DK173552B1 - Use of Prostaglandin E1 Derivatives for the Preparation of Pharmaceutical Preparations for Transcutaneous Administration - Google Patents

Abstract

Prostaglandin E1 derivatives as pharmacological active compounds and medicaments containing these compounds are described, in particular for transcutaneous application.

Description

DK 173552 B1

The present invention relates to the use of prostaglandin E, derivatives (PGE, derivatives) for the preparation of pharmaceutical preparations for transcutaneous administration.

U.S. Patent No. 27,533,686 and corresponding U.S. Patent No. 4,205,178 disclose 6-keto-prostaglandin-E, derivatives, in particular the 6-keto-PGE, methyl ester.

A number of biological and pharmacological effects are described for these compounds. Different routes of administration are indicated for different types of diseases to be treated, e.g. oral, intravenous, subcutaneous, intra-arterial, buccal, rectal and intravaginal administration.

Focal administration is described in association with skin damage and skin diseases at or near the site of the injury or disease.

10 6-keto-prostaglandin derivatives are also disclosed in DE patent specification 28 40 032, which also refers to various forms of pharmacological activity and administration.

Prostaglandin E, (PGE,) and 6-keto-prostaglandin E, (6-k-PGE,) may be used to treat multiple diseases. These diseases include peripheral occlusion diseases, atherosclerosis complications such as Meniere's disease or acute hearing loss, acute myocardial infarction, unstable angina pectoris, acute ischemic stroke, impotence, bronchial asthma, impaired hair growth and rejection; see H. Sinzinger and W. Rogatti, Prostaglandin E, in atherosclerosis, Springer Verlag, Berlin-Heidelberg - New York, 1986; S. Schrey, PGE ,, Therapy of arterial closure-20 disease, Universitatsdruckerei and Verlag Dr. C. Wolf and Son, Miinchen, 1985.

PGE, is used to treat chronic arterial occlusion diseases in stages ΙΠ and IV. This condition requires intra-arterial or intravenous infusion, which severely limits the use of PGE, as the infusion is not only a burden on the ^ patient, but also involves some risk of arterial bleeding. None of the routes 25 (i.a. and i.v.) are suitable for continuous treatment in ambulatory patient care. However, long-term administration will be most appropriate for these diseases. The DK 173552 B1 2 oral administration of PGE is always problematic, as either a very low bioavailability renders such an administration unusable or as the typical undesirable effects (nausea, vomiting, diarrhea) render such an administration impossible due to the high concentration of the drug in the digestive tract when administered orally.

EP-A-132,027 discloses fat emulsions containing prostaglandin E1 alky ester and which exhibit a blood pressure lowering effect. In particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl ester are mentioned.

C.A. 72: 70628w describes the effect of PGE₂ esters as bronchodilators. In particular, PGErmethyl ester is mentioned.

It is the object of the present invention to provide PGE, derivatives for use in the preparation of pharmaceutical preparations for transcathal administration. The PGE3 derivatives, which were especially developed as pharmacologically active agents for transcutaneous administration, are absorbed by the skin and then cleaved by hydrolases to prostaglandin E, or 6-keto-PGE, and alcohol. Thus, the PGE 1 derivatives fulfill the requirements of the idea of a "precursor drug" and avoid the disadvantages of PGE and 6- keto-PGE 11 when administered arterially, intravenously or orally.

Thus, the present invention relates to the use of prostaglandin E, derivatives of general formula I

° COOR

H0 'OH

Wherein R 1 is a hydrogen atom (PGE 1) or a carbon oxygen atom (6-k-PGE 1) and R 2 is a C 1-4 alkyl group for the preparation of a pharmaceutical preparation for transcutaneous administration.

FIG. Figure 1 shows the absorption rate of PGE, and PGE, ethyl ester, which has been determined as the cumulative urinary excretion after transcutaneous administration.

Specific examples of alkyl groups are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl groups.

Due to the non-toxicity of the fragments, the preferred group R2 is an ethyl group.

The preparation of the compounds of general formula I is carried out in accordance with per se known methods of esterification of PGE, and 6-k-PGE. Eg. the methyl ester and the ethyl ester are prepared by reacting the starting compound with diazomethane or diazoethane, respectively; see also Ch. J. Sih et al., J. Am. Chem. Soc., Vol. 97 (1975), pages 857 to 865.

