WO1992003128A1

WO1992003128A1 - Pharmaceutical compositions with mucolytic and antitussive activity containing (-)-trans-sobrerol

Info

Publication number: WO1992003128A1
Application number: PCT/EP1991/001530
Authority: WO
Inventors: Guillermo Bleichner
Original assignee: Riace Establishment
Priority date: 1990-08-22
Filing date: 1991-08-12
Publication date: 1992-03-05
Also published as: EP0496858A1; JPH05502892A; AU8327491A; CH681060A5

Abstract

Pharmacological characteristics of 1R-trans-5-hydroxy-α,α,4-trimethyl-3-cyclohexene-1-methanol and pharmaceutical compositions containing it as the active ingredient are described.

Description

PHARMACEUTICAL COMPOSITIONS WITH MUCOLYTIC AND

ANTITUSSIVE ACTIVITY CONTAINING (-)-TRANS-SOBREROL

The present invention relates to pharmaceutical compositions having mucolytic and central antitussive activities containing as the active ingredient (-)- trans-sobrerol, namely 1R-trans-5-hydroxy-α,α,4-trimethyl-3-cyclohexene-1-methanol, of formula (I).

Sobrerol is a well-known drug and it has been used in therapy for a long time because of its mucolytic activity.

Sobrerol has two asymmetric carbon atoms, therefore it is normally used in the form of a mixture of two diastereoisomer pairs of enantiomers, whose pharmacological properties have never been studied up to now.

On the contrary, physico-chemical characteris cs of sobrerol enantiomers have been studied widely (Congr. Int. Technol. Pharm. 1989 Vol. I 232-40, Chem Abstr. 112(8) 62485).

It has now been found that (-)-trans-sobrerol enantiomer has a central antitussive activity, which has never been described nor recognized for racemic sobrerol, as well as a lower toxicity than the latter.

Accordingly, the invention provides pharmaceutical compositions containing (-)trans-sobrerol as the active ingredient, said compositions being useful in the tre- atment of acute and chronic bronchopulmonary patholo-gies, like bronchitis, pneumonia, bronchopneumonia, bronchiectasis and, generally, all those conditions where soothing the tussive symptomatology and/or regu- lating mucus secretion are desirable.

The compositions of the invention can be prepared according to well-known techniques and excipients, like those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA 17^th Ed.

Suitable administration forms are tablets, capsu- les, sachets, syrups, solutions for the parenteral or aerosol administrations, nasal drops and the like. The single dose of active ingredient will range from 10 to 500 mg, while general posology will depend on several factors (pathology, patient conditions) : for instance, for an adult weighing about 70 kg a 100 to 1000 mg/day administration can be provided, optionally divided in several administrations.

(-)-Trans-sobrerol can be prepared by means of known methods like those described in the above mentioned reference, or conventional methods for the asymmetric synthesis, the isomer separation and the optical resolution. A suitable method consists in using 1-α-pinene oxide as starting material.

Useful teachings about the preparation of (-)- trans-sobrerol can be found, for example, in Helv. Chim. Acta 1987, 70(1), 71-8.

(-)-Trans-sobrerol may also be prepared by microbiological conversion of α-pinene and α-pinene epoxide, using a strain of Pseudomonas fluorescens, according to the following method:

a) Microorganism

The microorganism used for producing (-)-trans-sobrerol is Pseudomonas fluorescens, whose taxonomic properties have been controlled by the National Collection of Industrial Bacteria (NCIMB, Torry Research Station, Aberdeen, UK).

b) Growing of the microorganism

Pseudomonas fluorescens is being kept in plates with "nutrient" agar at 30°C. The cultures are used to inoculate Erlenmeyer flasks (250 ml) containing 50 ml of the culture medium disclosed in Table 1, and glucose (0.5% by volume) as a sole source of carbon. The flasks are then incubated in an orbitant mixer at 150 rpm and

30°C.

TABLE 1

Component (g/l)

NaH ₂PO₄.2H₂O 3.04

K₂HPO₄ 5.31

(NH₄)₂SO₄ 1.30

EDTA (disodium salt) 0.05

CaCO₃ 0.0050

ZnO 0.0010

FeSO ₄.7H₂O 0.0140

MnCl₂.2H₂O 0.0025

CuCl₂.6H₂O 0.0004

CoCl₂.6H₂O 0.0006

H₃BO₃ 0.0002

MgCl₂.6H₂O 0.2500

NaMoO ₄.2H₂O 0.0006 * The pH was adjusted to 7.0

c) Fermentation

After 24 hours growing of the microorganism, 1 ml of α- pinene is added to the flask. After 48 hours, 1 ml of α-pinene epoxide is added. The production of (-)-trans- sobrerol from α-pinene takes place in 24-36 hours.

d) Recovering of (-)-trans-sobrerol

The precipitated, raw (-)-trans-sobrerol is filtered and recrystallized from ethanol, giving microcrystals melting at 150°C in a 95.5% yield. The [α]_D ²⁰ is -149.5° (c = 1 g in 10 ml EtOH) ; m.p. 150°C and [α]_D ²⁰ = -150° (c = 10 in ethanol) are reported in the Merck Index 11^th Edition, 8514.

The result from pharmacological tests in comparison with racemic sobrerol are hereinafter reported.

MUCOLYTIC ACTIVITY

(Mawatari H. Kagoshima Daigaku Igaku Zasshi 27, 561;

1976)

Student's test

The following examples further illustrate the invention. FORMULATIONS

1) CAPSULES A B C (-)trans-sobrerol mg 100 200 300 lactose mg 12 24 36 maltodextrin mg 6 16 24 polyvinylpyrrolidone mg 7 14 21 magnesium stearate mg 2 4 6

2) SUPPOSITORIES

(-)-trans-sobrerol mg 20 100 200 glycerides mg 800 1000 1600

3) SACHETS

(-)-trans-sobrerol mg 100 200 330 flavours mg 110 220 330 citric acid mg 5 10 15 saccharin mg 4 8 12 aspartame mg 5 10 15 polysorbate 20 mg 1,5 3 4,5 sorbitol mg 750 1500 2250

) SYRUP

100 ml syrup contain

(-)-trans-sobrerol mg 1000 2000

sucrose mg 40 40

methyl-p-hydroxybenzoate mg 200 200

balsamic flavour mg 200 200

distiled. water g.s. to ml 100 100

5) ELIXIR

100 ml elixir contain

(-)-trans-sobrerol mg 1000 2000

sucrose mg 40 40

ethyl alcohol mg 10000 10000

balsamic extract mg 1000 1000 methyl-p-hydroxybenzoate mg 100 100 distiled water q.s. to ml 100 100

6) AMPOULES

(-)-trans-sobrerol mg 30 60 bidistilled water q.s. to ml 2 4

7) AEROSOL VIALS

(-)trans-sobrerol mg 30

bidistilled water q.s. to ml 3 3

Claims

1. Pharmaceutical compositions with mucolytic and antitussive activities containing (-)-trans-sobrerol as the active ingredient in admixture with a suitable carrier.

2. The use of (-)-trans-sobrerol for the preparation of a medicament with mucolytic and antitussive activities.

3. A process for the preparation of (-)-trans-sobrerol characterized in that a strain of Pseudomonas fluorescens is cultivated in the presence of α-pinene and α-pinene epoxide.