FR2959936A1 - NASAL COMPOSITION WITH A SYSTEMIC VIEW BASED ON COCOYL PROLINE OR AT LEAST ONE OF ITS COMPONENTS - Google Patents

Abstract

A nasally administrable pharmaceutical composition comprising cocoyl proline or at least one of its constituents and a therapeutic agent, its method of production and its uses.

Description

Systemic nasal compositions containing cocoyl proline or at least one of its constituents.

Among the different sites of application of drugs to the body, the nasal mucosa is of particular interest because of its ease of access and its rich vascularity.

It is thus possible to use this route of administration for therapeutic molecules intended not only to treat local disorders (topical administration used most of the time to treat inflammations or infections of the nasal cavity) but also to allow a active principle to reach the general circulation (systemic action which makes it possible to treat various and varied pathologies).

Thus, the use of the nasal mucosa as a site of administration of therapeutic molecules for systemic purposes is now known to those skilled in the art. By way of example, mention may be made of the following therapeutic molecules which use this route of administration: sumatriptan, desmopressin, calcitonin, buserelin, nafarelin, etc.

While the intranasal route of administration is of particular interest, it nevertheless has drawbacks that significantly limit the use of this route of administration, among which:

- A very small absorption surface, which is about 150 cm2, or 0.06% of the intestinal absorption surface, the latter developing, meanwhile, 250m2. Because of this very low absorption surface, the nasal route can be considered only to administer very low doses of therapeutic agents (the usual dosage is generally much less than 20 mg in amount of therapeutic agent per unit of administration) Thus, the following table presents the values found in the literature: Agent Therapeutic Area Average Dosage Therapeutic / Indication Usual (by principal nasal administration) Sumatriptan Treatment of the 10 to 20 milligrams migraine Desmopressin Hormone 0.5 to 1 microgram antidiuretic for diagnostic use Buserelin Treatment 0.4 milligrams Hormonal prostate cancer Nafarelin Treatment 160 to 240 Hormonal micrograms endometriosis Calcitonin Treatment 10 to 40 micrograms Hormonal osteoporosis On the other hand, the nasal mucosa offers low permeability to therapeutic agents because it naturally plays a role of barrier and defense of the organism vis-à-vis foreign bodies 10 potentially pathogenic or toxic. It should also be noted that within this mucous membrane sit immune defense mechanisms that may hinder the transmucosal passage of said therapeutic agents. Thus, as a rule, less than 10% or even less than 5% of the dose administered to the agent. therapeutic, is found in the systemic circulation, which highlights the low bioavailability of systemic therapeutic agents administered in the nasal mucosa. By way of example, the values mentioned in the literature have been included in the table below: Agent Therapeutic Area / Therapeutic dose fraction Principal indication administered in the systemic circulation (in%) Sumatriptan Treatment of -16% Migraine Desmopressin <10% Antidiuretic Hormone for Diagnostic Use Buserelin Treatment <3% Hormonal Prostate Cancer Nafarelin Treatment <3% Hormonal Endometriosis Calcitonin Treatment <5% Hormonal Osteoporosis In other words, it is common at least 90%, or even at least 95% of the dose administered as a therapeutic agent remains in the nasal mucosa and fails to reach the general circulation. This dose is called the residual dose. In addition to the fact that this residual dose represents a financial loss due to the non-use of a substantial amount of therapeutic agent (which can sometimes be very expensive), said residual dose is highly likely to cause adverse effects on the nasal mucosa, as explained below.

Indeed, the nasal mucosa is a fragile and easily irritable area. As previously mentioned, a significant residual dose of therapeutic agent may cause undesirable effects in the nasal mucosa, such as irritation. By way of example, the table presented below shows the undesirable effects observed on this mucosa, effects that can legitimately be attributed to the persistence of a significant residual dose of unabsorbed therapeutic agent.

