NO178457B - Process for the Preparation of a Salicylic Acid Preparation for the Treatment of Peel Skin Diseases - Google Patents
Process for the Preparation of a Salicylic Acid Preparation for the Treatment of Peel Skin Diseases Download PDFInfo
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- NO178457B NO178457B NO912890A NO912890A NO178457B NO 178457 B NO178457 B NO 178457B NO 912890 A NO912890 A NO 912890A NO 912890 A NO912890 A NO 912890A NO 178457 B NO178457 B NO 178457B
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- diol
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- acid
- aliphatic
- salicylic acid
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 title claims abstract description 74
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229960004889 salicylic acid Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 208000017520 skin disease Diseases 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 34
- -1 aliphatic 1,2-diol Chemical class 0.000 claims abstract description 27
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 19
- 150000002148 esters Chemical class 0.000 claims abstract description 19
- 239000000194 fatty acid Substances 0.000 claims abstract description 19
- 229930195729 fatty acid Natural products 0.000 claims abstract description 19
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 18
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 11
- 239000004146 Propane-1,2-diol Substances 0.000 claims description 17
- 229960004063 propylene glycol Drugs 0.000 claims description 17
- 235000013772 propylene glycol Nutrition 0.000 claims description 17
- 206010040844 Skin exfoliation Diseases 0.000 claims description 15
- 230000035618 desquamation Effects 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 10
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 10
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 claims description 6
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 6
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 5
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229960002446 octanoic acid Drugs 0.000 claims description 5
- 235000003441 saturated fatty acids Nutrition 0.000 claims description 5
- 239000012047 saturated solution Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 4
- 150000005690 diesters Chemical class 0.000 claims description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 4
- 150000005846 sugar alcohols Polymers 0.000 abstract description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 abstract 2
- 230000001496 desquamative effect Effects 0.000 abstract 1
- 235000011187 glycerol Nutrition 0.000 abstract 1
- 150000004667 medium chain fatty acids Chemical class 0.000 abstract 1
- 230000000699 topical effect Effects 0.000 abstract 1
- 239000010685 fatty oil Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 150000003626 triacylglycerols Chemical class 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 210000004761 scalp Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010039792 Seborrhoea Diseases 0.000 description 2
- 208000002474 Tinea Diseases 0.000 description 2
- 241000130764 Tinea Species 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical class OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229940102253 isopropanolamine Drugs 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Oppfinnelsen vedrører en fremgangsmåte for fremstilling av et salisylsyreholdig preparat for lokal behandling av hudsykdommer med avskalling innen human- og veterinærmedisin. Til disse hudsykdommene med avskalling regnes f.eks. psoriasis, tinea amiantacea og seborrhoea sicca. The invention relates to a method for producing a preparation containing salicylic acid for the local treatment of skin diseases with desquamation in human and veterinary medicine. These skin diseases with desquamation include e.g. psoriasis, tinea amiantacea and seborrhoea sicca.
Det er f.eks. fra E. Mutschler, "Arzneimittel-wirkungen", Wissenschaftliche Verlagsgesellschaft, Stuttgart 1975, s. 373, kjent at salisylsyre bevirker hudavskalling og oppmykning av hornmateriale, og anvendes i form av salisyl-vaselin, salisylsprit og salisylkollodium. Som ytterligere preparat for behandling av de ovenfor nevnte hudsykdommer er bl.a. salisylsmult, salisylleucerin og salisylgel i bruk. It is e.g. from E. Mutschler, "Arzneimittel-wirkungen", Wissenschaftliche Verlagsgesellschaft, Stuttgart 1975, p. 373, it is known that salicylic acid causes skin peeling and softening of horny material, and is used in the form of salicyl vaseline, salicyl alcohol and salicyl collodion. As an additional preparation for the treatment of the above-mentioned skin diseases, i.a. salicyl lard, salicyl leucerin and salicyl gel in use.
