AU649130B2 - Pharmaceutical compositions for transcutaneous administration - Google Patents
Pharmaceutical compositions for transcutaneous administration Download PDFInfo
- Publication number
- AU649130B2 AU649130B2 AU15184/92A AU1518492A AU649130B2 AU 649130 B2 AU649130 B2 AU 649130B2 AU 15184/92 A AU15184/92 A AU 15184/92A AU 1518492 A AU1518492 A AU 1518492A AU 649130 B2 AU649130 B2 AU 649130B2
- Authority
- AU
- Australia
- Prior art keywords
- composition according
- treatment
- pge1
- impotence
- gastrointestinal
- 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.)
- Ceased
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- 239000000203 mixture Substances 0.000 claims description 13
- 150000003180 prostaglandins Chemical class 0.000 claims description 12
- 230000001154 acute effect Effects 0.000 claims description 6
- 206010018852 Haematoma Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 230000003779 hair growth Effects 0.000 claims description 5
- 230000001771 impaired effect Effects 0.000 claims description 5
- 201000001881 impotence Diseases 0.000 claims description 5
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 5
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 4
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000002054 transplantation Methods 0.000 claims description 4
- 231100000397 ulcer Toxicity 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 206010065929 Cardiovascular insufficiency Diseases 0.000 claims description 3
- 206010061459 Gastrointestinal ulcer Diseases 0.000 claims description 3
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 3
- 208000007814 Unstable Angina Diseases 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 2
- 206010000891 acute myocardial infarction Diseases 0.000 claims 2
- 230000002496 gastric effect Effects 0.000 claims 2
- 210000000056 organ Anatomy 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- LVDCZROIKIHUKJ-QZCLESEGSA-N ethyl 7-[(1r,2r,3r)-3-hydroxy-2-[(e,3s)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OCC LVDCZROIKIHUKJ-QZCLESEGSA-N 0.000 description 3
- 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 description 2
- ROUDCKODIMKLNO-CTBSXBMHSA-N 6-oxoprostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(O)=O ROUDCKODIMKLNO-CTBSXBMHSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- 206010040943 Skin Ulcer Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940031578 diisopropyl adipate Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000016354 hearing loss disease Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 206010060964 Arterial haemorrhage Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011340 continuous therapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000014674 injury Diseases 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- -1 tubes Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 230000008673 vomiting Effects 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
Abstract
Prostaglandin E1 derivatives as pharmacological active compounds and medicaments containing these compounds are described, in particular for transcutaneous application.
Description
64 9 13
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Invention Title: PHARMACEUTICAL COMPOSITIONS FOR TRANSCUTANEOUS
ADMINISTRATION
The following statement is a full description of this invention, including the best method of performing it known to me:- *9 1A PHARMACEUTICAL COMPOSITIONS FOR TRANSCUTANEOUS
ADMINISTRATION
BACKGROUND OF THE INVENTION The invention relates to prostaglandin El derivatives (PGE1 derivatives) as pharmacologically active agents and to pharmaceutical compositions especially for transcutaneous application which contain a PGE1 derivative.
By "transcutaneous" we mean by absorption through unbroken skin, sometimes also referred to as "percutaneous".
DE-A-27 53 986 and the corresponding US-A- 4,205,178 disclose 6-keto prostaglandin El derivatives, especially the 6-keto PGEl methyl ester.
A number of biological and pharmacological effects are described for these compounds. Various routes of administration are indicated for the various kinds of illnesses to be treated, e.g. oral, intravenous, S 25 subcutaneous, intra-arterial, buccal, rectal and intravaginal administration. Topical administration is described in connection with skin injuries or skin diseases at or near the site of the injury or disease.
o 6-keto prostaglandin El derivatives are also described in DE-A-28 40 032, in which the authors also refer to various forms of pharmacological activity and administration.