Agent Area Residual Dose Side Effects Therapeutic Therapeutic I unabsorbed local reported Indication (frequency and main designation) Sumatriptan Treatment -8.4 to 16.8 Very common: migraine taste milligrams unpleasant + 84% of dose administered nausea Common: nose and throat irritation with burns and bleeding Desmopressin Hormone 4,5 to 9 Common: antidiuretic nasal micrograms congestion, epistaxis, diagnostic use is approximately 90% irritation, rhinitis of the administered dose Buserelin Treatment 390 Common: Hormonal irritation micrograms nose and throat, cancer of the near 97% prostatic nose disorder of the administered dose Nafarelin Treatment 155 to 233 Frequent: Hormonal irritation of nasal micrograms endometriosis is close to 97% of the administered dose Calcitonin Treatment 9.5 to 38 Very Common: Rhinitis, Hormonal Micrograms Edema, Congestion , osteoporosis is close to 95% irritation, bleeding of the administered dose The potentially irritable nature of the nasal mucosa limits the use of compounds such as surfactants, solvents or co-solvents to which humans The profession could be tempted to resort to facilitating the transmucosal passage of therapeutic agents. For all the reasons mentioned above, the nasal route is in practice an alternative route of administration, which is only considered in certain particular cases, especially when the skilled person is looking for a fast installation pharmacological response which can be the case in the treatment of migraine attacks for example. In other cases, this route may be of particular benefit for rapidly degraded molecules in the gastrointestinal tract or rapidly metabolized in the liver due to hepatic first-pass effect. In addition, the nasal route may be of particular interest when it is impossible to administer an oral drug, for example in the case of nausea in which the patient will tend to regurgitate the substances absorbed through vomiting. In addition, the nasal route may also be an interesting alternative for substances that can be administered to the patient only in injectable form.

There is therefore a real need to solve the problems described above, namely to allow on the one hand to administer a therapeutic agent nasally with a satisfactory bioavailability and on the other hand to significantly reduce the residual dose found at level of the nasal mucosa.

The Applicant has surprisingly found that nasally administrable and systemic pharmaceutical compositions comprising cocoyl proline or at least one of its constituents are capable not only of perfectly respecting the integrity of the nasal mucosa but also of significantly increase the dose of therapeutic agent found in the blood, that is to say to significantly improve the bioavailability of the therapeutic agent so that it becomes possible to administer a reduced dose of the agent therapeutic and to obtain an efficiency at least equivalent to that observed in the state of the art. It should be noted that this efficiency is obtained by using a dose of therapeutic agent significantly reduced compared to the usual doses. The consequence is not measured solely by the "economy" of reducing the dose administered. Indeed, by improving the fraction of the absorbed dose and significantly reducing the dose administered, it appears that the amount of unabsorbed therapeutic agent is very significantly reduced, thus reducing the exposure of the nasal mucosa to this amount of agent. unabsorbed therapeutic, which therefore limits the risk of occurrence of irritative phenomena at the level of said nasal mucosa.

This is quite unexpected and could not be deduced from the state of the art as a whole. Indeed, no systemic nasal composition comprising cocoyl proline or at least one of its constituents is disclosed or suggested in the prior art as having such properties with respect to the nasal mucosa.

Furthermore, this could not be inferred from the earlier patent applications filed on behalf of the applicant, including international patent applications WO 02/076506 and WO 03/055528.

Indeed, the international application WO 02/076506 discloses compositions based on lipoamino acids without disclosing any compositions suitable for nasal use. In addition, the compositions described in this application all relate to dispersed systems, which implement said lipoamino acids. Thus, Examples 1 to 8 relate to dispersed systems comprising in particular surfactants (such as PEG30 polyhydroxystearate) and solvents (such as propylene glycol or its derivatives), as well as lipophilic compounds (such as soya or oleic acid), and this in significant proportions (on average the total of these compounds exceeds 50% of the weight of the composition). However, the use of such compounds can not be compatible with nasal administration because of the predictable adverse effects that they induce as irritation, edema, congestions or bleeding (epistaxis). Therefore, the use of such systems can not be envisaged for an application on the nasal mucosa, so that this route of administration is not a preferred route of administration with respect to the object of WO 02 invention / 076506. The preferred routes of administration are in fact the oral route, the transdermal or pulmonary route (see WO 02/076506, page 8, lines 9-10), and preferably the oral and pulmonary routes (see claim 1). It is therefore logical that this international application has no example using a lipoamino acid in such a system dispersed for nasal administration.