Fra publikasjonen av U. Adams og F. Neuwald i Pharm. Ind., bind 44, nr. 6, s. 625-629, 1982, er anvendelsen av tri-glyseridgeler med middels kjedelengde for fremstilling av salisylsyreholdige salver, eventuelt under tilsetning av emul-gatorer som fullvoksalkoholer, kjent. Slike geler inneholder triglyserider med middels kjedelengde og et organisk modi-fisert magnesiumsjiktsilikat som geleringsmiddel. From the publication by U. Adams and F. Neuwald in Pharm. Ind., volume 44, no. 6, pp. 625-629, 1982, the use of triglyceride gels with a medium chain length for the production of ointments containing salicylic acid, possibly with the addition of emulsifiers such as full wax alcohols, is known. Such gels contain medium-chain triglycerides and an organically modified magnesium layer silicate as gelling agent.
I EP-A-0 063 870 er det beskrevet betennelseshemmende salver som inneholder slike betennelseshemmende stoffer som indomethacin, steroider o.l. i en salvebasis, som i det vesentlige inneholder triglyserider med middels kjedelengde (glyserider av C6-C12-karboksylsyrer), en karboksyvinylpolymer og vann i forholdet 1-25:0,3-3:75-99, samt en geldanner som isopropanolamin. In EP-A-0 063 870, anti-inflammatory ointments are described which contain such anti-inflammatory substances as indomethacin, steroids and the like. in an ointment base, which essentially contains triglycerides of medium chain length (glycerides of C6-C12 carboxylic acids), a carboxyvinyl polymer and water in the ratio 1-25:0.3-3:75-99, as well as a gel former such as isopropanolamine.
Videre er det også kjent å anvende oppløsninger av salisylsyre i fettoljer som olivenolje, ricinusolje og andre for behandling av de ovenfor nevnte hudsykdommer. Furthermore, it is also known to use solutions of salicylic acid in fatty oils such as olive oil, castor oil and others for the treatment of the above-mentioned skin diseases.
Fra DE-A-762 726 er det kjent at oppløseligheten av salisylsyre i fett og oljer, også salver, kan økes ved tilsetning av høyeremolekylaere alifatiske alkoholer (C8-C18) eller deres etere med flerverdige alkoholer som inneholder minst én fri hydroksylgruppe. From DE-A-762 726 it is known that the solubility of salicylic acid in fats and oils, also ointments, can be increased by the addition of higher molecular weight aliphatic alcohols (C8-C18) or their ethers with polyhydric alcohols containing at least one free hydroxyl group.
Den ikke forut offentliggjorte søknad PCT/EP 88/00649 beskriver et preparat av den i innledningen nevnte type som inneholder 4-10 vekt% salisylsyre, 1-7 vekt% av en alifatisk 1,2-diol som propan-1,2-diol og 83-95 vekt% av en fettolje, f.eks. et triglyserid med middels kjedelengde, og som i stedet for fettoljen også kan inneholde en ester av én- eller flerverdige alkoholer, særlig med fettsyrer av middels kjedelengde . The not previously published application PCT/EP 88/00649 describes a preparation of the type mentioned in the introduction which contains 4-10% by weight of salicylic acid, 1-7% by weight of an aliphatic 1,2-diol such as propane-1,2-diol and 83-95% by weight of a fatty oil, e.g. a triglyceride with medium chain length, and which instead of the fatty oil may also contain an ester of monohydric or polyhydric alcohols, particularly with fatty acids of medium chain length.
Ved bruk av de kjente salisylsyreholdige midler har det vist seg at disse kjente midlene ved anvendelsen for de således behandlede pasienter av en rekke grunner som f.eks. en betydelig luktbelastning gjennom harskningen av fettoljen under behandlingen, ikke er, eller er bare litt, akseptable og i praksis bringer de ønskede resultater bare ved stasjonær behandling. For pasientene som behandles med preparatet, er dette imidlertid av stor betydning, også av psykologiske grunner. When using the known agents containing salicylic acid, it has been shown that these known agents when used for the thus treated patients for a number of reasons such as e.g. a significant odor load through the rancidity of the fatty oil during the treatment, is not, or is only slightly, acceptable and in practice they only bring the desired results with stationary treatment. For the patients who are treated with the preparation, however, this is of great importance, also for psychological reasons.