Prostaglandin El (PGE1) and 6-keto prostaglandin El (6-k PGE1) can be used for the treatment of several diseases. These diseases include peripheral occlusive diseases, complications in arteriosclerosis such as Menidre's disease or acute loss of hearing, acute myocardial infarctation, unstable angina pectoris, acute ischaemic strokes, impotence, bronchial asthma, impaired hair growth and rejection following kidney transplants: see H. Sinzinger and W. Rogatti, Prostaglandin El in atherosclerosis, Springer Verlag Berlin Heidelberg New York, 1986; S. Schrey, PGIES, Therapie der arteriellen Verschlupkrankheit, UniversitAtsdruckerei and Verlag Dr.
C. Wolf und Sohn, Munich, 1985. PGE1 is used for the treatment of chronic arterial occlusive diseases in phase III and IV.
This condition calls for intra-arterial or intravenous infusion which results in a severe limitation in the use of 0 PGE1, as the infusion is not only a strain on the patient, but also involves a certain risk of arterial haemorrhage. Neither route of administration and is suitable for continuous therapy in ambulatory patient care. However, longterm administration would be most appropriate for these diseases. The oral adminstration of PGE1 is always problematic 2: as either the very low bio-availability rules out such administration, or the typical undesired effects (nausea, vomiting, diarrhoea) are prohibitive due to the high concentration of the drug in the gastrointestinal tract when orally administered.
SUMMARY OF THE INVENTION The object underlying the invention is to provide PGE1 and PGE1 derivatives as pharmaceutical compositions or pharmacologically active agents. The PGE1 derivatives, which were especially developed as pharmacologically active agents for transcutaneous adminstration, are absorbed by the skin and subsequently split by hydrolases into prostaglandin El or 6keto PGE1 and alcohol. The PGE1 derivatives thus fulfill the requirements of the "Pro-Drug" c)ncept and avoid the disadvantages of PGE1 and 6-keto PGE1 when adminstered arterially, intravenously or orally.
The subject matter of the invention is therefore prostaglandin El derivatives of the general formula I 0 R
(I)
HO
0 H in which R 1 is a hydrogen atom and R 2 is a C 1 -4 alkyl residue, as pharmacologically active agents.
A further subject matter of the invention is a pharmaceutical composition containing a prostaglandin El derivative according to formula I.
Still a further subject matter of the invention is the use of prostaglandin El derivatives of general formula I, S R 002 S. S (I)
HO
HO OH in which R1 is a hydrogen atom (PGE1) or a carbonyl oxygen atom (6-k-PGE1) and R2 is a C 1 4 alkyl residue for the preparation of a pharmaceutical composition to be administered S. transcutaneously.
BRIEF DESCRIPTION OF THE DRAWING Fig. 1 shows the absorption rate of PGE1 and PGE1 ethyl ester which has been determined as the cumulative urinary excretion following transcutaneous administration.
DETAILED DESCRIPTION Specific examples of alkyl residues are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl group.
Due to the non-toxicity of the fragments, the preferred group R 2 is the ethyl group.
The preparation of the compounds of general formula I is carried out according to methods known per se via esterification of PGE1 and 6-k PGE1. The methyl and ethyl ester, for instance, are prepared by reacting the same with diazomethane or diazoethane; also see Ch. J. Sih et al., J. Am. Chem. Soc., Vol. 97 (1975), pp. 857 to 865.
The compounds of general formula I can be used to treat circulatory insufficiencies, for instance of the brain, the heart and the extremities, to inhibit platelet aggregation (thrombocyte aggregation), impotence and to treat allergic 2 reactions such as bronchial asthma, rejection following transplantations and impaired hair growth. Typical examples of deficiencies in the cerebral blood supply are transitory cerebral ischaemia, acute loss of hearing, vertigo caused by circulatory inufficiencies and ischaemic strokes. Typical examples of deficiencies in the myocardial blood supply are angina pectoris and myocardial infarction. Typical examples of deficiencies in the blood supply of the extremities are periphal arterial circulatory insufficiencies in arteriosclerosis and Raynaud's disease and Raynaud's syndrom.
