EP2379110A1

EP2379110A1 - Formulation for the buccal transmucosal administration of setrons

Info

Publication number: EP2379110A1
Application number: EP09805726A
Authority: EP
Inventors: Philippe Perovitch; Marc Maury
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-12-19
Filing date: 2009-12-17
Publication date: 2011-10-26
Also published as: FR2940120A1; CN102245209A; CA2747846A1; FR2940120B1; BRPI0923379A2; RU2011129781A; JP5811404B2; US20110251233A1; JP2012512851A; CA2747846C; WO2010070236A1

Abstract

The subject of the invention is a formulation for the transmucosal administration of at least one active principle from the family of Setrons, constituted of said active principle in base form and/or in salt form, an aqueous-alcoholic solution titrating at least 30° alcohol, and optionally a pH correcting agent, said active principle being present in the state of stable and complete dissolution in the aqueous-alcoholic solution. The invention also relates to a process for preparing this formulation and to its use for the treatment and prevention of major nausea and/or emetic syndromes, and also for the treatment and prevention of digestive spasms.

Description

FORMULATION FOR ORAL TRANSMUCOSAL ADMINISTRATION OF SETRONS

The present invention relates to a formulation for the instantaneous oral mucosal systemic delivery of at least one active ingredient belonging to the family of Sétrons.

The invention also relates to a process for the preparation of this formulation and its use for the treatment and prevention of major nausea and / or emetic syndromes, as well as for the treatment and prevention of disabling spastic disorders of the digestive tract. Tetrons are pharmaceutical active ingredients mainly used for the prevention or treatment of nausea and vomiting syndromes related to anti-cancer therapies. They are potent lipophilic and low molecular weight anti-emetic molecules that act at the level of the central nervous system as 5-hydroxytryptamine-3 (5-HT3) receptor antagonists to serotonin. The best known Tetrons are Ondansetron, Tropisetron and Ranisetron respectively marketed as Zophren®, Navoban® and Kytril®. There are also other less known molecules such as Dolasetron and Itasetron, whose indications are similar, or Alosetron, Azasetron, Benesetron, Cilansetron, Ramosetron or Zatosetron, whose indications of Market introduction are rather turned towards the treatment of irritable bowel syndrome.

The Tetron have proven anti-emetic activity, but their administration to prevent or treat a nausea and / or emetic syndrome major related to the administration of chemotherapy or physical therapy anti-cancer, presents many difficulties.

The fastest and most effective route of administration of Tetrons is intravenous infusion. However this mode of administration requires dedicated personnel and the use of specific materials. It is expensive and its implementation is cumbersome for the patient who is already subject to very many infusion treatments, particularly for the administration of chemotherapy. In order to preserve the patient's venous capital, to facilitate drug intake and to reduce costs, it is therefore preferable to avoid the intravenous route and to administer oral Tetrons. The most commonly known oral form is enteral administration with the aid of tablets, but this mode of administration is not adapted to the administration of Sétrons. Indeed, the target patients are extremely sensitive to any oral medication and often reject them instantly. Thus the anti-emetics administered orally can already by themselves induce the syndrome that they are supposed to fight. In addition to this difficulty, if the Sétrons administered are suitably ingested, their time of action is between one and three hours after the taking, a disproportionate delay compared to waiting for a patient in pain. When introduced into the digestive tract and the stomach, the molecules of Létons of lipophilic nature suffer the so-called effect of "first digestive passage", alterations and losses related to the stomach environment or to variations in intestinal physiology. They are then subjected to an effect called "first pass liver" which causes their metabolism and / or their more or less intense degradation, with constitution of many metabolites, mostly inactive or toxic causing side effects. The dose of active ingredients truly bioavailable is therefore low: only a residual part that does not exceed, in the best case, 60% of the quantity administered, is effectively distributed to the central nervous system and reaches the brain receptors 5-HT3 to produce the pharmacologically expected effect.

There are therefore several major problems.