Furthermore, it is known to those skilled in the art that ionic compounds such as lipoamino acids are generally likely to cause irritating effects on the epidermis or on the mucous membranes. This property is also common to all ionic agents, because the latter are load carriers when they are dissolved. This terminal charge then allows them to organize into micelles. In contact with a biological membrane, these micelles can disorganize the membrane lipids, thus causing an alteration of the cellular barriers and a leak of cellular material. Such properties are incompatible with use on the nasal mucosa which is, as mentioned above, particularly fragile and irritable. It was therefore quite unexpected, in view of the potentially irritating properties of lipoamino acids, that cocoyl proline or at least one of its constituents could be used in a nasal composition.

The international application WO 03/055528, for its part, is limited to the description of ionic associations between a lipoamino acid and a biologically active molecule. The use of cocoyl proline or at least one of its constituents as lipoamino acid in a nasally administrable composition is not exemplified. In addition, this international application does not disclose, nor does it suggest, the use of cocoyl proline or at least one of its constituents in a systemically administrable nasal composition.

An object of the present invention is therefore a nasally administrable pharmaceutical composition comprising cocoyl proline or at least one of its constituents, preferably cocoyl L-proline or at least one of its constituents, and a therapeutic agent, said therapeutic agent being selected from the group consisting of therapeutic molecules and therapeutic peptides.

The present invention aims to allow a significant dose of therapeutic agent to reach the general circulation (systemic administration) via a transmembrane passage in the nasal mucosa, while limiting the residual dose of therapeutic agent at the level of the nasal mucosa, nasal mucosa.

By "administrable nasally" it should be understood that a nasal administration of the composition according to the invention would provide a satisfactory bioavailability of the therapeutic agent, while not inducing substantial side effects, such as as irritative and / or painful phenomena. Preferably, the nasal administration of the therapeutic agent in the sense of the present invention does not generate significant side effects, such as the aforementioned irritative and / or painful phenomena.

By "satisfactory bioavailability" is meant a significant fraction of the dose or a significant improvement in the fraction of the therapeutic agent dose that reaches the general circulation and a sufficient rate with which it reaches it. It should be noted that the impairment of the general circulation by the therapeutic agent thus constitutes a condition for it to exert its action at the level of the targets making it possible to obtain the pharmacological effect expected.

For the purposes of the present invention, the term "cocoyl proline or at least one of its constituents" means a product resulting from the condensation of the amine function borne by proline with the carboxylic acid function carried by one or more of the fatty acids. present in natural or purified coconut oil. The coconut oil generally contains a mixture of fatty acids whose length of the carbon chain may be between 6 and 18 carbon atoms (mixture of C6-C18 fatty acids). Thus, the expression "cocoyl proline or at least one of its constituents" denotes the condensation product of proline with the mixture of fatty acids included in the coconut oil, as well as any component resulting from this condensation. Among the main fatty acids present in coconut oil, there may be mentioned, for example, lauric and myristic acids (lauric acid being particularly preferred because it generally represents the fatty acid predominantly present in coconut oil) whose Condensation products with proline are respectively referred to as lauroyl proline and myristoyl proline.

The invention also relates to any systemic nasal composition comprising at least one C6-C18 proline acyl component, said acid consisting of a fatty chain present in coconut oil. By way of example, the naturally occurring fatty acids in coconut oil are generally caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, coconut palmitoleic acid, stearic acid, oleic acid, linoleic acid and linolenic acid.

According to a particularly preferred embodiment, for the purposes of the present invention, the levorotatory (L-form) form of proline, namely L-proline, which is the form found in the natural state, will be used. In this preferred embodiment, the product resulting from the condensation of L-proline with a natural or purified coconut oil will, logically, be cocoyl L-proline.

Preferably, the composition according to the invention comprises lauroyl proline and preferably lauroyl L-proline.

By way of example, it will be possible to provide the general formula of L-lauroyl proline indicated below: HOOC The term "therapeutic molecules" should be understood to mean any molecule having a systemic pharmacological activity administered as a preventive, curative or diagnostic, of natural or synthetic origin and of non-peptidic nature.

Preferably, for the purposes of the present invention, "therapeutic small molecules" corresponding to the abovementioned definition and having a molecular weight of less than 1000 g and whose dosage of administration is less than 1 mg / kg, will be used.