The compounds of general formula I can also be used to t t gastrointestinal ulcers and ulcers of the skin. Typical T:ples of gastrointestinal ulcers are ulcus ventriculi, duodenal ulcers and ulcerative colitis (Crohn's disease). A typical example of a skin ulcer is ulcus cruris. The compounds of general formula I have a cyto-protective effect. The cells exhibit increased resistance to noxious stimuli.
The compounds of general formula I can further be used to treat haematomas, especially surface haematomas.
In addition to transcutaneous administration, the compounds of general formula I can also be administered by inhalation, intravenously and intra-arterially and in each 1J.. case incorporated into microsomes.
S* S i, The preparation of pharmaceutical compositions is carried o. out according to conventional methods. For the preparation of pharmaceutical compositions to be administered transcutaneously, the compounds of general formula I can be mixed with a gel, ointment or liquid vehicle either with or without various solvents and stabilizers. The packages used are sprays, tubes, ampules and individual doses. Once applied to the skin either with or without an additional occlusive dressing, the active agent is absorbed.
The compounds of general formula I can also be placed either with or without stabilizers and solvents onto a plaster and can then be applied as such.
The conversion of the ethyl ester to PGE1 in the human body was demonstrated in the following way: an isotopically labelled PGE1 ethyl ester was applied in the manner described above. The isotopically labelled urinary metabolites were separated with HPLC and compared with the retention time of the main metabolite of PGE1 (7a-hydroxy-5, 1-diketotetranorprosta-1,20-dioic acid). It was found that after administration of the PGE1 ethyl ester, the main metabolite was identical to the main metabolite after administration of PGE1. This proves that the PGEI ethyl ester is a r -o-drug of 'GE1.
The following examples illustrate the invention.
EX M P L E 1 The preparation of prostaglandin El ethylester.
Excess diazoethane in diethyl ether (17 mg/ml; 0.3 mmol) is added to 500 jig PGE1 (1.31 pmol) in 500 al ethanol under S stirring and cooling. The reaction mixture is taken out of the cooler and is stirred until it reaches room temperature.
Stirring is then continued for a further 33 minutes. The
ISS«
S* excess diazoethane and the ethanol are removed at room temperature by a stream of nitrogen. The produce is purified by high-pressure liquid chromatography (RP 18), In the same manner and with excess diazoethane, 500 jg of '2t 6-keto PGE1 in 500 il of ethanol are reacted and processed in diethyl ether. The ester is purified by high-pressure liqid chromatography (RP 18).
*0* 0 E X A M P L E 2 250 ig of prostaglandin El ethyl ester together with an isotopically labelled PGEl-ethyl-ester in 250 il of ethanol were worked into 2 g of a gel vehicle of the composition as indicated below. The gel was applied to the upper arm and rubbed in for 1 minute. The application area was covered with a plastic foil.
One week later, 250 pg of prostaglandin El together with an isotopically labelled PGE! in 250 j1l of ethanol were mixed with 2 g of a gel vehicle of the composition as indicated below. It, too, was applied to the upper arm and rubbbed in for 1 minute.
Measurement of the absorbed quantity was carried out by determining the isotopically labelled prostaglandin metabolites in the urine. For this, the total urine was collected in portions from the beginning of the application onwards. Four hours after the application, the plastic film was removed and the excess gel wiped off. As can be seen in Fig. 1, the absorption rate of PGEI ethyl ester (23 was clearly better than that of PGE1 (approx. 4 The gel vehicle was prepared according to the following recipe: Isopropanol 40.0 g Diisopropyl adipate 0.5 g SCarbopol 940 2.0 g Trometamol 1.91 g Purified water ad 100.0 g The isopropanol can also be exchanged for ethanol.
*I The water, alcohol and diisopropyl adipate are mixed, the carbopol is dispersed in this mixture and left to swell. The gel is neutralized with the aqueous trometamol-solution.
