WO2011141685A2

WO2011141685A2 - Systemic nasal compositions comprising cocoyl proline or at least one of the constituents thereof

Info

Publication number: WO2011141685A2
Application number: PCT/FR2011/051082
Authority: WO
Inventors: Jean-Luc Pougnas; Olivier Broussaud
Original assignee: Physica Pharma Sas
Priority date: 2010-05-14
Filing date: 2011-05-13
Publication date: 2011-11-17
Also published as: FR2959936A1; FR2959936B1; WO2011141685A3

Abstract

The invention relates to a pharmaceutical composition that can be administered nasally, comprising cocoyl proline or at least one of its constituents and a therapeutic agent. The invention also relates to the production method thereof and uses of same.

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.

If the intra-nasal route of administration is of particular interest, it nevertheless has drawbacks that limit

the use of this route of administration, including:

- A very small absorption surface, which represents about 50 cm ² , or 0.06% of the intestinal absorption surface, the latter developing, meanwhile, 250m ² . Due to this very low absorption surface, the nasal route can only be considered to administer very low doses of therapeutic agents (the usual dosage is generally much less than 20 mg in amount of therapeutic agent per administration unit) Thus, the following table presents the values found in the literature:

On the other hand, the nasal mucosa offers a low permeability to therapeutic agents because it naturally has a role of barrier and defense of the body vis-à-vis foreign bodies potentially pathogenic or toxic. It should also be noted that within this mucosa 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 therapeutic agent dose, is found in the systemic circulation, which highlights the low

bioavailability of systemic therapeutic agents administered at the level of the nasal mucosa. By way of example, the values mentioned in the literature have been included in the table below:

Therapeutic Area Agent / Dose Fraction

Therapeutic Principal indication administered in the systemic circulation (in%)

Sumatriptan Treatment of the -16%

migraine

Desmopressin Hormone <10%

antidiuretic

diagnostic use

Buserelin Treatment <3%

Hormonal cancer

Prostate

Nafarelin Treatment <3%

Hormonal

endometriosis

Calcitonin Treatment <5%

Hormonal

osteoporosis In other words, it is common that 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 agent

therapeutic (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 / Non Absorbed Local Deferred

Indication (frequency and main designation)

Sumatriptan Treatment -8.4 to 16.8 Very common: migraine milligrams taste unpleasant +

84% of the dose nausea

administered Common: irritation of the nose and throat with burning and bleeding

Desmopressin Hormone 4,5 to 9 Frequent: antidiuretic congestion with nasal micrograms, epistaxis, diagnostic use is close to 90% irritation, rhinitis

dose

administered

Buserelin Treatment 390 Common: irritation of

Hormonal micrograms of the nose and throat, cancer of the near 97% prostatic smell disorder of the dose

administered

Nafarelin Treatment 155 to 233 Common: irritation

Hormonal microgram nasal endometriosis is almost 97%

dose

administered

Calcitonin Treatment 9.5 to 38 Very common: rhinitis,

Hormonal micrograms edema, congestion, osteoporosis is about 95% irritation, bleeding dose

administered The potentially irritable nature of the nasal mucosa also limits the use of compounds such as surfactants, solvents or co-solvents to which the skilled person might be tempted to resort in order to facilitate the transmucosal passage of the nasal mucosa. 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 can also be an interesting alternative for substances that can not be

administered to the patient only in injectable form.

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

The plaintiff has discovered, surprisingly, that

nasally administrable and systemic pharmaceutical compositions comprising cocoyl proline or at least one of its constituents were likely not only to fully respect the integrity of the nasal mucosa but also to increase

significantly the dose of therapeutic agent found in the blood, that is to significantly improve the bioavailability of the therapeutic agent so that it becomes possible to administer a reduced dose of the therapeutic agent 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 low.

significantly reduced, thus reducing the exposure of the nasal mucosa to this amount of unabsorbed therapeutic agent, 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. Moreover, 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 any disclosure of compositions adapted 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 (cf.

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 membrane these micelles can disrupt membrane lipids, leading to altered cell barriers and leakage 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.