Preferably, the therapeutic molecules belong to the family of antimigraine agents such as triptan derivatives (sumatriptan, naratriptan, rizatriptan ...) anti-nausea agents such as 5-HT3 antagonists (ondanstron, granisetron, dolasetron ...) , analgesics such as morphine analgesics (fentanyl, alfentanyl, sufentanyl ....), hypnotics such as zolpidem, anxiolytics such as benzodiazepines (diazepam, triazolam, estazolam, etc ...).

The term "therapeutic peptide" refers to any molecule having a pharmacological activity, administered as a preventive, curative or diagnostic, comprising a sequence of at least two amino acids. Among these therapeutic peptides may be mentioned synthetic therapeutic peptides (such as buserelin, nafarelin, goserelin), natural peptides whose peptide chain contains up to ten amino acids (such as glutathione whose peptide chain contains three amino acids), peptides of intermediate size whose peptide chain contains up to fifty amino acids (such as salmon calcitonin whose peptide chain contains thirty-two amino acids) the larger therapeutic proteins whose peptide chain may comprise several hundred amino acids (like somatropin).

Preferably, the composition according to the invention comprises, as sole constituent of cocoyl proline, lauroyl proline, and preferably lauroyl L-proline.

According to a particularly preferred embodiment, the composition according to the invention does not comprise irritating agents, that is to say agents, such as surfactants, organic solvents or cosolvents, etc. which may induce irritation of the nasal mucosa at commonly used doses.

Preferably, the composition according to the invention is presented in the form of at least one unit dose of administration. Thus, the composition according to the invention may be commercially in the form of one or more unit doses of administration, depending on the nature of the therapeutic agent chosen and its administration dosage. The treatment may be single-dose or multi-dose, depending in particular on the therapeutic agent used and the pathology to be treated. The conditioning will be selected accordingly. Preferably a diffuser type of packaging suitable for nasal drug delivery such as a spray or nebulizer will be used depending on the intended application. This sprayer or nebulizer may, depending on the case, deliver the composition according to kinetics of immediate diffusion - classical kinetics - or according to a slow or prolonged diffusion kinetics that may range from a few seconds to a few tens of seconds.

Surprisingly, it has been found that the composition according to the present invention has properties that are just as unexpected as they are interesting, insofar as it makes it possible to reduce the doses of therapeutic agent used in the context of nasal administration. without altering the local tolerance and the safety of use of the treatment.

Another significant advantage is that the composition according to the invention makes it possible to make the nasal administration route available (for systemic purposes) to molecules whose dosage of administration is greater than 5 mg or even 10 or 20 mg.

However, and preferentially, the amount of therapeutic agent is less than 50 mg per unit dose of administration, and preferably less than 10 mg per unit dose of administration in order to reduce the exposure of the therapeutic agent to the nasal mucosa. during each administration.

Advantageously, the cocoyl proline molar ratio or at least one of its constituents / therapeutic agent is less than 50, and preferably less than 10, the cocoyl proline or at least one of its constituents acting most of the time in a molar ratio close to 1/1 with the therapeutic agent, this making it possible to reduce the exposure of cocoyl proline or at least one of its constituents to the nasal mucosa during each administration.

Advantageously, said composition comprises an aqueous liquid vehicle or powder.

According to a preferred embodiment, said aqueous or powdered vehicle represents more than 50%, and preferably more than 75%, of the volume of the unit dose to be administered; said aqueous or powdery vehicle also exerting the function of "diluent", and this in order to avoid the exposure of compositions too concentrated in therapeutic agent on the nasal mucosa during each administration.

Preferably, the unit dose of administration represents a volume of less than 1 ml and more generally close to 100 μl. These volumes are compatible with nasal administration of the invention and can be envisaged according to a kinetics of immediate (rapid) or prolonged administration over several seconds or several tens of seconds depending on the diffuser system used. In addition, this nasal administration can be performed in one or two nostrils, consecutively or simultaneously, depending on the nasal tip used.

Another object of the present invention is a pharmaceutical composition as previously described for use as a nasally administrable medicament.