This application is divided from our copending application 11776/88 (623336) and the entire disclosure in the specification and claims of that application as originally filed is by this cross-reference incorporated into the present specification.
Claims (12)
1. A transcutaneous pharmaceutical composition when used in the treatment of a condition selected from peripheral occlusive disease, a complication of arteriosclerosis, acute myocardial infarction, unstable angina pectoris, acute ischaemic stroke, impotence, bronchial asthma, impaired hair growth, rejection following the transplantation of an organ, gastrointestinal or cutaneous ulcer, and haematoma, comprising as its active ingredient a prostaglandin El derivative of general formula (I) HO OH 1CooR 2 (E) HO I 20 in which R 1 is a hydrogen atom and R, is a C,. 4 alkyl residue, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier,
2. A composition according to Claim 1, wherein R 2 is an ethyl group.
3. A composition according to Claim 1 or 2 when used S: for the treatment of circulatory insufficiencies. 30
4. A composition according to Claim 1 or 2 when used S for the treatment of impotence.
A composition according to Claim 1 or 2 when used for the inhibit:ion of platelet aggregation.
6. A composition according to Claim 1 or 2 when used for the treatment of bronchial asthma.
7. A composition according to Claim 1 or 2 when used for the treatment of gastrointestinal ulcers and ulcers of the skin.
8. A composition according to Claim 1 or 2 when used for the treatment of haematomas.
9. A composition according to Claim 1 or 2 when used for the treatment of impaired hair growth.
A composition according to Claim 1 or 2 when used for the treatment of a rejection following the transplantation of an organ.
11. A composition according to any one of Claims 1 to wherein the carrier is selected from the group consisting of a gel, ointment or liquid vehicle.
12. A method of treatment of a condition selected from peripheral occlusive disease, a complication of arteriosclerosis, acute myocardial infarction, unstable angina pectoris, acute ischaemic stroke, impotence, bronchial asthma, impaired hair growth, rejection following the transplantation of an otgan, gastrointestinal or cutaneous ulcer, and haematoma, comprising the step of transcutaneously administering to a patient in need of such treatment a therapeutically effective dose of a pharmaceutical composition according to any one of claims I to 11, which method includes using an occlusive dressing. o DATED THIS 2ND DAY OF MARCH 1994 HERBERT BIPPI and JURGEN C. FROLICH By Its Patent Attorneys GRIFFITH HACK CO Fellows Institute of Patent Attorneys of Australia
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873704825 DE3704825A1 (en) | 1987-02-16 | 1987-02-16 | PROSTAGLANDIN E1 DERIVATIVES AS PHARMACEUTICAL ACTIVE SUBSTANCES AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, IN PARTICULAR FOR TRANSCUTANEAL USE |
| DE3704825 | 1987-02-16 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11766/88A Division AU623336B2 (en) | 1987-02-16 | 1988-02-16 | Method of treatment comprising transcutaneous administration of prostaglandin E1 derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1518492A AU1518492A (en) | 1992-06-25 |
| AU649130B2 true AU649130B2 (en) | 1994-05-12 |
Family
ID=6321070
