Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-06-19
1998-02-17
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514966, 514808, 424433, 424436, A61K 3730
Patent
active
057191220
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/02874.
The present invention relates to novel pharmaceutical compositions containing calcitonins, and to a novel method of enhancing the absorption of a calcitonin across a mucosal membrane.
The calcitonins are a class of pharmacologically active peptides, of both natural and synthetic origin, which contain approximately thirty two amino acids, and which have the ability to regulate serum calcium levels.
Various calcitonins, including e.g. natural human, salmon and eel calcitonins and the synthetic eel calcitonin analogue elcatonin are now commercially available and commonly employed, e.g. in the treatment of Paget's disease, Sudeck's disease and osteoporosis.
A considerable and well known problem with the administration of peptides is that they are susceptible to rapid acid and enzyme-induced degradation when administered orally. For this reason, parenteral administration has been, hitherto, the most widely used means of administration and, in the case of peptides of higher molecular weight, such as the calcitonins, has been the only significant effective means of administration.
It is widely recognised that administration by injection can be both inconvenient and unpleasant for the patient, particularly when the administration has to be repeated at regular intervals for long periods, e.g. in the treatment of post-menopausal osteoporosis with calcitonins. Thus, there has been growing interest in the administration of peptides by more acceptable non-invasive alternative routes, for example in the form of sublingual tablets, suppositories, intrapulmonary powders, intranasal drops, sprays, powders, gels, ointments and inserts.
A significant problem with many peptides, particularly those of higher molecular weights, is that they are only poorly absorbed across biological membranes, e.g. mucosal membranes, and thus the bioavailability of the peptide is often very low. Considerable research has therefore been carried out in order to find methods of improving the transepithelial absorption of peptides. One approach is to use an adjuvant or absorption enhancer and there are numerous published reports of compounds which are claimed to have peptide absorption-enhancing properties.
Thus, for example, choline esters (EP 214898), acyl carnitines (EP 215697), aldoses and glucosamines (Japanese Pat. Appl. No. 61 126034), ascorbates and salicylates (EP 37943), alpha-cyclodextrin (EP 0094157), pyroglutamate esters (EP 173990), chelating agents U.S. Pat. No. 4,476,116) ethanol, benzyl alcohol and polyethylene glycol 400 (EP 371010) have been proposed as absorption enhancers.
There are many published reports that surfactants can enhance the absorption of polypeptides, see for example EP 115627 (Armour), GB 2,127,689 (Sandoz), U.S. Pat. No. 4,548,922 (Carey et al) and Hirai et al., Int. J. Pharm., 9, 165-184, 1981. However, a recognised problem with surfactant absorption promoters is that, they can cause irritation and histolesion at the site of administration. In some cases this may depend upon the amount employed. These problems become of great importance when the peptide is administered regularly over a prolonged period.
We have now found that absorption of elcatonin following rectal administration is surprisingly enhanced when it is administered as a formulation with a polyglycolysed glyceride, and that such formulations do not cause irritation or histolesion. We have also found a surprising enhancement in absorption when elcatonin is administered as a formulation with a polyglycolysed glyceride, to the colonic mucosa.
In a first aspect therefore the present invention provides a composition containing a calcitonin, a polyglycolysed glyceride and a pharmaceutically acceptable carrier.
The invention also provides a method of enhancing the absorption of a calcitonin across a mucosal membrane, which method comprises co-administering with the calcitonin an effective amount of an absorption enhancer which is a polyglycolysed glyceride.
The polyglycolysed glycerides according to the inventi
REFERENCES:
patent: 5430021 (1995-07-01), Rudnic et al.
WPIDS abstract 81-80457D JP56118013, Sep. 16, 1981.
WPIDS abstract 91-214557 US5002771 Feb. 3, 1989.
The Merck Manual 15th edition, 1987, pp. 1295-1297, 1644, 2309, 1729, 2657-58.
Chiodini Laura
Fonio Teodoro
Rancati Gianfranco
Cook Rebecca
Dinner Dara L.
Lentz Edward T.
SmithKline Beecham Farmaceutici S.P.A.
Venetianer Stephen
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