More specifically, the present invention also relates to the aforementioned pharmaceutical composition for its nasal use as a medicament in the treatment of: migraine when the therapeutic agent is chosen from therapeutic molecules belonging to the family of antimigraine agents such as derivatives triptans such as sumatriptan, naratriptan and rizatriptan; nausea when the therapeutic agent is chosen from therapeutic molecules belonging to the family of anti-nausea agents such as 5-HT3 antagonists such as ondanstron, granisetron and dolasetron; pain when the therapeutic agent is chosen from therapeutic molecules belonging to the analgesic family, such as morphine analgesics such as fentanyl, alfentanyl and sufentanyl; sleep disorders when the therapeutic agent is chosen from therapeutic molecules belonging to the family of hypnotics such as zolpidem; anxiety disorders when the therapeutic agent is chosen from therapeutic molecules belonging to the family of anxiolytics such as benzodiazepines such as diazepam, triazolam, and estazolam; proliferative diseases or cancers, in particular of a hormone-dependent nature, when the therapeutic agent is chosen from the group of synthetic peptides such as nafarelin, buserelin or goserelin; hormonal disorders or metabolic disorders when the therapeutic agent is chosen from the group of small natural peptides, namely up to ten amino acids, of medium size, namely between eleven and fifty amino acids, and of size important, namely a number of amino acids greater than fifty, such as glutathione, calcitonin and somatropin respectively.

Preferably, the therapeutic agent is selected from the group consisting of therapeutic molecules belonging to the family of triptans such as sumatriptan, rizatriptan or naratriptan. According to a particularly preferred embodiment, the therapeutic agent is sumatriptan. .

Sumatriptan has the chemical name 3- [2- (dimethylamino) ethyl] -5 N-methyl-1H-indole-5-methanesulfonamide.

The chemical formula of sumatriptan is as follows: As mentioned earlier, sumatriptan belongs to the therapeutic class of triptans, a family of molecules widely used to treat migraine episodes.

According to a particularly preferred embodiment, the composition according to the invention comprises sumatriptan as a therapeutic agent and can be used nasally (systemically) as a medicament for the treatment of migraine, and preferably migraine attacks.

In other words, the invention also relates to the use of a pharmaceutical composition comprising cocoyl proline or at least one of its constituents, preferably cocoyl L-proline or at least one of its constituents and the sumatriptan as a therapeutic agent for the preparation of a nasally administrable medicament for treating migraine, and preferably migraine attacks.

The invention also relates to a method for treating migraine, and preferably migraine attacks, said method comprising the nasal administration to an individual of a pharmaceutical composition comprising cocoyl L-proline or at least one of its constituents and sumatriptan as a therapeutic agent.

Another subject of the invention is the use of cocoyl L-proline or at least one of its constituents in a nasally administrable pharmaceutical composition comprising a therapeutic agent in order to promote the transmucosal passage of said therapeutic agent at the level of the mucosa. nasal and / or decrease the residual dose of said therapeutic agent at said nasal mucosa.

The invention also relates to a nasally administrable pharmaceutical composition comprising cocoyl proline or at least one of its constituents, preferably cocoyl L-proline or at least one of its constituents, and a therapeutic agent, as defined above. said composition further comprising at least one non-irritating excipient for promoting transmucosal passage in the nasal mucosa.

Yet another object of the present invention is a process for obtaining the present pharmaceutical composition, said process comprising the following steps:

at. Introduction of a volume of water representing between 70% and 90%, and preferably about 80%, of the weight of the composition obtained in fine in a container equipped with a stirrer; b. Addition of a desired amount of cocoyl proline or at least one of its constituents and therapeutic agent with moderate agitation at a temperature of about 50 ° C; vs. Cooling of the solution formed with stirring; d. Addition of a desired amount of water in order to obtain a duly dosed therapeutic agent solution.

In general, the process for obtaining the composition according to the invention generally consists in introducing into an aqueous vehicle, such as water, the desired therapeutic agent and cocoyl proline or at least one of its constituents. with stirring.

Preferably, in step b of the above process, lauroyl proline, and preferably lauroyl L-proline, will be used as the sole constituent of cocoyl proline.