Oppgaven for oppfinnelsen bestod i å skaffe til veie en fremgangsmåte for fremstilling av et salisylsyreholdig preparat av den i innledningen nevnte type som ved god forenlighet er uten ugunstige virkninger for pasientene, og som muliggjør en ikke-stasjonær behandling. The task of the invention was to provide a method for the production of a preparation containing salicylic acid of the type mentioned in the introduction which, if compatible, has no adverse effects for the patients, and which enables a non-stationary treatment.
Ifølge oppfinnelsen ble denne oppgave løst ved en fremgangsmåte for fremstilling av et salisylsyreholdig preparat som inneholder en alifatisk 1,2-diol og en ester, for lokal behandling av hudsykdommer med avskalling innenfor det human- og veterinærmedisinske område, kjennetegnet ved at 1-15 vektdeler salisylsyre tritureres med 1-15 vektdeler av en alifatisk 1,2-diol og blandes med 70-98 vektdeler av en ester valgt fra gruppen av estere av en enverdig alkohol og diestere av en toverdig alkohol, og minst én fettsyre valgt fra gruppen av mettede (C8-C12)-fettsyrer med middels kjedelengde og mettede, langkjedede, forgrenede (C13-C18)-fettsyrer og blandinger derav, alt beregnet på at totalvekten av preparatet = 100, under omrøring til en klar, oljeaktig væske. According to the invention, this task was solved by a method for the production of a preparation containing salicylic acid containing an aliphatic 1,2-diol and an ester, for the local treatment of skin diseases with desquamation within the field of human and veterinary medicine, characterized in that 1-15 parts by weight salicylic acid is triturated with 1-15 parts by weight of an aliphatic 1,2-diol and mixed with 70-98 parts by weight of an ester selected from the group of esters of a monohydric alcohol and diesters of a dihydric alcohol, and at least one fatty acid selected from the group of saturated Medium-chain (C8-C12) fatty acids and saturated, long-chain, branched (C13-C18) fatty acids and mixtures thereof, all calculated so that the total weight of the preparation = 100, with stirring to a clear, oily liquid.
Ifølge oppfinnelsen er det også tilveiebrakt en fremgangsmåte for fremstilling av et salisylsyreholdig preparat som inneholder en alifatisk 1,2-diol og en ester, for lokal behandling av hudsykdommer med avskalling innenfor det human- og veterinærmedisinske område, kjennetegnet ved at 1-15 vektdeler salisylsyre, unntatt 4-10 vektdeler, tritureres med 1-15 vektdeler, unntatt 1-7 vektdeler, av en alifatisk 1,2-diol og blandes med 70-98, unntatt 83-95, vektdeler av et triglyserid av minst én fettsyre valgt fra gruppen av mettede (C8-C12)-fettsyrer med middels kjedelengde eller blandinger derav med mettede fettsyrer med middels kjedelengde, alt beregnet på at totalvekten av preparatet = 100, under omrøring til en klar, oljeaktig væske. According to the invention, a method is also provided for the production of a preparation containing salicylic acid containing an aliphatic 1,2-diol and an ester, for the local treatment of skin diseases with desquamation within the human and veterinary medical field, characterized in that 1-15 parts by weight of salicylic acid , except 4-10 parts by weight, triturated with 1-15 parts by weight, except 1-7 parts by weight, of an aliphatic 1,2-diol and mixed with 70-98, except 83-95, parts by weight of a triglyceride of at least one fatty acid selected from the group of saturated (C8-C12) fatty acids of medium chain length or mixtures thereof with saturated fatty acids of medium chain length, all calculated so that the total weight of the preparation = 100, with stirring to a clear, oily liquid.
