and filled into 5 ml glass bottles, on to?
of ~7hich a pump ato.rizer i5 afflxed.
_7~ 723~
Startinq materials:
1. 10 kg of isosorbide dinitrate 2. 26 kg of isosorbide dimethyl ether 3~ 64 kg of polyF~thylene glyc:ol 400 Starting material 1 is dissolved in starting ma~eria:l 2 with stirring. After completa solution, starting material 3 is added with further stirring.
The solution is then filtered and filled into 10 5Q ml glass bottles, on top of which pump atomizers are af f ixed .
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A sustained action pharmaceutical formulation for topical use comprising isosorbide dinitrate and (a) a liquid lipophilic solvent for isosorbide dinitrate; and (b) a liquid hydrophilic solvent for isosorbide dinitrate;
wherein the weight ratio of a:b is between about 0.2 and about 0.8.
wherein the weight ratio of a:b is between about 0.2 and about 0.8.
2. A formulation according to claim 1 wherein the weight ratio is between about 0.3 and about 0.5.
3. A formulation according to claim 2 which contains from about 5 to about 25 percent by weight of isosorbide dinitrate.
4. A formulation according to claim 3 wherein the liquid lipophilic solvent and the liquid hydrophilic solvent are chosen as that the isosorbide dinitrate is soluble to the extent of at least about 5 percent by weight.
5. A formulation according to claim 4 wherein the liquid lipophilic solvent comprises diisopropyl adipate, isopropyl myristate or isosorbide dimethyl ether.
6. A formulation according to claim 5 wherein the liquid hydrophilic solvent comprises polyethylene glycol or a polyhydroxyethylene/polyhydroxypropylene condensate.
7. A formulation according to claim 6 wherein liquid hydrophilic solvent additionally comprises ethanol.
8. A formulation according to claim 7 comprising not greater than about 4 percent by weight of water.
9. A formulation according to claim 1 comprising about 10 percent by weight isosorbide dinitrate, about 27 percent by weight diisopropyl adipate, about 27 percent by weight poly-ethylene glycol 400 and about 35 percent by weight ethanol.
10. A process for producing a sustained action pharmac-eutical formulation as defined in claim 1, which process comprises admixing isosorbide dinitrate with the liquid lipophilic solvent (a) and the liquid hydrophilic solvent (b).
11. A process for producing a sustained action pharmaceuti-cal formulation as defined in claim 7, which process comprises:
mixing isosorbide dinitrate, the liquid lipophilic solvent and the liquid hydrophilic solvent selected from the group consisting of polyethylene glycol and a polyhydroxyethylene polyhydroxypropylene condensate, and then mixing the resulting mixture with ethanol.
mixing isosorbide dinitrate, the liquid lipophilic solvent and the liquid hydrophilic solvent selected from the group consisting of polyethylene glycol and a polyhydroxyethylene polyhydroxypropylene condensate, and then mixing the resulting mixture with ethanol.
12. A process for producing a sustained action pharmaceutical formulation as defined in claim 4, which process comprises mixing isosorbide dinitrate with the liquid lipophilic solvent,and then mixing the resulting mixture with the liquid hydrophilic solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3305689A DE3305689A1 (en) | 1983-02-18 | 1983-02-18 | PHARMACEUTICAL PREPARATION WITH RETARDIVE EFFECT |
| DEP3305689.7 | 1983-02-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1207236A true CA1207236A (en) | 1986-07-08 |
Family
ID=6191225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000447580A Expired CA1207236A (en) | 1983-02-18 | 1984-02-16 | Isosorbide dinitrate solution |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0120262B1 (en) |
| JP (1) | JPS59219218A (en) |
| AT (1) | ATE35620T1 (en) |
| CA (1) | CA1207236A (en) |