Alternatively, a method of obtaining useful especially for therapeutic agents sensitive to temperature can be used. The latter consists for example in the preliminary preparation of a cocoyl proline solution or at least one of its constituents in the presence of a large volume of water that can represent up to 80% of the final volume of the solution and in which a amount of sodium hydroxide is introduced to obtain a solution whose pH is close to neutrality. According to this alternative method, it is possible to heat the initial solution in order to accelerate the solubilization of cocoyl proline or at least one of its constituents with moderate stirring. In this case, the solution obtained will then be allowed to cool with stirring at room temperature before introducing the therapeutic agent. Still with stirring, the therapeutic agent can then be introduced into the solution thus prepared according to the proportions described in the invention to obtain, as the case may be: - a nasal solution that can be distributed directly into a diffuser of the sprayer or nebulizer type afterwards, if necessary, sterilizing treatment by filtration; a solid preparation obtained after drying the solution, for example by means of a lyophilization technique for administration in the form of a nasal powder or reconstituted nasal solution.

The invention also relates to a diffuser of the sprayer or nebulizer type comprising the composition according to the invention.

In the particular case of the composition which is the subject of Example 1 (see Example 1 infra), the preparation method used is as follows:

- For 10 ml of solution:

In a suitable container equipped with a stirrer, introduce a volume of water representing approximately a volume of between 70% and 90% and preferably 80% by weight of the finished product;

- Introduce with moderate stirring at a temperature between 50 ° C and 60 ° C, the amount indicated in Example 1 below lauroyl L-proline (or 6% of the final weight of the product) and the amount indicated in Sumatriptan Example 1 (ie 6% of the final weight of the product). The solution formed is clear and can be slowly cooled with stirring; - Maintain the stirring until cooling then complete with the volume of water necessary to obtain a solution dosed at 6% by weight of sumatriptan.

The solution thus obtained is translucent and can be distributed for example after sterilizing filtration in previously sterilized nebulization systems.

The composition according to the present invention can be used in various therapeutic areas, for curative purposes in the context of acute or chronic conditions, as well as for preventive or medical diagnostic purposes.

Thus, for the curative treatment of acute conditions, there may be mentioned for example a composition according to the invention comprising sumatriptan as a therapeutic agent for the treatment of migraine attacks.

For the curative treatment of chronic conditions, there may be mentioned, for example, the treatment of primary or secondary hormonal disorders as well as metabolic disorders by peptide hormones or peptide analogues of these hormones such as buserelin, goserelin or nafarelin.

As regards the preventive type of treatment, there may be mentioned, by way of example, the administration of molecules of an antigenic nature in order to induce immunity with respect to infectious diseases. Thus, the therapeutic agent used may be represented by a protein of an antigenic nature or a portion of this protein capable of inducing an immune response. It will be noted that in the case of such a therapeutic agent, the composition of the invention may be modified to include additives (such as polymers of natural origin such as chitosan or synthetic polymers resulting from the condensation of ethylene oxide, propylene oxide, lactic acid or glycolic acid or condensation of a combination thereof) for extending the residence time of the composition on the nasal mucosa to increase the immune response at the mucosal level.

The invention can also be considered for diagnostic uses. Thus desmopressin is a peptide analogue of vasopressin synthesis which is considered in particular to study the power of concentration of the kidney. This octapeptide can be prepared according to the invention for this diagnostic use.

The examples below will make it possible to better understand the present invention. However, these examples are for illustrative purposes only and should in no way be construed as limiting the scope of the invention in any way.

Example 1: Obtaining a Composition Comprising a Constituent of Cocoyl Proline, Iauroyl Proline, and Sumatriptan

The composition is prepared as follows:

- Introduction of a volume of water representing about 80% by weight of the composition obtained in fine in a container equipped with a stirrer; Addition of a desired amount of lauroyl L-proline and therapeutic agent with moderate agitation at a temperature of about 50 ° C; Cooling of the solution formed with stirring. The following solution is obtained (for a unit dose of administration of a volume of 100 μL): Sumatriptan 6 mg lauroyl proline 6 mg 5 demineralized water qs 100 μL

A clear solution of pale yellow color is thus obtained. Example 2: Tolerance vis-à-vis the nasal mucosa The composition shown in Example 1 was evaluated on a model of epithelium of human nasal cells differentiated (obtained from primary cultures).