US Pat. No. 4,837,026 generally deals with absorption promoters making it possible to promote the transdermal or transmucosal passage of active substances such as steroids. These absorption promoters may have different structures and may be derivatives of pyrrolidine, piperidine, or azepine derivatives. Among the fifty-three examples of absorption promoters mentioned in column 4 of this document is 1-dodecanoyl-2-carboxypyrrolidine, also referred to as 1-dodecanoyl-L-proline (lauroyl L-proline). However, no specific relationship is established between this compound and the administration

transmucosal nasal active substances. On the contrary, the only example of formulation comprising lauroyl L-proline, namely Example 20 relates to a cosmetic composition intended to moisturize the skin comprising in particular, in addition to 1-dodecanoyl-L-proline, allantoin and oleth-15 (nonionic surfactant). A US patent application, US 2004/0248846, discloses the nasal administration of triptans, such as sumatriptan. This patent application mentions a very large number of absorption promoters (see in particular paragraphs 43 and 44) among which are N-acetylproline and N-acetylhydroxyproline, namely N-acyl proline compounds in which the acyl part comprises two carbon atoms. In any case, this patent application does not disclose any specific use of these two compounds and does not suggest in any way to substitute the acetyl chain with acyl chains longer than two carbon atoms.

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 to obtain a satisfactory bioavailability of the therapeutic agent, while not inducing substantial side effects, such 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. Coconut oil usually contains a mixture of fatty acids, the length of the carbon chain may be between 6 and 18 carbon atoms (mixture of fatty acids C6-C _18). 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, for example lauric and myristic acids may be mentioned (lauric acid being particularly preferred because it represents

generally 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 acyl C ₆ -C ₈ proline 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 be strong

logically, cocoyl L-proline. According to a particular embodiment, 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:

According to a particularly preferred embodiment, cocoyl proline (preferably cocoyl L-proline), namely the condensation product of the "cocoyl proline" or at least one of its constituents, is used as cocoyl proline. proline (preferably L-proline) with the fatty acid mixture included in the coconut oil. Indeed, and contrary to all expectations, the Applicant has discovered that the use of cocoyl proline makes it possible to obtain a pharmaceutical composition that can be administered nasally according to the present invention at ambient temperature, that is to say without requiring the use of cocoyl proline. heating step, which is of particular interest especially when the therapeutic agent envisaged is heat-sensitive and can, therefore, be denatured during said heating step. As heat-sensitive agents, mention may in particular be made of peptides and proteins.

By "therapeutic molecules", it is appropriate to understand any molecule having a systemic pharmacological activity, administered as a preventive, curative or diagnostic, of natural or synthetic origin and nonpeptide nature.

Preferably, for the purposes of the present invention,

"Small therapeutic molecules" corresponding to the above definition and having a molecular weight of less than 1000 g and whose dosage of administration is less than 1 mg / kg.

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

benzodiazepines (diazepam, bromazepam, 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 therapeutic synthetic 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). According to one embodiment of the invention, 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 therefore be selected accordingly. We will preferably use a diffuser-type packaging suitable for

administering nasal drug such as a spray (spray) or nebulizer 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 to reduce the exposure of the therapeutic agent to the nasal mucosa at 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

pharmaceutical composition referred to above for its nasal use as a medicament in the treatment of:

migraine when the therapeutic agent is chosen from therapeutic molecules belonging to the antimigraine family such as 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, bromazepam, triazolam, and estazolam;

proliferative diseases or cancers, in particular of a hormone-dependent nature, when the therapeutic agent is chosen from the group consisting of 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 agent

therapeutic is sumatriptan.

Sumatriptan has the chemical name 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide. The chemical formula of sumatriptan is as follows:

As previously mentioned, 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 drug in the treatment of migraine, and preferably seizures. of migraine.

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 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 composition

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. 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 the 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.