The compounds of general formula I can be used to treat circuit failure, e.g. in the brain, heart, and extremities, to inhibit platelet aggregation (platelet aggregation), impotence, and to treat allergic reactions such as bronchial asthma, post-transplant rejection, and impaired hair growth. Typical examples of deficiencies in cerebral blood supply are transient cerebral ischemia, acute hearing loss, dizziness caused by circulatory insufficiency and ischemic stroke. Typical examples of deficiencies in myocardial blood supply are angina pectoris and 20 myocardial infarction. Typical examples of deficiencies in the blood supply to the ectrochemicals are peripheral arterial circulatory insufficiency in atherosclerosis and Raynaud's disease and Reaynaud's syndrome.

The compounds of general formula I can also be used to treat gastrointestinal ulcerations and skin ulcerations. Typical examples of gastrointestinal ulcers are ulcer ventriculus, duodenal ulcer and ulcerative colitis (Crohn's disease).

A typical example of skin ulceration is ulcer cruris. The compounds of general formula I have a cell protective effect. The cells exhibit increased resistance to harmful stimuli.

The compounds of general formula I can be further used to treat hematomas, especially surface hematomas.

The preparation of pharmaceutical compositions is carried out according to conventional methods. For the preparation of pharmaceutical compositions to be administered transcutaneously, the compounds of general formula I may be mixed with a carrier in the form of a gel, ointment or liquid carrier either with or without various solvents and stabilizers. The packages used are syringe preparation packages, tubes, glasses, ampoules and individual doses. Once applied to the skin either with or without a further sealing compound, the active agent is absorbed.

The compounds of general formula I can also be applied either with or without 15 stabilizers and solvents to a patch and can then be applied as such.

The conversion of the ethyl ester to PGE 1 in the human body has been demonstrated as follows: an isotope labeled PGE ethyl ester was applied in the manner described above. The isotope-labeled urinary metabolites were separated by HPLC and compared with the retention time of the main metal bolite of PGE 2 It was found that after administration of the PGE 2 ethyl ester, the main metabolite was identical to the main metabolite after PGE administration. This proves that PGE ethyl ester is a precursor drug and PGE 1.

The following examples illustrate the invention.

Example 1 5 DK 173552 B1

Preparation of Prostelandin-Eyethyl Ester.

Excess diazoethane in diethyl ether (17 mg / ml; 0.3 mmol) is added to 500 µg PGE, (1.31 μπιοί) in 500 μg ethanol with stirring and cooling. The reaction mixture is taken out of the cooler and stirred until it reaches room temperature. Stirring is then continued for another 30 minutes. The excess diazoethane and ethanol are removed at room temperature by a stream of nitrogen. The product is purified by high-pressure liquid chromatography (RP 18).

Similarly, with an excess of diazoethane, 500 µg of 6-keto-PGE, in 500 10 µl of ethanol, is reacted and processed into diethyl ether. The ester is purified by high-pressure liquid chromatography (RP 18).

Example 2 250 µl of prostaglandin E, ethyl ester together with an isotope labeled PGE 2 ethyl ester in 250 µl of ethanol were worked up to 2 g in a gel carrier of the composition shown below.

The gel was applied to the upper arm and rubbed for 1 minute. The application area was covered with a plastic wrap.

One week later, 250 μ $ prostaglandin-E, together with the isotope-labeled PGE, in 250 μΐ ethanol was mixed with 2 g of a gel carrier of the composition shown below. This gel was also applied to the upper arm and rubbed for 1 minute.

Measurement of the absorbed amount was performed by determining the isotope-labeled prostaglandin metabolites in the urine. For this, the total urine was collected in portions \ from the beginning of application and thereafter. 4 hours after application, the plastic film

Claims (3)

10 Water, alcohol and diisopropyl adipate are mixed, carbopol dispersed in this mixture and left to swell. The gel is neutralized with the aqueous trometamol solution. Use of Prostaglandin E1 Derivatives of General Formula I 0 Ri «i L ^. coor 2 XCX H 0 OH where R 1 is a hydrogen atom or a carbonyl oxygen atom and R 2 is a Cualkyl group, for the preparation of a pharmaceutical preparation for transcutaneous administration. Use according to claim 1, characterized in that R 2 is an ethyl group. DK 173552 B1 Use according to claim 1 or 2, characterized in that the pharmaceutical preparation for transcutaneous administration is intended for the treatment of circulatory insufficiency, for the treatment of impotence, for the inhibition of platelet aggregation, for the treatment of bronchial asthma, for the treatment of gastrointestinal ulcerations or skin ulcerations. for the treatment of hematomas, for the treatment of impaired hair growth or for the treatment of rejection after transplantation of an organ.