The results obtained show that exposure for 2 hours of incubation of human nasal cells differentiated to the composition obtained in Example 1 (dose of 0.15 mg / cm 2, ie approximately 4 times the value of the exposure to the therapeutic dose envisaged) has no impact on cell viability thus reflecting a very good tolerance of the product to this epithelial barrier model.

It is therefore noted that the theoretical exposure to the product at the envisaged therapeutic dose is 0.04 mg / cm 2, which corresponds to the administration of 6 mg on a mucosal surface of 150 cm 2. Thus, the theoretical exposure of the solution to the envisaged therapeutic dose is four times lower than the dose for which no irritation effect has been observed on a reconstituted epithelium of nasal cells, which makes it possible to envisage an interval of very favorable safety for the use of the composition on the nasal mucosa. Example 3: Tolerance to the nasal mucosa when lauroyl proline is substituted with lauroyl valine

As a comparative example, the substitution of proline within lauroyl proline by another amino acid, in this case valine, on a carbon chain of the same length of lauroyl type, makes it possible to obtain a compound of structure next, lauroyl valine, which differs from lauroyl proline only by its terminal amino acid.

Those skilled in the art will know how to obtain or prepare lauroyl valine and may, in any case, obtain it commercially.

Lauroyl valine is thus substituted for lauroyl proline in the composition obtained in Example 1, prepared according to an identical procedure.

This composition is thus evaluated on the cell model under the same experimental conditions as those described in Example 2.

This composition comprising lauroyl proline and sumatriptan resulted in the same test conditions a cell mortality close to 70%, thus translating a very poor tolerance on the nasal mucosa.

EXAMPLE 4 Tolerance to the Nasal Mucosa When Lauroyl Proline is Substituted by Cocoyl Valine

A new composition is prepared under the same conditions as that obtained in Example 1 by substituting lauroyl proline with cocoyl valine, that is to say using this time the fatty acid mixture contained in the coconut oil. . The product thus obtained is cocoyl valine.

Cocoyl valine is thus substituted for lauroyl proline in the composition obtained according to Example 1 and prepared according to an identical procedure.

This composition is evaluated on a cell model under the same experimental conditions as those described in Example 2. This composition (sumatriptan + cocoyl valine) resulted in a mortality of nearly 80% thus translating a very poor tolerance on the nasal mucosa. It has thus been demonstrated, quite surprisingly, that the nature of the terminal amino acid makes it possible to modulate the tolerance on the nasal mucosa very significantly.

Example 5: Dose Reduction Study

This study has demonstrated that the composition according to the invention obtained in Example 1 has a pharmacokinetic profile, after nasal administration, greater than that of the current standard commercial profile assayed at 20 mg.

The reference product used in this example is sumatriptan marketed as a 20 mg nasal spray by GlaxoSmithKline (GSK). Its trade name is Imigrane® 20mg but this name may differ depending on the country where the product is marketed. Those skilled in the art can easily obtain this product whose specifications are summarized as follows: Product indicated for the treatment of migraine attacks which is administered nasally at the usual administration dose of 20 mg of sumatriptan, the product is presenting in the form of a single-use nasal spray delivering a volume of 100 μl per administration.

The Applicant has prepared a composition according to Example 1 dosed at only 6 mg and has evaluated in a comparative manner the performance of this preparation in the context of a study carried out in 6 sheep, the person skilled in the art knowing sheep as the most appropriate animal species to carry out such a comparative study.

The results obtained surprisingly show that the absorption of the product prepared according to the invention, which included only 6 mg of sumatriptan, was significantly higher than that of the commercially available reference product which contains 20 mg of sumatriptan.

Thus, it was possible, with a reduced dose of a factor of 3.33, to obtain significantly higher plasma concentrations of sumatriptan (up to ten times more), especially during the first thirty minutes after administration of the drug. product, allowing to prejudge a more intense action of the product but also faster, this effect being particularly sought after by migraine patients, who wish a very fast relief during the occurrence of a migraine attack.

It is thus demonstrated that the product described according to Example 1 could be advantageously used to treat migraine attacks in migraine patients.