According to a particular embodiment, lauroyl proline, and preferably lauroyl L-proline, as the sole constituent of cocoyl proline, is used in step b of the aforementioned process. According to a particularly advantageous embodiment, the condensation product of proline (and preferably L-proline) with the mixture of fatty acids included in the coconut oil, namely cocoyl proline (and preferably cocoyl). L-proline) is used in step b of said process.

As noted above, it should be noted that when cocoyl proline (and preferably cocoyl L-proline) is used, the heating step at a temperature of about 50 ° C with moderate agitation is optional and not is not necessary to obtain the composition according to the present invention. The choice of whether or not to perform this heating step is left to the discretion of the user.

Thus, the subject of the invention is also 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 (from

preference of cocoyl L-proline) and therapeutic agent with moderate agitation;

- vs. Maintaining the formed solution with stirring; - d. Addition of a desired amount of water in order to obtain a duly dosed therapeutic agent solution.

In order to obtain good compatibility with the nasal mucosa, an alternative obtaining method can be used. The latter consists for example in the preliminary preparation of a solution of cocoyl proline or at at least one of its constituents in the presence of a large volume of water that may represent up to 80% of the final volume of the solution and in which a quantity of sodium hydroxide is introduced in order to obtain a solution whose pH is approximately between 5 and 8 (which makes it possible to obtain compositions having a good compatibility with the nasal mucosa). 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 agitation, the therapeutic agent can then be introduced into the solution thus prepared according to the proportions described in the invention in order to obtain, as appropriate:

- A nasal solution that can be distributed directly into a sprayer or nebulizer-type diffuser after, if necessary, sterilizing treatment by filtration;

a solid preparation obtained after drying the solution, for example using a freeze-drying technique with a view to

administration as 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 agitation to a temperature between

At 50 ° C. and 60 ° C., the amount indicated in Example 1 below of lauroyl L-proline (ie 6% of the final weight of the product) as well as the amount indicated in Example 1 of sumatriptan (ie 6% 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 fields, 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 an agent

therapeutic, the composition of the invention may be modified to include additives (such as polymers of natural origin such as chitosan or synthetic polymers derived from the condensation of ethylene oxide, propylene oxide, lactic or glycolic acid or condensation of a combination thereof) to extend the residence time of the composition on the nasal mucosa to increase the mucosal immune response.

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. Within said examples, the terms "cocoyl proline" and "lauroyl proline" should be understood to mean respectively "cocoyl L-proline" and "lauroyl L-proline". EXAMPLE 1 Preparation of a Composition Comprising a Constituent of Cocoyl Proline, Lauroyl Proline, and Sumatriptan The composition is prepared as follows:

• Introduction of a volume of water representing about 80% of the 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

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 microliters):

- Sumatriptan 6 milligrams (mg)

- lauroyl proline 6 milligrams (mg)

- Demineralized water qs 100 microliters (pL) A clear solution of pale yellow color is thus obtained.

Example 2: tolerance towards the nasal mucosa

The composition presented in Example 1 was evaluated on a model of epithelium of differentiated human nasal cells (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 exposure to the therapeutic dose envisaged) has no impact on the cell viability thus reflecting a very good tolerance of the product on this epithelial barrier model. It is therefore noted that the theoretical exposure to the product at the dose

considered therapeutic 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 therapeutic dose envisaged 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 a safety interval. very favorable for the use of the composition on the nasal mucosa.

Example 3: tolerance towards 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 valine 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 had a pharmacokinetic profile, after nasal administration, higher than that of the current commercial reference profile assayed at 20 mg.

The reference product used in this example is sumatriptan marketed as a 20 mg nasal spray by the company.

GlaxoSmithKIine (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 being in the form of a single-use nasal spray delivering a volume of 100μΙ 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 a study conducted in 6 sheep, the skilled person knowing the sheep as the most appropriate animal species to perform 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 plasma concentrations of sumatriptan

significantly higher (up to ten times more) especially during the first thirty minutes after administration of the product, allowing to prejudge a more intense action of the product but also faster, this effect being particularly sought after by migraine patients, who want a very fast relief when a migraine attack occurs. It is thus demonstrated that the product described according to Example 1 could be advantageously used to treat migraine attacks in migraine patients.