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11766/88A Ceased AU623336B2 (en) | 1987-02-16 | 1988-02-16 | Method of treatment comprising transcutaneous administration of prostaglandin E1 derivatives |
| AU15184/92A Ceased AU649130B2 (en) | 1987-02-16 | 1992-04-24 | Pharmaceutical compositions for transcutaneous administration |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11766/88A Ceased AU623336B2 (en) | 1987-02-16 | 1988-02-16 | Method of treatment comprising transcutaneous administration of prostaglandin E1 derivatives |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0292643B1 (en) |
| JP (1) | JPS63246331A (en) |
| AT (1) | ATE80616T1 (en) |
| AU (2) | AU623336B2 (en) |
| CA (1) | CA1327359C (en) |
| DE (2) | DE3704825A1 (en) |
| DK (1) | DK173552B1 (en) |
| ES (1) | ES2043696T3 (en) |
| GR (1) | GR3005743T3 (en) |
| HU (1) | HU199687B (en) |
| ZA (1) | ZA881053B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2939569A (en) * | 1957-10-16 | 1960-06-07 | Gay W Roach | Cotton weighing machine |
| US5530027A (en) * | 1993-02-03 | 1996-06-25 | Teijin Limited | External skin treatment agent composition containing prostacyclins as active ingredient |
| US5656663A (en) * | 1993-02-03 | 1997-08-12 | Teijin Limited | External skin treatment agent composition containing isocarbacyclins as active ingredient |
| US6007836A (en) * | 1993-05-28 | 1999-12-28 | Vericade, Inc. | Transdermal vasodilator |
| FR2812191B1 (en) * | 2000-07-28 | 2003-10-17 | Oreal | USE OF PROSTAGLANDIN E2 RECEPTOR AGONISTS (EP-3) TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS |
| FR2812193B1 (en) * | 2000-07-28 | 2003-10-24 | Oreal | USE OF AN ANTAGONIST OF PROSTAGLANDIN EP-2 AND / OR EP-4 RECEPTORS TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS |
| FR2812192B1 (en) * | 2000-07-28 | 2003-01-31 | Oreal | USE OF PROSTAGLANDIN EP-3 RECEPTOR ANTAGONISTS AS A COSMETIC AGENT FOR MITIGATING, REDUCING OR STOPPING HAIR AND HAIR LOSS |
| FR2812190B1 (en) * | 2000-07-28 | 2003-01-31 | Oreal | USE OF NON-PROSTANOIC AGONISTS OF EP-2 AND / OR EP-4 PROSTAGLANDIN RECEPTORS AS A COSMETIC AGENT FOR MITIGATING, DECREASING OR STOPPING HAIR AND HAIR LOSS |
| JP2006522136A (en) | 2003-04-02 | 2006-09-28 | ネックスメド ホールディングス インコーポレイテッド | Prostaglandin composition and its use for the treatment of vasospasm |
| IT1402047B1 (en) * | 2010-10-19 | 2013-08-28 | Cross Pharma Sa | USE OF MEXIPROSTIL IN THE TREATMENT OF INTESTINAL INFLAMMATORY DISEASES |
| CA2838109C (en) | 2011-04-07 | 2020-06-09 | Nexmed Holdings, Inc. | Topical semisolid prostaglandin e1 composition for treating raynaud's disease |
| US8865685B2 (en) * | 2011-06-30 | 2014-10-21 | Johnson & Johnson Vision Care, Inc. | Esters for treatment of ocular inflammatory conditions |
| ITRM20120036A1 (en) * | 2012-02-02 | 2013-08-03 | Robert Davis Steigerwalt Jr | TRANSDERMAL APPLICATION OF PROSTAGLANDINE E1 FOR THE TREATMENT OF OCULAR ISCHEMIA. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0132027A1 (en) * | 1983-05-20 | 1985-01-23 | Taisho Pharmaceutical Co. Ltd | Fat emulsion containing prostaglandin |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3735005A (en) * | 1970-08-19 | 1973-05-22 | Alza Corp | Method for preparing a viable platelet concentrate |
| AU511711B2 (en) * | 1976-12-30 | 1980-09-04 | Upjohn Company, The | 6-Oxo and 5, 6-Dihalo prostaglandin analogues |
| US4205178A (en) * | 1976-12-30 | 1980-05-27 | The Upjohn Company | 6-Keto prostaglandin E-type compounds |