Claims (14)

REVENDICATIONS1. A nasally administrable pharmaceutical composition comprising cocoyl proline or at least one of its constituents, preferably cocoyl L-proline or at least one of its constituents, and a therapeutic agent, said therapeutic agent being selected from the group consisting of therapeutic molecules and therapeutic peptics. 2. Composition according to claim 1, said composition comprising as sole constituent of cocoyl proline lauroyl proline, and preferably lauroyl L-proline. 3. Composition according to claim 1 or 2, said composition not comprising irritating agents, such as surfactants and organic solvents or co-solvents. 4. Composition according to one of claims 1 to 3, wherein the amount of therapeutic agent is less than 50 mg per unit dose of administration, and preferably less than 10 mg per unit dose of administration. 5. Composition according to one of claims 1 to 4, wherein the molar ratio cocoyl proline or at least one of its constituents / therapeutic agent is less than 50, and preferably less than 10, said molar ratio being advantageously from order of 1/1. 6. Composition according to one of claims 1 to 5, said composition comprising an aqueous vehicle liquid or powder. 7. Composition according to claim 6, said aqueous or powdered vehicle representing more than 50%, and preferably more than 75%, of the volume of the unit dose to be administered. 8. Composition according to one of claims 1 to 7, said unit dose of administration representing a volume less than 1 ml, and preferably about 100 pI. 9. Composition according to one of claims 1 to 8, wherein the therapeutic molecules are chosen from therapeutic molecules belonging to the family: - antimigraine agents such as triptan derivatives such as sumatriptan, naratriptan and rizatriptan, - anti-nausea agents such as 5-HT3 antagonists such as ondanstron, granisetron and dolasetron, - analgesics such as morphine analgesics such as fentanyl, alfentanyl and sufentanyl, - hypnotics such as zolpidem, - anxiolytics such as benzodiazepines such as diazepam, triazolam and estazolam; and the therapeutic peptides are chosen from: synthetic therapeutic peptides such as buserelin, nafarelin and goserelin, natural peptides in which the peptide chain contains up to ten amino acids such as glutathione, and peptides of size intermediate whose peptide chain contains up to fifty amino acids such as salmon calcitonin, - the larger therapeutic proteins whose peptide chain may include several hundred amino acids such as somatropin. 10. Composition according to one of claims 1 to 9, wherein said therapeutic agent is a therapeutic molecule belonging to the family of triptans, such as sumatriptan, naratriptan or rizatriptan. 11. Composition according to one of claims 1 to 10 for its use as a drug administered nasally. 12. Composition according to one of claims 1 to 11 for its nasal use as a medicament in the treatment of: migraine when the therapeutic agent is selected from therapeutic molecules belonging to the family of antimigraine as the triptan derivatives such as sumatriptan, naratriptan and rizatriptan; nausea when the therapeutic agent is chosen from therapeutic molecules belonging to the family of anti-nausea agents such as 5-HT3 antagonists such as ondanstron, granisetron and dolasetron; pain when the therapeutic agent is chosen from therapeutic molecules belonging to the analgesic family, such as morphine analgesics such as fentanyl, alfentanyl and sufentanyl; sleep disorders when the therapeutic agent is chosen from therapeutic molecules belonging to the family of hypnotics such as zolpidem; anxiety disorders when the therapeutic agent is chosen from therapeutic molecules belonging to the family of anxiolytics such as benzodiazepines such as diazepam, triazolam and estazolam; proliferative diseases or cancers, in particular hormone-dependent nature, when the therapeutic agent is selected from the group of synthetic peptides such as nafarelin, buserelin or goserelin; hormonal disorders or metabolic disorders when the therapeutic agent is chosen from the group of small natural peptides, namely up to ten amino acids, of medium size, namely between eleven and fifty amino acids, and of size important, namely a number of amino acids greater than fifty, such as glutathione, calcitonin and somatropin respectively. 13. Process for obtaining a composition according to one of claims 1 to 10, said process comprising the following steps: a. Introduction of a volume of water representing between 70% and 90%, and preferably about 80%, of the weight of the composition obtained in fine in a container equipped with a stirrer; b. Addition of a desired amount of cocoyl proline or at least one of its constituents and therapeutic agent with moderate agitation at a temperature of about 50 ° C; vs. Cooling of the solution formed with stirring; d. Addition of a desired amount of water in order to obtain a duly dosed therapeutic agent solution. 14. Diffuser type sprayer or nebulizer comprising the composition according to one of claims 1 to 10.