Metningskonsentrasjonen av salisylsyre i fettoljer eller andre blandinger ligger i området fra 3 % til ca. 6 %. Riktignok er salisylsyre oppløselig i ricinusolje inntil ca. 10 %, dette er imidlertid ikke noe brukbart oppløsningsmiddel innenfor rammen av oppfinnelsen på grunn av den høye viskosi-tet og oksidasjonsømfintlighet (harskning). The saturation concentration of salicylic acid in fatty oils or other mixtures is in the range from 3% to approx. 6%. Admittedly, salicylic acid is soluble in castor oil up to approx. 10%, however, this is not a usable solvent within the scope of the invention due to its high viscosity and sensitivity to oxidation (rancidity).
Oppløseligheten av salisylsyre i alifatiske 1,2-dioler er svært mye høyere og utgjør eksempelvis i propan-1,2-diol ca. 20 %. Slike alifatiske 1,2-dioler er imidlertid ikke blandbare med de ovenfor nevnte fettoljer. The solubility of salicylic acid in aliphatic 1,2-diols is much higher and, for example, in propane-1,2-diol amounts to approx. 20%. However, such aliphatic 1,2-diols are not miscible with the above-mentioned fatty oils.
På overraskende måte ble det nå funnet at klare og énfasede oppløsninger kan erholdes når man blander den tidligere nevnte ester, alifatiske 1,2-dioler og salisylsyre med hverandre i de ovenfor nevnte blandingsforhold. Derved kan det komme til anvendelse forskjellige alifatiske 1,2-dioler, idet propan-1,2-diol og de forskjellige butylenglykoler med nabostilte hydroksylgrupper har vist seg som særlig gunstige. Surprisingly, it was now found that clear and single-phase solutions can be obtained when mixing the previously mentioned ester, aliphatic 1,2-diols and salicylic acid with each other in the above-mentioned mixing ratios. Thereby, various aliphatic 1,2-diols can be used, propane-1,2-diol and the various butylene glycols with adjacent hydroxyl groups having proven to be particularly beneficial.
I det fremstilte preparat kan det anvendes estere av énverdige eller toverdige alkoholer, særlig av propan-1,2-diol, med mettede fettsyrer med midlere og større kjede-lengder, særlig med liketallige og uliketallige, forgrenede eller uforgrenede fettsyrer med middels kjedelengde (C8-C12) eller forgrenede, langkjedede (C13-C18) fettsyrer eller blandinger derav, eller triglyserider av de samme fettsyrer. Særlig foretrukket er det med enkle eller blandede estere av kaprylsyre, kaprinsyre, nonansyre og isostearinsyre (blanding av forgrenede oktadekansyrer (Fiedler, Lexikon der Hilfsstoffe flir Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor, Aulendorf, 1981, s. 505). I stedet for de ovenfor nevnte triglyserider kan det imidlertid også anvendes alminne-lige fettoljer, fortrinnsvis vegetabilske fettoljer. In the prepared preparation, esters of monohydric or dihydric alcohols, especially of propane-1,2-diol, with saturated fatty acids with medium and longer chain lengths, especially with even and odd-numbered, branched or unbranched fatty acids of medium chain length (C8 -C12) or branched, long-chain (C13-C18) fatty acids or mixtures thereof, or triglycerides of the same fatty acids. Particular preference is given to single or mixed esters of caprylic acid, capric acid, nonanoic acid and isostearic acid (mixture of branched octadecanoic acids (Fiedler, Lexikon der Hilfsstoffe flir Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor, Aulendorf, 1981, p. 505). Instead however, ordinary fatty oils, preferably vegetable fatty oils, can also be used for the above-mentioned triglycerides.