Example 6 Nasal Composition for Seismic Purpose Comprising Cocoyl Proline and a Reference Antimigraine Agent, Sumatriptan

The composition is prepared according to the procedure described

This solution can also be manufactured at room temperature which is of particular interest when the therapeutic agent is heat-sensitive:

We obtain the following solution for a volume of 100 μΙ_:

- Sumatriptan 3 mg

- Cocoyl Proline 3 mg

- Aqueous excipient qsp 100 μΙ_

EXAMPLE 7 Nasal Composition with Severe Targeting Comprising Cocoyl Proline and a Reference Antiemetic, ondansetron

As a reminder, ondasetron is the leader in the family of 5HT3 serotonin receptor antagonists. It is an antiemetic, used in the prevention and treatment of nausea and vomiting induced by cytotoxic chemotherapy and cytotoxic radiotherapy

emetogenic. It is also used in postoperative nausea and vomiting. Its chemical formula is as follows:

A systemic nasal composition of ondansetron is prepared as follows:

· Introduction of a volume of water representing about 80% of the weight of the composition obtained in fine in a container equipped with a stirrer;

Addition of a desired amount of cocoyl L-proline and adjustment of the solution obtained for a pH of between 5 and 7 using a sodium hydroxide solution; introduction of the therapeutic agent with moderate agitation at room temperature (about 25 ° C);

• The solution formed is stirred for a few minutes.

The following solution is obtained (for a volume of about 500

- Ondansetron 4 mg

- Cocoyl Proline 4 mg

- Aqueous excipient qsp 500 μ! _ A clear solution for nasal administration is thus obtained.

EXAMPLE 8 Systemic Nasal Composition Comprising Lauroyl Proline and Ondansetron

A systemic nasal composition of ondansetron is prepared according to the procedure described in Example 7 above at a temperature of 50 ° C:

After cooling, the following solution is obtained (for a volume of approximately 500 μΙ_):

- Ondansetron 4 mg

- Lauroyl Proline 4 mg

- Aqueous excipient qsp 500 μΙ_

A clear solution for nasal administration is thus obtained.

Example 9: Nasal composition with a svstemic aim including cocoyl proline and a reference hypnotic, Zolpidem As a reminder, Zolpidem is a sedative - hypnotic of the imidazopyridine class, derived from benzodiazepines. Tartrate salt is used therapeutically for the treatment of occasional, transient or chronic insomnia. It is marketed under various trade names (Silnox®, Ambien® ...) presented in the form of 10 mg tablets scored. It has a limited duration of action, and is particularly recommended in sleep insomnia, hence the interest of proposing a nasal presentation that can be administered in the evening at bedtime. It usually does not cause any residual effect upon waking. Its chemical formula is as follows:

A systemic nasal composition of Zolpidem is prepared according to the procedure described in Example 7 above:

The following solution is obtained (for a volume of approximately 100 μL)

- Zolpidem 2 mg

- Cocoyl Proline 2 mg - Aqueous excipient qsp 100 μΙ_

A clear solution for nasal administration is thus obtained. Example 10: Nose composition for svstemic purpose including Lauroyl Proline and Zolpidem

A systemic nasal composition of Zolpidem is prepared according to the procedure described in Example 8 above:

After cooling, the following solution is obtained (for a volume of approximately 100 μΙ_):

- Zolpidem 2 mg

- Lauroyl Proline 2 mg

- Aqueous excipient qs 100 L

A clear solution for nasal administration is thus obtained.

EXAMPLE 1 Nasal Composition for Seismic Purpose Comprising Cocoyl Proline and a Reference Analgesic Fentanyl

As a reminder, Fentanyl is a reference opioid analgesic that has a strong analgesic effect. Citrate salts or hydrochloride are used therapeutically for the treatment of severe and generally chronic pain of cancerous origin when other analgesics have been shown to be ineffective. It has a narcotic status because of its structural analogy with morphine which has an analgesic action about 80 times greater. It is usually presented as an injectable solution, as a preparation transdermal or tablets for oral or peroral use. Its chemical formula is as follows:

A nasal systemic systemic composition of Fentanyl is prepared according to the procedure described in Example 7 above:

We obtain the following solution (for a volume of about 100 μΐ.):

- Fentanyl 200 pg

- Cocoyl Proline 200 pg

- Aqueous excipient qsp 100 pl_

A clear solution for nasal administration is thus obtained.