The first problem is that we must succeed in having a product absorbed by an already weakened subject, burdened with important nauseating reflexes. The drug intake should not be rejected once swallowed and the active ingredient must be sufficiently absorbed despite the patient's digestive disorders.

A second difficulty lies in the administration of a sufficient dose of Sétrons to the patient, taking into account the weight status of the subject, the dilution and the dispersion of this active principle in the body, so that the only significantly active part which reaches the brain receptors 5-HT3 is effective.

Another problem is the lag time due to metabolism and diffusion in the body before the molecule Sétron acts and the patient feels the benefits. The administration of Tetron digestive is not appropriate. Other possible routes of administration of Tetron are known, such as the transdermal route. Transdermal administration is generally performed using semi-solid gel systems or solid systems with reservoirs. For example, the application US-2007/0225379 which describes in its examples J and K, gels based on <9ranisetron or Ondansetron and their administration through the skin. However, these are complex systems intended for prolonged administration over time, which do not allow the instantaneous passage into the blood of a therapeutic dose of active principle, therefore incompatible with immediate treatment of nausea and / or emetic syndrome.

Finally, there is also the per / sublingual route. The per-sublingual route is used to administer medications by passive crossing of sublingual, jugal, gingival, lingual, palatal or pharyngeal mucosa, then passing into the sub-lingual veins and distribution to the general circulation, thereby bypassing the digestive tract. and hepatic metabolism. However, the use of this route is not obvious because the Tetron molecules are all lipophilic and therefore virtually insoluble in the oral mucosa atmosphere exclusively aqueous and hydrophilic.

Patent applications WO-2008/079295 and WO-2005/032520 describe per / sublingual formulations to be administered in the form of sprays. However, these products have characteristics which are unsatisfactory in terms of the accuracy of administration, the absorption efficiency and the bioavailability of the dosages administered. These are complex liquid formulations that involve a combination of multiple ingredients to solubilize and stabilize Ondansetron salts, and create a very specific viscosity state for a particle size distribution determined by spray. During administration, the distribution in the oral cavity remains diffuse and random and upon receipt of the particles propelled spray, they are instantly mixed with the saliva produced reflexively and mechanically in the oral cavity. This mixture is usually deglued automatically by the patient before the active ingredient has had the opportunity to cross the oral mucosa to pass into the venous vascular circuit. The bioavailability curves disclosed in the patent application WO-2008/079295 demonstrate this dose loss, the Sparrones molecules administered by spray according to the process described being only partially absorbed per mucosal oral route and mainly by digestive tract. Only a very small fraction of the active ingredient formulated, never more than 20% (see WO-2008/079295 page 6 Example 6) is therefore directly available per mucosal passage, and the effectiveness is still very far from that obtained by intravenous. There is therefore still a need for a simple, cheaper, readily available and minimally invasive formulation and use formulation for administering an immediately and completely bioavailable amount of Sétrons, so that syndromes can be treated very rapidly and effectively. nausea and / or major emetics, or disabling spastic disorders of the digestive tract.

This is what the present invention provides by proposing a very specific formulation or dosage form, in the form of a solution, which makes it possible to guarantee the instantaneous administration by the mucosal route of at least one active anti-nausea, anti- emetic and / or anti-spasmodic digestive of the family of Sétrons, constituted:

at least one active ingredient of the family of the Sétrons in base form and / or in salt form,

a hydroalcoholic solution, consisting of water and ethanol, containing at least 30 degrees of alcohol, wherein said active ingredient is present in a stable and complete dissolution state, and

optionally, a pH-correcting agent. The pH of the formulation is between 5.0 and 9.0.

The invention also provides a method of preparation and the use of this formulation for the treatment or prevention of major nausea and / or emetic syndromes, as well as for the treatment or prevention of disabling spastic disorders of the digestive tract.

Advantageously, compared to existing formulations, the formulation according to the invention is very simple to manufacture and use and allows the passage immediate mucosa and complete of a therapeutic preparation based on

Sétrons, by limiting any salivary dilution and deglutition of the Sétrons molecules that are delivered almost instantaneously to the vascular system for a distribution of the totality of the assay to the central nervous system receptor centers. The dose of Sterons administered is in addition lower than that which is necessary to introduce into existing formulations. Other features and advantages will become apparent from the following description of the invention.