Fremstilte preparater er også godt forenlige ved langtidsanvendelse; hittil er det heller ikke ved langtidsanvendelse iakttatt noen allergiske reaksjoner. Derved oppnås en høy aktivitet, særlig oppnås etter forholdsvis kort anven-delsestid, alt etter sykdommens alvorlighet, en fullstendig avskalling, dvs. at det oppnås symptomfrihet som vedvarer med passende etterbehandling. Manufactured preparations are also well compatible with long-term use; so far, no allergic reactions have been observed with long-term use either. Thereby, a high activity is achieved, in particular a complete desquamation is achieved after a relatively short period of use, depending on the severity of the disease, i.e. freedom from symptoms is achieved which persists with appropriate after-treatment.
Et særlig virkningsfullt, foretrukket preparat inneholder 4-7,5 vekt% salisylsyre, 1-4,5 vekt% propan-1,2-diol og 88-95 vekt% propan-1,2-diolester av kaprylsyre, kaprinsyre eller blanding derav. Andelen av propan-1,2-diol er så høy at salisylsyren foreligger nesten i mettet oppløsning. A particularly effective, preferred preparation contains 4-7.5% by weight salicylic acid, 1-4.5% by weight propane-1,2-diol and 88-95% by weight propane-1,2-diol ester of caprylic acid, capric acid or a mixture thereof . The proportion of propane-1,2-diol is so high that the salicylic acid is almost in saturated solution.
En viktig årsak for den høye aktiviteten av preparatene fremstilt ifølge oppfinnelsen ligger muligens i at de utvalgte oppløsningsmiddelblandinger virker på terapeutisk særlig gunstig måte på den syke huden og derved danner en svært aktiv bærer som bringer salisylsyren til dens virkningssted. An important reason for the high activity of the preparations produced according to the invention possibly lies in the fact that the selected solvent mixtures work in a therapeutically particularly beneficial way on the diseased skin and thereby form a highly active carrier that brings the salicylic acid to its site of action.
Dessuten er behandlingen med preparatene fremstilt ifølge oppfinnelsen ikke forbundet med uønskede og uakseptable belastninger for pasientene, samtidig som de resorberes hurtig og fullstendig i huden. Derved får pasientene ikke utålelige luktbelastninger gjennom harskning av fettet eller fettoljene, og ikke den uønskede tilgrising av klær eller sengetøy. En ytterligere ganske vesentlig fordel ved de fremstilte preparater består i at et sykehusopphold ikke lenger er nødvendig i de fleste tilfeller. Derved oppnås en totalt svært høy akseptans hos pasientene. Moreover, the treatment with the preparations produced according to the invention is not associated with unwanted and unacceptable burdens for the patients, while at the same time they are quickly and completely absorbed into the skin. Thereby, the patients do not get intolerable odor burdens through rancidity of the fat or fatty oils, and not the unwanted soiling of clothes or bedding. A further rather significant advantage of the prepared preparations consists in the fact that a hospital stay is no longer necessary in most cases. This results in an overall very high level of acceptance by the patients.
Foretrukne utførelseseksempler for oppfinnelsen er gitt nedenunder. Preferred embodiments of the invention are given below.