Example 12: Systemic Nasal Composition Comprising Lauroyl Proline and Fentanyl

A systemic nasal composition of Fentanyl is prepared according to the procedure described in Example 8 above:

After cooling, the following solution is obtained (for a volume of approximately 100 μ! _):

- Fentanyl 200 pg

- Lauroyl Proline 200 pg - Aqueous excipient qs 100 pL

A clear solution for nasal administration is thus obtained. EXAMPLE 13 Systemic Nasal Composition Comprising Cocoyl Proline and a Reference Anxiolytic, Bromazepam

As a reminder, Bromazepam is a reference medicine in the benzodiazepine family that has sedative, anxiolytic and hypnotic properties. It is used for the different manifestations of anxiety, especially neurotic anxiety, reaction and

somatic manifestations associated with anxiety. It is also used to treat weaning alcoholic in particular in the prevention and treatment of delirium tremens. Its chemical formula is as follows:

A systemic nasal composition of Bromazepam is prepared according to the procedure described in Example 7 above:

The following solution is obtained (for a volume of about 100 μl) - Bromozepam 1, 5 mg

- Cocoyl Proline 1, 5 mg

- Aqueous excipient qsp 100 μΙ_

A clear solution for nasal administration is thus obtained.

EXAMPLE 14 Systemic Nasal Composition Comprising Lauroyl Proline and Bromazepam

A systemic nasal composition of Bromazepam is prepared according to the procedure described in Example 8 above:

- Bromazepam 1, 5 mg

- Lauroyl Proline 1, 5 mg

- Aqueous excipient qsp 100 μΐ_

A clear solution for nasal administration is thus obtained.

Example 15 Systemic Nasal Composition Comprising Cocoyl Proline and an Endogenous Short Reference Peptide Glutathione

As a reminder, Glutathione is an endogenous tri-peptide, formed by the condensation of glutamic acid, cysteine and glycine: α-Glutamyl-L-cysteinylglycine. Virtually all cells contain a high concentration. It is represented in a simplified way by GSH (reduced form) or GSSG (oxidized form), the thiol function giving it its main biochemical properties. Its chemical formula is as follows:

Glutathione SH (reduced) or S-S (oxidized) forms a very important redox couple because it allows the exchange of electrons (thus energy) inside the cell.

Glutathione is an essential cellular component and its level can significantly decrease in certain conditions related to aging such as Alzheimer's and Parkinson's, neurological disorders, diabetes, heart disease (action on cholesterol) and pulmonary (asthma, chronic bronchitis, fibrosis pulmonary), digestive disorders (pancreatitis, Crohn's disease, hepatitis of alcoholic or viral origin). It seems that high levels of glutathione prevent the appearance of symptoms symptomés related to these pathologies from where a study use in the treatment of these conditions. Because glutathione is rapidly degraded in the gastrointestinal tract, systemic nasal solution administration prepared according to the invention is a treatment of choice for maintaining the glutathione concentration in the body. A nasal systemic systemic composition of Glutathione is prepared according to the procedure described in Example 7 above:

The following solution is obtained (for a volume of approximately 1 milliliter (or ml):

- Glutathione 50 mg

- Cocoyl Proline 50 mg - Aqueous excipient qs 1 ml

A clear solution for nasal administration is thus obtained.

Example 16: Systemic Nasal Composition Comprising Lauroyl Proline and Glutathione

A systemic nasal composition of Glutathione is prepared according to the procedure described in Example 8 above:

After cooling, the following solution is obtained (for a volume of approximately 1 ml):

- Glutathione 50 mg

- Lauroyl Proline 50 mg

- Aqueous excipient qs 1 ml

A clear solution for nasal administration is thus obtained.