| JPS6022710B2 (en) * | 1977-09-16 | 1985-06-03 | 小野薬品工業株式会社 | Prostaglandin-like compounds |
| US4707495A (en) * | 1985-10-28 | 1987-11-17 | Ortho Pharmaceutical | Peptic ulcer treatment method |
-
1987
- 1987-02-16 DE DE19873704825 patent/DE3704825A1/en not_active Withdrawn
-
1988
- 1988-02-15 JP JP63032571A patent/JPS63246331A/en active Pending
- 1988-02-15 DE DE88102189T patent/DE3874610D1/de not_active Expired - Lifetime
- 1988-02-15 ES ES88102189T patent/ES2043696T3/en not_active Expired - Lifetime
- 1988-02-15 EP EP88102189A patent/EP0292643B1/en not_active Expired - Lifetime
- 1988-02-15 DK DK198800775A patent/DK173552B1/en not_active IP Right Cessation
- 1988-02-15 AT AT88102189T patent/ATE80616T1/en not_active IP Right Cessation
- 1988-02-16 AU AU11766/88A patent/AU623336B2/en not_active Ceased
- 1988-02-16 ZA ZA881053A patent/ZA881053B/en unknown
- 1988-02-16 CA CA000559004A patent/CA1327359C/en not_active Expired - Fee Related
- 1988-02-16 HU HU88742A patent/HU199687B/en not_active IP Right Cessation
-
1992
- 1992-04-24 AU AU15184/92A patent/AU649130B2/en not_active Ceased
- 1992-09-17 GR GR920402069T patent/GR3005743T3/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0132027A1 (en) * | 1983-05-20 | 1985-01-23 | Taisho Pharmaceutical Co. Ltd | Fat emulsion containing prostaglandin |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1518492A (en) | 1992-06-25 |
| HU199687B (en) | 1990-03-28 |
| ES2043696T3 (en) | 1994-01-01 |
| ZA881053B (en) | 1988-08-12 |
| GR3005743T3 (en) | 1993-06-07 |
| JPS63246331A (en) | 1988-10-13 |
| DK77588A (en) | 1988-08-17 |
| AU623336B2 (en) | 1992-05-14 |
| EP0292643A1 (en) | 1988-11-30 |
| HUT46224A (en) | 1988-10-28 |
| DE3704825A1 (en) | 1988-08-25 |
| EP0292643B1 (en) | 1992-09-16 |
| DK77588D0 (en) | 1988-02-15 |
| DE3874610D1 (en) | 1992-10-22 |
| AU1176688A (en) | 1988-08-18 |
| ATE80616T1 (en) | 1992-10-15 |
| CA1327359C (en) | 1994-03-01 |
| DK173552B1 (en) | 2001-02-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5464868A (en) | Prostaglandin E1 derivatives for transdermal administration and methods of treatment therewith | |
| JP3701870B2 (en) | 9-Deoxy-2 ', 9-α-methano-3-oxa-4,5,6-trinol-3,7- (1', 3'-interpheny for the treatment of peripheral vascular disease | |
| CA2562614C (en) | Use of treprostinil to treat neuropathic diabetic foot ulcers | |
| US8071613B2 (en) | Anti-constipation composition | |
| JP5378219B2 (en) | Positively charged water-soluble prodrugs of prostaglandins and related compounds with very high skin permeability | |
| CA2549801C (en) | Use of treprostinil to improve kidney functions | |
| AU649130B2 (en) | Pharmaceutical compositions for transcutaneous administration | |
| US6562868B1 (en) | Method for treatment of female sexual dysfunction | |
| JPS6020365B2 (en) | Composition | |
| JPS60120995A (en) | Production of new amino acid derivative | |
| JP6030168B2 (en) | Positively charged water-soluble prodrugs of prostaglandins and related compounds with very high skin permeability | |
| JP5925158B2 (en) | Positively charged water-soluble prodrugs of prostaglandins and related compounds with very high skin permeability | |
| JP2522962B2 (en) | Remedy for psoriasis | |
| JP6306067B2 (en) | Positively charged water-soluble prodrugs of prostaglandins and related compounds with very high skin permeability | |
| EP0402477B1 (en) | Use of isocarbacyclins for preventing or treating organ diseases |