Ifølge et foretrukket utførelseseksempel utveies salisylsyre i mengder på 4, 5, 7,5 og 10 g og tritureres med en mengde på hhv. 1, 2, 4,5 og 7 g propan-1,2-diol på vanlig måte. Deretter ble det til de 5, 7, 12 og 17 g av propan-1,2-dioltriturasjon tilsatt hhv. 95, 93, 88 og 83 g av en enkelt eller blandet ester av propan-1,2-diol med mettede fettsyrer av middels kjedelengde (C8-C12), som kaprylsyre, kaprinsyre eller nonansyre, eller forgrenede, langkjedede (C13-C18) fettsyrer, som isostearinsyre e.l., og blandingene ble omrørt inntil det oppstod en klar, oljeaktig oppløsning. Dette preparatet inneholdt således i vekt%, og beregnet på totalvekt = 100, According to a preferred embodiment, salicylic acid is weighed out in amounts of 4, 5, 7.5 and 10 g and triturated with an amount of respectively 1, 2, 4.5 and 7 g of propane-1,2-diol in the usual way. Subsequently, the 5, 7, 12 and 17 g of propane-1,2-diol trituration were added respectively. 95, 93, 88 and 83 g of a single or mixed ester of propane-1,2-diol with saturated fatty acids of medium chain length (C8-C12), such as caprylic acid, capric acid or nonanoic acid, or branched, long chain (C13-C18) fatty acids, such as isostearic acid and the like, and the mixtures were stirred until a clear, oily solution appeared. This preparation thus contained in % by weight, and calculated on total weight = 100,
I stedet for denne ester kan det også anvendes egnede fettalkoholestere, fettoljer, særlig vegetabilske fettoljer. Instead of this ester, suitable fatty alcohol esters, fatty oils, especially vegetable fatty oils can also be used.
Det ble på foretrukket måte gått frem slik at, idet man gikk ut fra metningskonsentrasjonen av salisylsyre i esteren, det ble tilsatt så mye propan-1,2-diol at det ble erholdt en mettet eller tilnærmet mettet oppløsning av den ønskede salisylsyremengde i propan-1,2-diolesterblandingen. Det har vist seg gunstig ved behandlingen å anvende mettede eller tilnærmet mettede oppløsninger av salisylsyren. It was preferably proceeded in such a way that, proceeding from the saturation concentration of salicylic acid in the ester, so much propane-1,2-diol was added that a saturated or nearly saturated solution of the desired amount of salicylic acid in propane- The 1,2-diol ester mixture. It has proven beneficial in the treatment to use saturated or nearly saturated solutions of salicylic acid.
Dette preparatet ble anvendt på den nedenfor beskrevne måte for behandling av hudsykdommer med avskalling, som psoriasis, tinea amiantacea, seborrhoea sicca hos mennesker, og av sommerskabb og andre sykdommer med avskalling f.eks. hos ponnier. Til sammen har det ved disse og andre sammenlignbare undersøkelser vist seg at preparatet som inneholder fra 4 vekt% til 7,5 vekt% salisylsyre, fra 1 vekt% til 4,5 vekt% av den alifatiske 1,2-diol og fra 88 vekt% til 93 vekt% av esteren, utviste den relativt beste virkning under syns-punktene vedrørende forenlighet, aktivitet og behandlingsvarighet inntil manifestasjonsfrihet. This preparation was used in the manner described below for the treatment of skin diseases with scaling, such as psoriasis, tinea amiantacea, seborrhoea sicca in humans, and of summer scabies and other diseases with scaling, e.g. in ponies. Altogether, these and other comparable investigations have shown that the preparation containing from 4% by weight to 7.5% by weight of salicylic acid, from 1% by weight to 4.5% by weight of the aliphatic 1,2-diol and from 88% by weight % to 93% by weight of the ester, showed the relatively best effect under the points of view regarding compatibility, activity and duration of treatment until freedom from manifestation.
Ved ytterligere undersøkelser ble det funnet at også de forskjellige butylenglykoler med nabostilte hydroksylgrupper og eventuelt også andre alifatiske 1,2-dioler kunne anvendes i stedet for propan-1,2-diol. During further investigations, it was found that the various butylene glycols with neighboring hydroxyl groups and possibly other aliphatic 1,2-diols could also be used instead of propane-1,2-diol.