EXAMPLE 17 Systemic Nasal Composition Comprising Cocoyl Proline and an Endogenous Hormone Peptide, Calcitonin

As a reminder, calcitonin is an endogenous hormonal peptide of 32 amino acids that participates in the metabolism of calcium and phosphorus. Its therapeutic use in the form of salmon calcitonin is mainly indicated for the treatment of Paget's disease, bone loss (postmenopausal osteoporosis) or malignant hypercalcemia.

A systemic nasal composition of Calcitonin is prepared according to the procedure described in Example 7 above:

We obtain the following solution (for a volume of about 100 μΙ_): - Calcitonin Synthetic Salmon 50 Units International (or Ul)

- Cocoyl Proline 2 mg

- Aqueous excipient qsp 100 μΙ_

A clear solution for nasal administration is thus obtained.

Example 18: Systemic Nasal Composition Comprising Lauroyl Proline and Calcitonin

A nasal systemically targeted composition of calcitonin is prepared according to the procedure described in Example 8 above:

We obtain the following solution (for a volume of about 100 μΙ_):

- Synthetic Salmon Calcitonin 50 Ul

- Lauroyl Proline 2 mg

- Aqueous excipient qsp 100 μ! _

A clear solution for nasal administration is thus obtained.

Example 19: Systemic Nasal Composition Comprising Cocoyl Proline and Endogenous Hormone Polypeptide, Somatropin

As a reminder, somatropin is an endogenous hormonal protein of 191 amino acids that participates in cell metabolism and bone growth during bone development. Its therapeutic use in the form of recombinant human somatropin is mainly reserved for the treatment of pituitary dwarfism and intrauterine growth retardation and is generally performed in the form of daily subcutaneous injections. A systemic nasal composition of somatropin is prepared according to the procedure described in Example 7 above:

We obtain the following solution (for a volume of about 100 μΙ_):

- recombinant human somatropin 1 mg

- Cocoyl Proline 0.5 mg

- Aqueous excipient qsp 100 μΙ

A clear solution for nasal administration is thus obtained which can be lyophilized to ensure its preservation.

Example 20: Systemic Nasal Composition Comprising Lauroyl Proline and Somatropin

A systemic nasal composition of somatropin is prepared according to the procedure described in Example 8 above.

We obtain the following solution (for a volume of about 100 μΙ_):

- Somatropin 1 mg

- Lauroyl Proline 0.5 mg

- Aqueous excipient qsp 100 μΙ_

A clear solution for nasal administration is thus obtained.

Example 21: Systemic nasal composition comprising cocoyl proline and a synthetic hormone peptide, nafarelin.

As a reminder, nafarelin is a synthetic decapeptide analog of natural GnRH secreted by the pituitary gland. Nafarelin stimulates the secretion of pituitary gonadotropins, LH and FSH, with the consequent stimulation of the secretion of ovarian steroids. It is especially used in the form of acetate in the treatment of endometriosis as well as in pituitary desensitization during induction of ovulation for in vitro fertilization followed by embryo transfer. Its chemical formula is as follows:

A systemic nasal composition of nafarelin is prepared according to the procedure described in Example 7 above:

We obtain the following solution (for a volume of about 100 μΙ_):

- Nafarelin 100 pg

- Cocoyl Proline 0.5 mg

- Aqueous excipient qs 100 pL A clear solution for nasal administration is thus obtained.

Example 22: Nose composition for svstemic purpose including lauroyl Proline and nafarelin

A systemic nasal composition of nafarelin is prepared according to the procedure described in Example 8 above:

The following solution is obtained (for a volume of about 100 μl):

- Nafarelin 100

- Lauroyl Proline 0.5 mg

- Aqueous excipient qsp 100 μ1_

A clear solution for nasal administration is thus obtained.

EXAMPLE 23 Evaluation on a model of in vitro study (predictive) of the svstemic absorption of nasal compositions prepared according to the invention: The systemic absorption of nasal compositions prepared according to the invention can be evaluated using a predictive model using human nasal cells.

