Formulation for the oromucosal, in particular pernasal, route

Details Formulation for the oromucosal, in particular pernasal, route Formulation for the oromucosal, in particular pernasal, route

1999-01-06

2001-12-04

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S966000

Reexamination Certificate

active

06326401

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a new formulation for the oromucosal, in particular the pernasal, route.
BACKGROUND OF THE INVENTION
The oral administration route for medicamentous active substances, in particular solid active substances, is by far the most widely used. In fact, solid forms administered by the oral route are particularly suitable for ambulatory treatment, and this type of formulation usually offers a good stability with respect to time. However, this administration route, in which the active substance is administered by the buccal route, to be delivered into the stomach and the small intestine, has its limits, in particular because a large number of active substances are degraded in the gastrointestinal tract. As a result, it is often necessary to administer to the patient a dose of active substance which is considerably higher than the dose actually necessary for the activity of the product such as can be obtained by parenteral, intravenous, subcutaneous or intramuscular administration, for example, which leads to an increase in the volume of active substance to be administered. It is therefore necessary to manufacture considerably more active substance that is actually necessary in theory to obtain the desired therapeutic effect.
For this reason, new pharmaceutical forms are still being sought, in particular for active substances which are degraded particularly in the gastrointestinal tract.
Alternatives to parenteral administration, which involves sterile equipment and also aseptic conditions during the administration, which limits commercial distribution, are also still being sought.
Among the formulations suitable for ambulatory use, formulations for administration via the intermediary of the bucco-pharyngeal or nasal mucosa are also well known.
The formulations for the nasal route are generally intended for treatment of conditions of the nasal and rhinopharyngeal mucosa, and are thus essentially reserved for local treatment. This pharmaceutical form is rarely used for more general uses.
The formulations for the buccal route are generally intended for local treatment of conditions of the buccal mucosa, such as aphthae. This pharmaceutical form is also rarely used for systemic uses.
It would thus be desirable to have available an effective pharmaceutical formulation which is particularly suitable for ambulatory treatment, in particular suitable for medicaments which have a tendency to be degraded particularly by oral administration. Such a pharmaceutical formulation should cause neither irritation nor lesion of the mucosa.
Practice in the pharmaceuticals industry demands a large number of quality controls, and it would also be desirable if the nature of such a formulation is such that it does not interfere with direct assay of the active substance, such that it is easy to follow the product in a manufacturing chain or to identify the product. The phase of extraction of the active substance for its characterization would thus be avoided.
It would also be desirable to administer significant doses of active substances in volumes which are as reduced as possible.
In the majority of pathologies, it is desirable to obtain the fastest possible effect. For this reason, a particularly advantageous pharmaceutical formulation would be capable of achieving the fastest possible medicamentous effect, in addition with a good reproducibility of the administration.
SUMMARY OF THE INVENTION
The Applicant has now discovered, surprisingly, that particular pharmaceutical formulations for the oro-mucosal route, in particular for the nasal route, are a solution which is particularly suitable for the problems described above.
The present invention thus relates to a liquid pharmaceutical formulation for administration by the oro-mucosal, in particular nasal, route, characterized in that it comprises at least one non-polypeptidic active substance and less than 5% W/W of capryl caproyl macrogol glycerides (sometimes referred to as C
8
-C
10
saturated polyglycolysated glycerides).
WO-A-94/08622 discloses pharmaceutical formulations comprising an active substance and saturated or unsaturated polyglycolysed glyceride, but the active substance is a polypeptide of about 32 amino acids, particularly calcitonin, and the saturated or unsaturated polyglycolysed glycerides represents 7% or more, generally 35 to 90% by weight and more of the formulation which usually is a gel or is solid. Whenever these formulations comprise caproyl macrogol glycerides such as Labrasol, such compounds represent 20% or more of the formulation.
In the present invention and hereafter, “oro-mucosal route” is understood as meaning the mucosa lining the buccal, nasal or pharyngeal cavities.
“Polypeptidic active substance” is understood as meaning an active substance comprising a chain of at least 10 amino acids.
The administration of an active substance by the oro-mucosal route can involve administration of an effective dose of active substance in the form of a single dose or fractionated doses.
The active substance can be of any nature with the above proviso, and there may be mentioned, for example, antibiotics, bacteriostatics, antihistamines, analgesics and medicaments for cardioangiology, such as antihypertensives, diuretics, vasodilators and vasoconstrictors. The active substance can also be for endocrinology, and in this respect there may be mentioned oestrogens, oestroprogestogens, glucocorticoids, hypothalamic or hypophysial hormones or progestogens. It can also be an active substance for infectiology, such as antibiotics or antibacterial agents, antiviral agents or vaccines. It can also be a compound for neurology, such as analgesics.
The active substance can be, in particular, a compound derived from an endogenous mediator, in particular one of those described in EP-A-0 457 701, that is to say a derivative of biologically active molecules containing a primary amine function and a hydroxylated nucleus or one of their addition salts with mineral or organic acids, of the formula (I):
 [R′R″N—A—B—O—CH
2
—CO]
n
R
1
  (I)
or of the formula (II)
R′R″N—A—B—O—CH
2
—CO—NH—R—NH—CO—CH
2
—O—B—A—NR′R″  (II)
in which
n represents an integer from 1 to 10; A represents a linear or branched alkylene chain containing 1 to 5 carbon atoms; B represents an aromatic nucleus containing 6 to 10 optionally substituted carbon atoms and optionally a heteroatom; R
1
represents an amino radical or an alcohol radical chosen from phenols, which are optionally substituted, and aliphatic C
1
-C
16
alcohols; R′ and R″ represent an alkyl radical containing 1 to 5 carbon atoms or a hydrogen atom and R represents a divalent diamine or polyamine radical, in particular the derivatives mentioned as preferred in this patent, and especially tryptamine 5-O-carboxymethyl-tyrosyl-glycinamide (IS 159), called “IS 159” below, or one of its salts.
The active substance can also be, in particular, an antimigraine active substance, such as a triptan, such as sumatriptan or zolmitriptan.
The active substance may represent important amounts in the formulation, up to the limit of solubility of the active substance in the said formulation.
The capryl caproyl macrogol glycerides are also known by the name of saturated polyglycosylated C
8
-C
10
glycerides. Some of them are marketed by the company GATTEFOSSE under the name Labrasol®.
Capryl caproyl macrogol glycerides are mixtures of monoesters, diesters and triesters of glycerol and monoesters and diesters of macrogol with an average molecular weight of between 200 and 400.
These compounds can also be obtained by partial alcoholysis of medium-chain triglycerides using macrogol, or by esterification of glycerol and macrogol with caprylic acid and capric acid or of a mixture of esters of glycerol and an ethylene oxide condensate with caprylic acid and capric acid.
In preferred embodiments of the invention, less than 3% weight/weight of capryl caproyl macrogol glycerides is used in a finished pharmaceutic

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