Den terapeutiske anvendelse av et utførelseseksempel som inneholder 5 vekt% salisylsyre, 2 vekt% propan-1,2-diol og 93 vekt% triglyserider med middels kjedelengde (totalvekt av preparatet=100), belyses nedenunder ved hjelp av en pasient-gruppe på 150 personer som hovedsakelig led av psoriasis og for en mindre dels vedkommende av andre hud- og hodehudsykdom-mer med avskalling, f.eks. seboreiske eksemer. Behandlingen bestod i at The therapeutic use of an embodiment example containing 5% by weight of salicylic acid, 2% by weight of propane-1,2-diol and 93% by weight of medium-chain triglycerides (total weight of the preparation=100) is illustrated below using a patient group of 150 people who mainly suffered from psoriasis and to a lesser extent from other skin and scalp diseases with scaling, e.g. seborrheic eczema. The treatment consisted of
a) ved sykdommer i hodehuden a) in diseases of the scalp
ble preparatet påført 2-3 ganger ukentlig på de an-grepne steder av hodehuden; behandlingen kan skje over natten under benyttelse av en dusjplastikkhette med tilsluttende the preparation was applied 2-3 times weekly to the affected areas of the scalp; the treatment can take place overnight using a plastic shower cap with a connector
gummirand og en kommersielt tilgjengelig operasjonshette for fiksering, og rubber band and a commercially available surgical cap for fixation, and
b) ved sykdommer på kroppen b) in the case of diseases of the body
ble preparatet påført 1-2 ganger daglig på de an-grepne steder; etter 10-15 minutters virketid er preparatet tatt opp av huden. the preparation was applied 1-2 times a day to the affected areas; after 10-15 minutes of working time, the preparation is absorbed by the skin.
Hos 8 personer i pasientgruppen ble behandlingen av-brutt før tiden av grunner som ikke hadde å gjøre med den egentlige behandling. Hos 50 personer i pasientgruppen ble det, avhengig av den opprinnelige sykdoms alvorlighet, oppnådd total avskalling og dermed den ønskede manifestasjonsfrihet etter en behandlingstid på In 8 people in the patient group, the treatment was discontinued prematurely for reasons unrelated to the actual treatment. In 50 people in the patient group, depending on the severity of the original disease, total desquamation and thus the desired freedom from manifestation was achieved after a treatment period of
1 måned ved lettere opprinnelig sykdom, inntil 1 month in case of mild original illness, up to
3 måneder ved middels opprinnelig sykdom og inntil 4 måneder ved alvorlig opprinnelig sykdom, 3 months in the case of moderate original illness and up to 4 months in the case of severe original illness,
idet den begynnende avskalling inntrådte allerede i de første ukene av behandlingen. as the initial desquamation already occurred in the first weeks of treatment.
Hos de fleste av de gjenværende 92 pasienter var av-skallingen etter inntil en ettårig behandlingsvarighet svært langt fremskredet, og også her lot den totale avskalling og dermed den ønskede manifestasjonsfrihet seg vente på. Allergiske reaksjoner ble ikke observert, og behandlingen ble akseptert av pasientene på fremragende måte. Dertil kommer det at preparatet er luktnøytralt og trekker hurtig inn i huden, hvorved det ikke skjer noen tilgrising av klær eller sengetøy, samt det forhold at det bare ved særlige omstendigheter og svært alvorlige sykdommer er nødvendig med sykehusopphold. In most of the remaining 92 patients, the desquamation was very far advanced after up to a one-year treatment duration, and here too the total desquamation and thus the desired freedom of manifestation had to wait. Allergic reactions were not observed, and the treatment was accepted by the patients in an outstanding manner. There is also the fact that the preparation is odorless and absorbs quickly into the skin, whereby no soiling of clothes or bed linen occurs, as well as the fact that hospital stay is only necessary in special circumstances and very serious illnesses.
Like eller lignende virkninger ble oppnådd når tri-glyseridene ble erstattet med andre av de tidligere nevnte estere. Equal or similar effects were obtained when the tri-glycerides were replaced by other of the previously mentioned esters.
Som særlig fordelaktig bivirkning ble det fastslått tydelig påvisbar økt vekst også på det veterinærmedisinske område. As a particularly beneficial side effect, clearly demonstrable increased growth was also found in the veterinary medicine area.