This model uses nasal cells that are deposited in monolayers on a semipermeable membrane of known porosity, polycarbonate (opaque), on which the cells are seeded in primary cultures. The nasal cells thus differentiated form a monolayer, which is impervious to the passage of water and ions. This monolayer separates a donor medium (apical compartment), where the test solution is deposited, from a receiving medium (basal compartment) where the molecule that has diffused is dosed. The passage of the agent

Therapeutic of the apical compartment in the basal compartment is thus evaluated by determining its concentration in the receiving medium at the beginning of the experiment and then at the end of a defined incubation time.

The protocol used in the study is to deposit the therapeutic agent at a concentration of 100 μg / ml in the apical compartment and then to measure the concentration in the basal compartment after a period of 60 minutes. The table below shows the results obtained which are expressed as a percentage increase of the

concentration of therapeutic agent in the basal compartment (recipient medium) from compositions prepared according to the invention and compared to a control composition containing the agent

therapeutic alone, that is to say not comprising cocoyl proline or lauroyl proline.

Therapeutic Agent Composition% means of increase Used of the observed systemic effect

Sumatriptan Composition + 350%

example 1

Ondansetron Composition + 280%

example 7

Glutathione Composition + 340%

example 15

Calcitonin Composition of + 310%

example 18

Fentanyl Composition of + 180% example 12

Nafarelin Composition of + 380%

example 21

Somatropin Composition + 240%

example 19

Bromazepam Composition + 270%

example 14

The use of the cellular predictive model described above has made it possible to demonstrate that the compositions prepared according to the invention have all made it possible to observe an improvement in the systemic diffusion generally ranging between 200% and 400% under the conditions of the test. and this on therapeutic agents representing the therapeutic classes described in the invention.

Claims

claims

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

components, and a therapeutic agent, said therapeutic agent being selected from the group consisting of therapeutic molecules and therapeutic peptides.

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, wherein the cocoyl proline or at least one of its constituents consists of cocoyl proline, and preferably cocoyl L-proline.

4. Composition according to one of claims 1 to 3, said composition does not comprise irritants, such as surfactants and organic solvents or cosolvents.

5. Composition according to one of claims 1 to 4, 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.

6. Composition according to one of claims 1 to 5, 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.

7. Composition according to one of claims 1 to 6, said composition comprising an aqueous vehicle liquid or powder.

8. Composition according to claim 7, said aqueous or powdered vehicle representing more than 50%, and preferably more than 75%, of the volume of the unit dose to be administered.

9. Composition according to one of claims 1 to 8, said unit dose of administration representing a volume of less than 1 ml, and preferably about 100 μΙ.

10. Composition according to one of claims 1 to 9, wherein the therapeutic molecules are chosen from the molecules

therapeutic family-owned:

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 like zolpidem,

anxiolytics such as benzodiazepines such as diazepam, bromazepam, triazolam and estazolam;

and the therapeutic peptides are chosen from:

synthetic therapeutic peptides such as buserelin, nafarelin and goserelin,

natural peptides whose peptide chain contains up to ten amino acids such as glutathione, peptides of intermediate size 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.

11. Composition according to one of claims 1 to 10, wherein said therapeutic agent is a therapeutic molecule belonging to the family of triptans, such as sumatriptan, naratriptan or rizatriptan.

12. Composition according to one of claims 1 to 11 for its use as a drug administered nasally.

13. Composition according to one of claims 1 to 12, for its use nasally as a medicament in the treatment:

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, bromazepam, 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.

14. Process for obtaining a composition according to one of the

claims 1 to 1 1, said method comprising the steps of:

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;

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;

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.

15. Process for obtaining a composition according to claim 3, or according to one of claims 4 to 11 when dependent on claim 3, 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 - preferably cocoyl L-proline - and therapeutic agent with moderate agitation;

vs. Maintaining the formed solution with stirring;

d. Addition of a desired amount of water in order to obtain a duly dosed therapeutic agent solution.

16. Diffuser of the sprayer or nebulizer type comprising the composition according to one of claims 1 to 11.