According to a first aspect, the subject of the invention is therefore a formulation for the oral transmucosal administration of at least one active anti-nausea, anti-emetic and / or antispasmodic digestive active ingredient of the family of the Sétrons. This formulation is a solution having a pH of between 5.0 and 9.0, consisting of:

a hydroalcoholic solution, consisting of water and ethanol, containing at least 30 degrees of alcohol, and

optionally, a pH-correcting agent.

The active ingredient is present in a stable and complete dissolution state in the hydroalcoholic solution of less than 2 mL volume, so as to allow rapid absorption of said active ingredient through the mucous membranes of the oral cavity.

The term "transmucosal route" means any passive crossing of a lipophilic or amphiphilic molecule presented in a state of stable dissolution through the lingual, sublingual, gingival, palatal, jugal, or any other mucous membranes constituting the oral cavity.

By "stable and complete dissolution state" is meant a state of dissolution restoring the active ingredient to the molecular state and weakly ionized in its medium of dissolution, state of dissolution preventing any eventuality of an inopportune recrystallization. This stable and complete dissolution state can be controlled as soon as the formulation according to the invention is used by evaluating the visual appearance of the solution obtained (measurement of the degree of clarity) and then at the level of the filtration residues (appearance or no crystals), and finally in the medium and long term during stability monitoring tests at varying temperatures and degrees of hygrometry.

By "hydroalcoholic solution titrating X degrees of alcohol" is meant a solution having an alcohol degree of X, corresponding to the ratio between the volume of pure alcohol (100 °) contained in the hydroalcoholic solution and the total volume of this alcoholic solution. solution. The degree of alcohol in the hydroalcoholic solution varies depending on the degree of alcohol used to form the solution and the water / alcohol ratio of the solution. For example for an initial alcohol at 100 degrees and a 50/50 water / alcohol ratio, the hydroalcoholic solution titrates 50 degrees alcohol. By pH corrector agent is meant any acidic agent or any basic agent that does not alter the physicochemical characteristics of the active ingredient (s). Preferably, the pH-correcting agent is chosen from sodium carbonates and bicarbonates, monosodium or disodium phosphates, triethanolamine, sodium hydroxide (NaOH) and potassium hydroxide (KOH), but also hydrochloric, sulphuric acid agents. Phosphoric, Citric, Malic, Lactic, Succinic and / or Butyric.

The active substance in the family Sétrons is present in base form and / or in salt form. When the active ingredient is present in base form only, preferably the formulation according to the invention comprises a pH correcting agent, acid. When the active ingredient is present in salt form only, preferably the formulation according to the invention comprises a basic pH corrector agent.

When the active ingredient is present in base form and in salt form, for example in the form of succinate, hydrochloride or sulphate, the distribution gradient between base and salt is determined extemporaneously according to the specific physicochemical characteristics of each principle. active ingredient and its salt, as well as the dosage, that is to say the concentration of active ingredient relative to the volume of solution. According to a preferred embodiment, the active ingredient is present in base form. Cetron in base form, of lower molecular weight than the salt-form Tetron, dissolve and stabilize more easily in the formulation according to the invention and have a better ability to pass through the mucosa at a higher velocity. The active ingredient may be selected from Ondansetron, Tropisetron, Ranisetron, Dolasetron, Itasetron, Alosetron, Azasetron, Benesetron, Cilansetron, Ramosetron or Zatosetron. Preferably the active ingredient is Ondansetron, <9ranisetron or Tropisetron. Even more preferentially, the active ingredient is Ondansetron base. Preferably, the formulation according to the invention is in the form of a hydroalcoholic solution comprising between 30 and 95% of alcohol by volume and a water content of between 5 and 70%. Even more preferably, the formulation according to the invention is in the form of a hydroalcoholic solution comprising between 40 and 85% of ethanol by volume and a water content of between 15 and 60%.

The hydroalcoholic solution has a variable degree of alcohol of at least 30 °, preferably between 30 and 70 °, even more preferably between 40 ° and 70 °, and ideally around 50 °. Advantageously, the hydroalcoholic solution is the only solvent used in the formulation according to the invention.

In addition, the ethanol of the hydroalcoholic solution not only acts as a diluent, but also as a promoter of an accelerated peri-mucous absorption, whose speed increases as a function of the elevation of the degree of alcohol used. The degree of alcohol in the formulation should not exceed 70 °, however, because a higher degree would be incompatible with a pharmaceutical product for oral application due to mucosal burn. By way of illustration, the dissolution coefficient of ondansetron in ethanol makes it possible to obtain a complete dissolution of said active ingredient at a level of 2 mg, of ondansetron for 0.75 ml of ethanol at approximately 50.degree. This coefficient can be modulated according to the degree of alcohol and the water / ethanol ratio used. The pH of the formulation according to the invention is between 5.0 and 9.0, preferably between 5.5 and 7.5. These pHs are favorable for optimal absorption of the solution.

The formulation according to the invention allows the active ingredient passively pass through the oral mucosa in less than 6 seconds after administration. This very fast absorption time makes it possible to prevent any stagnation of the solution and of the active principle in the oral atmosphere, as well as their untimely mixing with saliva which can alter them, which would introduce a break in the continuity and stability of the dissolution of the active ingredient (s). This short delay also makes it possible to prevent any reflex swallowing of the solution and of the active principle that it contains. The trans-mucosal passage of the active principle presented in the state of dissolution according to the invention on the side of the external epithelial membrane, consisting of phospholipidic structures which passively absorb, by elective affinity, the lipophilic molecules presented in a stable and complete dissolution state, is based on an osmotic call to the other side of said membrane, in which together the concentration of dissolved active ingredient and that of the alcoholic solution considered. The osmotic appeal is all the more perennial and powerful as the degree of alcohol that serves as an absorption promoter is high. In the particular case of Ondansetron, according to the invention, a suitable degree of alcohol is between 40 ° and 70 °, preferably between 45 ° and 60 °. This makes it possible simultaneously to obtain and adjust the best dissolution and stabilization coefficient of the Ondansetron as well as promote its passage through the mucosa within 4 to 6 seconds. A particularly suitable embodiment corresponds to 0.75ml of hydroalcoholic solution with an alcohol degree of about 50 ° for 2mg or 4mg of ondansetron.

The mucous membranes of the mouth possess a very dense, quasi-spongy network of micro-vessels, so that the molecules, both of alcohol solvent and of dissolved active principle, which cross the lipophilic pores of the epithelial membrane, are instantly captured by the micro-circulation and collected towards the sublingual veins, then the jugular veins towards the heart. This phenomenon is accentuated by the presence of alcohol which causes vasodilation and an increase in the local microvascular flow of the mucous membranes. Because of this locally high circulatory flow, increased by alcohol, there is never equilibrium on either side of the epithelial membrane: the concentration in the mouth is always greater, until exhaustion. the default mechanism of molecules to absorb.

Thus, to the marked difference of all the other forms called "sub-lingual", all of the alcohol and the active ingredient dissolved therein according to the invention passes through the mucosa.

The use of the dosage form according to the invention makes it possible to passively administer a dose of Tetron immediately absorbed as soon as deposited in contact with the mucosa, to be distributed in the instant by vascular route, without any delay for its pharmacological action and without undergoing the prior destructive effects of digestive and hepatic passage. The galenic form according to the invention thus allows an immediacy of complete tissue absorption of the Sétron molecules, then their distribution in the central circulation of the organism, generating a rapid pharmacological response of "flash" type.

For example, with a dosage form according to the invention made from 2 mg Ondansetron base solubilized in 0.75 ml of a 50 ° ethanol solution, it is possible to administer almost instantaneously and passively a very significant dose of ondansetron. This dose of 2 mg corresponds to the theoretically available maximum fraction of a dose normally administered orally, ie between 40 and 50% of the dose usually administered orally. With the formulation according to the invention, the bioavailability of the dose administered by the local mucous membrane is complete. The hydroalcoholic solution according to the invention, containing at least 30 degrees of alcohol, also has the advantage of solubilizing the Sétrons molecules, although they are lipophilic, which allows their spontaneous per-mucous absorption and to protect the pharmaceutical formulation. against microbiological contamination without having to introduce antimicrobial preservative (s). Thus, the hydroalcoholic solution according to the invention has a quadruple competence:

it plays the role of solvent of the active principle of the family of Sétrons, lipophilic and low molecular weight molecules,

it activates the per-mucosal passage of this dissolved active ingredient thus presented in the molecular state at the level of the lipophilic membrane,

the degree of alcohol doubly increases the rate of mucosal absorption, by osmotic effect and by causing reflex microvascular vasodilatation, which accelerates the local micro-circulatory flow, and - It is its own stability agent which avoids the use of conventional additives.

Advantageously, the present invention offers a great simplicity of realization and a very good galenic stability: the solution water / ethanol extremely simplified guarantees the solubilization of the active principle and makes it possible to disregard the excipients usually used for the conventional pharmaceutical preparations, including the preservatives . Only a pH corrector may be added to adjust the pH of the solution to between 5.0 and 9.0. It thus makes it possible both to reduce manufacturing costs and to reduce the risks of intolerance and the possible interactions between active ingredient and excipients.

According to another advantage, the pharmacodynamic action time of the galenic form according to the invention is very short, compared to the absorption delays of drugs based on existing Tetrons that require a waiting time of 45 minutes to 2 hours between taking the drug and starting the pharmacological action anti-nausea, anti-emetic or anti-spasmodic. The quasi-instantaneous pharmacological delivery can allow a patient to self-administer a product for an effect equivalent to the efficacy of an intravenous injection of Sétrons flash into the circulation, without the disadvantages associated with this type of administration, in particular the risks of nosocomial infections.

This is a much better route of administration in terms of simplicity and availability of non-traumatic administration but also of unit and therapeutic cost compared to the modes of administration of existing Sétrons. The gain in terms of dose / effect ratio is at least 40 to 50%. the formulation according to the invention uses at least 40 to 50% less dose for a therapeutic effect obtained without delay. The molecules of Sétrons do not encountering no significant obstacle to their instantaneous carotid arterial distribution to the central nervous system 5-HT3 target receptors, which they gain in a few seconds, the basic dose administered is reduced, comparable to the bioavailable dose required to exercise the pharmacological activity required. The dose of active ingredient contained in the formulation according to the invention is therefore lower than the doses conventionally administered. This dose is of course dependent on the administered Tetron and the desired effect. It is preferably between 2 mg and 8 mg of active ingredient, for volumes of hydroalcoholic solution ranging from 0.5 ml to 2 ml.

Furthermore, the oral mucosa having a total surface of extremely broad absorption, multiplied by its character of pleated villous tissue, the administration of the dosage form according to the invention is devoid of any risk of inadvertent swallowing or wrong way. Indeed, it allows an extremely fast peri-mucous passage that prevents any salivary dissolution or swallowing of the active ingredient administered, with the advantage of not destabilizing the mucous membranes, bone / ec of various elements or excipients, as is the case. some existing "sublingual" formulations in the form of sprays, slow diffusion tablets, polymeric membranes or capsules. In addition, the formulation according to the invention is particularly suitable for patients suffering from major nausea or emetic syndromes, because it avoids any possible vomiting of the ingested medicine. In addition, the effects of alcohol are insignificant. For example, an aqueous alcohol solution of 0.75 ml ethanol at 50 ° can only produce a circulating blood alcohol content of less than 0.005 g per liter of blood, according to Widmark's official reference formula, ie one hundredth of the legal tolerance in France established at 0.5g per liter of blood. In addition, the initial passage of the alcoholic solution by pulmonary route, must allow the near complete elimination of ethanol in the form of vapor extracted by breathing and exhaled, before Ethanol can be distributed in the body. The alcoholic vector is eliminated almost completely through the respiratory parenchyma. According to a second aspect, the invention relates to a process for preparing the formulation.

A method of manufacturing the galenic form according to the invention, particularly adapted, comprises the following steps:

- mix alcohol and purified water and introduce into this mixture at least one active ingredient of the family of Sétrons,

- stir the preparation until a homogeneous suspension,

optionally, gradually introducing a pH-correcting agent until the desired pH of between 5.0 and 9.0 is reached,

- continue stirring until complete dissolution of the active ingredient - add water if necessary to complete the desired volume, and

- filter.

According to a preferred embodiment, the method comprises the following steps:

- mixing ethanol and purified water and introducing into this mixture of Ondansetron base and / or salt, - stir the preparation, preferably for 10 to 60 minutes, until a homogeneous suspension,

optionally, gradually introducing a pH-correcting agent until a desired pH of between 5.0 and 9.0 is reached,

continue stirring, preferably for 5 to 30 minutes, until complete dissolution of the active ingredient,

- add water if necessary to complete the desired volume, and

- filter. According to a first variant, the method according to the invention comprises the following steps:

- Mix ethanol and water and introduce into this mixture an active ingredient of the family of Sétrons base form, - stir the preparation, preferably for 10 to 60 minutes, until a homogeneous suspension,

gradually introducing a pH-correcting acidic agent until a pH of between 5.0 and 7.0 is obtained, preferably in the region of 6.0,

- add water if necessary to complete the desired volume, and

- Filter on a 5μm filter of porosity and distribute the preparation in single dose vials.

According to a second variant, the method according to the invention comprises the following steps:

- mix ethanol and water and introduce into this mixture an active ingredient of the family of Sétrons in salt form,

stir the preparation, preferably for 10 to 60 minutes, until a homogeneous suspension is obtained; gradually introduce a basic pH-correcting agent until a pH of between 6.0 and 8.0 is obtained, preferably neighbor of 7.0,

- Add water if necessary to complete the desired volume, and - filter on a 5μm filter of porosity and distribute the preparation in single dose vials.

According to another variant embodiment, the method according to the invention comprises the following steps: - mix ethanol and water and introduce into this mixture an active ingredient of the family of Sétrons in base form and in salt form,

- Agitate the preparation, preferably for 10 to 60 minutes, until a homogeneous suspension and complete dissolution of the active ingredient, - add water if necessary to complete the desired volume, and

The present invention can be used for instantaneous, reduced-dose and useful systemic administration of Sétrons, including ondansetron. In particular, the formulation according to the present invention may be used for producing a medicament for the treatment and / or prevention of major nausea and / or emetic syndromes, in particular related to anti-cancer treatment. Such a drug has an anti-emetic therapeutic activity in a very short time and at very small doses compared to traditional doses.

The formulation according to the present invention may also be used for producing a medicament for the treatment and / or prevention of digestive spasms.

The formulation according to the invention, corresponding to a very small fluid volume, is very easy to administer. A patient can easily place it in his mouth in direct contact with a specific mucosal area of reduced surface, buccal, para-gingival or sublingual.

According to a last aspect, the formulation according to the invention requires a specific industrial packaging, in order to allow its safe, simple and ergonomic use and to prevent degradation of the active ingredient in contact with the air.

A particular embodiment consists of using a packaging, preferably of small size, of flexible plastic or metalloplastic or of glass, opaque filled under an inert atmosphere such as nitrogen, for the protection of the stability of the composition and the impermeability to oxygen and radiation. These packages guarantee the dissolution and the stability over time of the dissolved active ingredients in hydroalcoholic solution according to the invention.

Preferably, these packages comprise a cannula allowing the precise deposition of the solution according to the invention in contact with a suitable mucosal area.

For ease of use by the patient, for easy transport, it may preferentially use packaging in the form of specific waterproof cases. Even more preferably, the dosage form according to the invention is packaged in single-dose packages of 0.5 to 2 ml, capable of providing an adequate dose of active ingredient. Advantageously, this packaging is easy to transport and allows easy use of the dosage form at any time of the day.

Several examples of formulation of Sétrons according to the invention, with a volume of 0.75 ml or 1.00 ml, at approximately 50 ° of alcohol, are particularly suitable for producing an efficacy at the level of the central nervous system in a delay of only a few minutes:

Formulation 1: Ondansetron 2mq, 0,75ml at 50 ° alcohol

- Ondansetron base (active ingredient): 2.0mg

95 ° ethyl alcohol (diluent and absorption promoter): 0.375 ml

- Purified water (diluent): qsp 0.75mL - Hydrochloric acid (pH corrector): qsp pH 6.0

This first example of formulation can be obtained by the implementation of the method described in the following for a batch of 1000 doses, or 0.75 L. In a stainless steel tank add 0.375 L of 95% V / V ethanol and 0.150 L of purified water.

Introduce in the hydroalcoholic solution 2g Ondansetron base. Using a propeller stirrer, shake the preparation for 20 to 40 minutes until a homogeneous suspension is obtained.

Then gradually introduce hydrochloric acid until a pH of about 6 (plus or minus 1).

Continue agitation until complete dissolution of Ondansetron. Complement with the purified water to obtain a solution of a volume of 0.75L and shake the preparation for 10 to 30 minutes to ensure homogeneity.

Filter the preparation on a polypropylene filter or equivalent of 5μm porosity and distribute the preparation in single dose vials of 0.75mL.

Formulation 2: Ondansetron 4mq, 0.75ml at 50 ° alcohol - Ondansetron base (active principle): 4.0 mg

95 ° ethyl alcohol (diluent and absorption promoter): 0.375 mL

- Purified water (thinner): qsp 0,75mL

Hydrochloric acid (pH corrector): qsp pH 6.0 This second formulation example can be obtained by carrying out the process described below for a batch of 1000 doses, ie 0.75 L.

In a stainless steel tank add 0.375 L of 95% V / V ethanol and 0.15 L of purified water.

Introduce into the hydroalcoholic solution 4g Ondansetron base.

Using a propeller stirrer, shake the preparation for 20 to 40 minutes until a homogeneous suspension is obtained.

Continue agitation until complete dissolution of Ondansetron. Complement with the purified water to obtain a solution of a volume of 0.75L and shake the preparation for 10 to 30 minutes to ensure homogeneity. Filter the preparation on a polypropylene filter or equivalent of 5μm porosity and distribute the preparation in single dose vials of 0.75mL.

Formulation 3: Ondansetron 4mq, 1.0ml at 50 ° alcohol

- Ondansetron base (active principle): 2.0 mg

- Ondansetron HCl (active substance): 2.0 mg

- 95 ° ethyl alcohol (diluent and absorption promoter): 0.5 mL - Purified water (diluent): qs 1.0 mL

This formulation example can be obtained by carrying out the method described below for a batch of 1000 doses, ie 1 L.

In a stainless steel tank add 0.5 L of 95% V / V ethanol and 0.5 L of purified water. Introduce in the hydroalcoholic solution 2g of Ondansetron base and 2g of Ondansetron HCl.

Using a propeller stirrer, shake the preparation for 20 to 40 minutes until a homogeneous suspension is obtained and complete dissolution of Ondansetron. Filter the preparation onto a polypropylene filter or equivalent of 5μm porosity and dispense the preparation into 1.0 mL single dose vials.

Formulation 4: Granisetron 3mq, 1.0ml at 50 ° alcohol

<9H-ionitrile (active principle): 3.0 mg - 95 ° ethyl alcohol (diluent and absorption promoter): 0.5 mL

- Purified water (diluent): qsp 1, OmL

- NaOH (pH corrector): qsp pH 7.5 This second example of formulation can be obtained by the implementation of the method described by following for a batch of 1000 doses, ie 1, OL.

In a stainless steel tank, introduce 0.500 L of 95% V / V ethanol and 0.35 L of purified water. Introduce into the hydroalcoholic solution 3 g of 9 HCl.

Then gradually introduce hydrochloric acid until a pH of 7.5 (plus or minus 1) is reached. Continue stirring until completely dissolved.

Make up with the purified water to obtain a solution with a volume of 1, OL and stir the preparation for 10 to 30 minutes to ensure homogeneity.

Filter the preparation on a polypropylene filter or equivalent of 5μm porosity and distribute the preparation in 1.0ml single dose vials. Of course, the invention is obviously not limited to the examples shown and described above, but covers all variants.

Claims

1. Formulation for the oral transmucosal administration of at least one active anti-nausea, anti-emetic and / or antispasmodic digestive active ingredient of the family of Sétrons, characterized in that it is a solution having a pH of between 5.0 and 9.0, consisting of: - at least one active ingredient of the family of the Sétrons in base form and / or in salt form,

a hydroalcoholic solution, consisting of water and ethanol, containing at least 30 degrees of alcohol, wherein said active ingredient is present in a stable and complete dissolution state, and optionally a pH-correcting agent; .

2. Formulation according to Claim 1, characterized in that the pH-correcting agent is chosen from sodium carbonates and bicarbonates, monosodium or disodium phosphates, triethanolamine, sodium hydroxide, potassium hydroxide and / or from among acidic agents Hydrochloric, Sulfuric, Succinic, Butyric, Phosphoric, Citric, Malic and / or Lactic.

3. Formulation according to claim 1 or 2, characterized in that the active ingredient is in base form and the pH correcting agent is an acidic agent.

4. Formulation according to claim 1 or 2, characterized in that the active ingredient is in the form of salt and the corrector agent is a basic agent.

5. Formulation according to claim 1 or 2, characterized in that the active ingredient is present in base form and in the form of succinate, hydrochloride or sulphate.

6. Formulation according to one of the preceding claims, characterized in that the pH is between 5.5 and 7.5.

7. Formulation according to one of the preceding claims, characterized in that the hydroalcoholic solution title between 30 and 70 degrees of alcohol.

8. Formulation according to one of the preceding claims, characterized in that the hydroalcoholic solution comprises between 30 and 95% alcohol and between 5 and 70% water by volume.

9. Formulation according to one of the preceding claims, characterized in that the active ingredient is Ondansetron, <9ranisetron, Tropisetron, Dolasetron, Itasetron, Azasetron, Benesetron, Cilansetron, Ramosetron or Zalosetron.

10. Formulation according to one of the preceding claims, characterized in that it comprises between 2 mg and 8 mg of active ingredient, for volumes of hydroalcoholic solution ranging from 0.5ml to 2ml.

11. Process for the preparation of a formulation according to one of claims 1 to 10, characterized in that it comprises the following steps: - mixing alcohol and purified water and introducing into this mixture at least one active ingredient of the family of Sétrons,

- stir the preparation until a homogeneous suspension,

optionally, gradually introducing a pH-correcting agent until the desired pH of between 5.0 and 9.0 is obtained; continue stirring until the active ingredient is completely dissolved;

- add water if necessary to complete the desired volume, and

- filter.

12. Preparation process according to claim 11, characterized in that it comprises the following steps: - mixing ethanol and purified water and introducing into this mixture of Ondansetron base and / or salt,

stir the preparation, preferably for 10 to 60 minutes, until a homogeneous suspension is obtained, optionally, gradually introducing a pH-correcting agent until a desired pH of between 5.0 and 8.0 is reached,

continue stirring, preferably for 5 to 30 minutes, until complete dissolution of the active ingredient, add water if necessary to complete the desired volume, and

- filter.

13. Use of the formulation according to one of claims 1 to 10 for the production of a medicament for the treatment by oral mucosal administration of nausea and / or major emetic syndromes.

14. Use of the formulation according to one of claims 1 to 10 for the production of a medicament for the treatment and / or prevention of digestive spasms by oral mucosal administration.