Den først oppnådde manifestasjonsfrihet kan også The first achieved freedom of expression can also
senere opprettholdes. For dette anbefales en oppfølgingsterapi under anvendelse av kommersielt tilgjengelige midler som reduserer fornyet avskallingsdannelse, slik som dithranol, veksel-vis med de ovenfor beskrevne midler. later maintained. For this, a follow-up therapy is recommended using commercially available agents that reduce renewed desquamation, such as dithranol, alternating with the agents described above.
Claims (15)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP1989/000034 WO1990008547A1 (en) | 1989-01-25 | 1989-01-25 | Preparation containing salicylic acid for treating desquamative skin diseases |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO912890D0 NO912890D0 (en) | 1991-07-24 |
| NO912890L NO912890L (en) | 1991-09-24 |
| NO178457B true NO178457B (en) | 1995-12-27 |
| NO178457C NO178457C (en) | 1996-04-03 |
Family
ID=8165367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO912890A NO178457C (en) | 1989-01-25 | 1991-07-24 | Process for the Preparation of a Salicylic Acid Preparation for the Treatment of Peel Skin Diseases |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0455631B1 (en) |
| AT (1) | ATE91079T1 (en) |
| DE (1) | DE58904851D1 (en) |
| DK (1) | DK138191A (en) |
| FI (1) | FI100695B (en) |
| NO (1) | NO178457C (en) |
| WO (1) | WO1990008547A1 (en) |
| ZA (1) | ZA892101B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR1001303B (en) * | 1989-01-23 | 1993-07-30 | Wolff Chem Pharm Gmbh | Method for preparation of a means that contains salicyloxyd against scaling sick |
| WO1994008599A1 (en) * | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
| DE4434781A1 (en) * | 1994-09-29 | 1996-04-04 | Beiersdorf Ag | Use of fatty acid esters to combat superinfections |
| US5736580A (en) * | 1994-11-14 | 1998-04-07 | Alza Croporation | Composition, device, and method for electrotransport agent delivery |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE762726C (en) * | 1942-05-02 | 1952-09-15 | Hydrierwerke A G Deutsche | Solvent or solubilizer for salicylic acid |
| CA1165240A (en) * | 1980-07-09 | 1984-04-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
| JPS57171912A (en) * | 1981-04-14 | 1982-10-22 | Sumitomo Chem Co Ltd | Cream |
| DE3724691C2 (en) * | 1987-07-25 | 1999-03-18 | Konrad Minninger | Pharmaceutical agent for the local therapy of flaking skin diseases |
-
1989
- 1989-01-25 WO PCT/EP1989/000034 patent/WO1990008547A1/en active IP Right Grant
- 1989-01-25 EP EP89902505A patent/EP0455631B1/en not_active Expired - Lifetime
- 1989-01-25 AT AT89902505T patent/ATE91079T1/en not_active IP Right Cessation
- 1989-01-25 DE DE8989902505T patent/DE58904851D1/en not_active Expired - Fee Related
- 1989-03-20 ZA ZA892101A patent/ZA892101B/en unknown
-
1991
- 1991-07-23 FI FI913517A patent/FI100695B/en active
- 1991-07-23 DK DK138191A patent/DK138191A/en not_active Application Discontinuation
- 1991-07-24 NO NO912890A patent/NO178457C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE91079T1 (en) | 1993-07-15 |
| FI100695B (en) | 1998-02-13 |
| NO912890D0 (en) | 1991-07-24 |
| WO1990008547A1 (en) | 1990-08-09 |
| DK138191D0 (en) | 1991-07-23 |
| EP0455631A1 (en) | 1991-11-13 |
| NO912890L (en) | 1991-09-24 |
| ZA892101B (en) | 1989-11-29 |
| NO178457C (en) | 1996-04-03 |
| FI913517A0 (en) | 1991-07-23 |
| DK138191A (en) | 1991-09-25 |
| DE58904851D1 (en) | 1993-08-05 |
| EP0455631B1 (en) | 1993-06-30 |
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