| DE (2) | DE3305689A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5613958A (en) * | 1993-05-12 | 1997-03-25 | Pp Holdings Inc. | Transdermal delivery systems for the modulated administration of drugs |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3522550A1 (en) * | 1985-06-24 | 1987-01-02 | Klinge Co Chem Pharm Fab | SPRAYABLE PHARMACEUTICAL PREPARATION FOR TOPICAL APPLICATION |
| JPS6450816A (en) * | 1987-08-21 | 1989-02-27 | Kanebo Ltd | Isosorbide nitrate agent for transcutaneous use |
| ATE107517T1 (en) * | 1989-05-25 | 1994-07-15 | Takeda Chemical Industries Ltd | TRANSDERMAL THERAPEUTIC AGENT. |
| US5314685A (en) * | 1992-05-11 | 1994-05-24 | Agouron Pharmaceuticals, Inc. | Anhydrous formulations for administering lipophilic agents |
| TW537894B (en) | 1998-05-26 | 2003-06-21 | Novartis Ag | A spontaneously dispersible pharmaceutical composition comprising a piperidine substance P antagonist |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2621214C3 (en) * | 1976-05-13 | 1981-11-12 | Koronis Gmbh Chemisch-Pharmazeutische Praeparate, 5441 Sassen | Use of stabilizers in drugs with monoethyl fumarate and its mineral salts |
| US4336243A (en) * | 1980-08-11 | 1982-06-22 | G. D. Searle & Co. | Transdermal nitroglycerin pad |
-
1983
- 1983-02-18 DE DE3305689A patent/DE3305689A1/en not_active Withdrawn
-
1984
- 1984-02-15 DE DE8484101528T patent/DE3472623D1/en not_active Expired
- 1984-02-15 AT AT84101528T patent/ATE35620T1/en not_active IP Right Cessation
- 1984-02-15 EP EP84101528A patent/EP0120262B1/en not_active Expired
- 1984-02-16 CA CA000447580A patent/CA1207236A/en not_active Expired
- 1984-02-17 JP JP59028415A patent/JPS59219218A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5613958A (en) * | 1993-05-12 | 1997-03-25 | Pp Holdings Inc. | Transdermal delivery systems for the modulated administration of drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE35620T1 (en) | 1988-07-15 |
| DE3305689A1 (en) | 1984-08-23 |
| EP0120262B1 (en) | 1988-07-13 |
| JPS59219218A (en) | 1984-12-10 |
| JPH0157091B2 (en) | 1989-12-04 |
| EP0120262A3 (en) | 1985-10-30 |
| DE3472623D1 (en) | 1988-08-18 |
| EP0120262A2 (en) | 1984-10-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5807568A (en) | Enhanced delivery of topical compositions containing flurbiprofen | |
| US6299889B1 (en) | Stable ascorbic acid preparation for topical use | |
| CN113164511B (en) | Foaming composition for external use | |
| FI69753B (en) | FRAMEWORK FOR THE FRAMSTATION OF AV IS SALOR BASIS AV ISOSORBIDINE NITRATES | |
| CZ25793A3 (en) | Pharmaceutical mixtures of phlorphenicol | |
| JP2555555B2 (en) | Antifungal topical formulation | |
| CA2352915C (en) | Pharmaceutical compositions containing mupirocin | |
| JPS6368518A (en) | Cosmetic composition | |
| US4923862A (en) | Topical preparation containing ofloxacin | |
| CA1207236A (en) | Isosorbide dinitrate solution | |
| JPS6061518A (en) | Gelatinous external composition | |
| JP2000229841A (en) | Mixed type bath preparation | |
| JP2001513093A (en) | Topical Nimusulide gel system | |
| EP0010437B1 (en) | Stable erythromycin solution and process therefor | |
| JPH11349451A (en) | Hair grower | |
| CN100431531C (en) | Transdermal pharmaceutical spray formulations comprising a vp/va copolymer and a non-aqueous vehicle | |
| KR102147642B1 (en) | Cosmetic composition for acne improvement | |
| JPS5869806A (en) | Cosmetic lotion containing stable collagen | |
| JP2000198719A (en) | Hair growth agent | |
| JP5881879B1 (en) | External composition for improving acne vulgaris | |
| EP0756870B1 (en) | Pharmaceutical compositions for topic use on the basis of ketoprofen | |
| KR102624091B1 (en) | Cosmetic composition of pump spray type | |
| EP0322197A1 (en) | New dithranol compositions | |
| US20100286216A1 (en) | Composition having a high osmotic activity and exhibiting antimicrobial, anti-inflammatory, and regenerative effects | |
| RU2093146C1 (en) | Liquid self-foaming pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |