Title of Invention	"GALENICAL FORM FOR THE ADMINISTRATION OF ACTIVE INGREDIENTS BY TRANSMUCOUS MEANS"
Abstract	The present invention relates to a galenic form for the trans-mucosal delivery of at least one active ingredient, characterised in that said active ingredient is in a stable and full dissolution state in a hydro-alcoholic solution that comprises at least 20 mass % of alcohol so as to allow for a rapid absorption of said active ingredient through the mucous membranes of the oral cavity and/or the oropharynx. The invention also relates to the uses of the galenic form.

Title of Invention

"GALENICAL FORM FOR THE ADMINISTRATION OF ACTIVE INGREDIENTS BY TRANSMUCOUS MEANS"

Abstract

The present invention relates to a galenic form for the trans-mucosal delivery of at least one active ingredient, characterised in that said active ingredient is in a stable and full dissolution state in a hydro-alcoholic solution that comprises at least 20 mass % of alcohol so as to allow for a rapid absorption of said active ingredient through the mucous membranes of the oral cavity and/or the oropharynx. The invention also relates to the uses of the galenic form.

Full Text	GALENICAL FORM FOR THE ADMINISTRATION OF ACTIVE INGREDIENTS BY TRANSMUCOUS MEANS This invention relates to a galenical form for the instantaneous systemic administration by transmucous means of at least one active ingredient The invention also relates to its uses Currently, there are a large number of pharmaceutical active ingredients that are designed to be self-administered by the patient himself This self-administration is generally earned out via the digestive tract However, when they are introduced into the alimentary canal and the stomach, the active ingredients undergo the so-called first digestive pass effect, alterations and losses related to the stomach environment or to variations of intestinal physiologies They are then subjected to a so-called "first hepatic pass" effect, which brings about their metabohzation and/or their more or less intense degradation, with composition of numerous metabolites, for the most part inactive or toxic The dose of truly bioavailable active ingredients is therefore extremely small only one very residual part of the administered quantity remains valid to produce the pharmacologically expected effect Thus, by way of example, administered via the digestive tract, certain hormones are destroyed at more than 80% Other substances such as Sumatriptan have a residual bioavailability that is reduced to less than 14% of the administered dose It is also possible to cite analgesic opioids that have a bioavailability that varies between 10 and 40% In addition, these active ingredients generally have very short half-lives, less than the time it takes to reach plasmatic peaks It is also known that the beginning of the therapeutic effectiveness for the patient takes place at the earliest 45 minutes after intake, corresponding to the length of time for digestive absorption, metabohzation and vascular diffusion, then tissue and optionally intracellular diffusion Actually, there are two major problems The first problem is that it is necessary to administer an adequate dose to the patient, taking into consideration the dilution and the dispersion in the organism, so that the significantly active part that reaches the affected zone is effective The second is the latency period due to the metabohzation and the diffusion in the organism before the molecule acts and the patient feels its benefits Another administrative path, the per/sublingual path, which makes it possible to administer medications by passively passing through sublingual, jugal, gingival, lingual, palatine or pharyngeal mucous membranes, then passage into the sublingual veins and distribution to the general circulatory system, thus short-circuiting the digestive passage and the hepatic metabolism, is known Nevertheless, the existing sublingual formulations are not satisfactory, in particular because of the fact that most of the medications are unstable and consist of molecules that are by nature insoluble in biological liquids such as saliva They are often complex, and a large portion of the molecules generally remains in crystalline form, thus making absorption, and therefore passage into the general circulatory system, impossible A need therefore persists for a galenical formulation that makes it possible to administer an immediately bioavailable quantity of active ingredient so as to be able to treat painful symptoms or incapacitating problems very promptly and effectively This is the purpose of this invention in proposing a galenical form for the administration by transmucous means of at least one active ingredient, whereby said active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that comprises at least 20% by mass of alcohol so as to allow rapid absorption of said active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx Transmucous means is defined as any passive passing-through of a lipophilic or amphiphihc molecule through the lingual, sublingual, gingival, palatine, jugal mucous membranes or any other mucous membranes that constitute the buccal cavity and the oropharynx The stable and complete dissolved state is defined as a dissolved state that restores the active ingredient to the molecular and weakly ionized state in its dissolved medium, dissolved state that precludes any possibility of an inopportune recrystallization The active ingredients that are able to be formulated according to the invention are soluble molecules in hydroalcoholic mixtures They are preferably lipophilic or amphiphihc in nature and of low molecular weight, less than 10,000 Da Preferably, the galenical form according to the invention comes in the form of a hydroalcoholic solution that comprises between 20 and 95% alcohol by mass and a water content of between 5 and 80% The passage in the systemic circulation of the active mgredient(s) formulated according to the invention is therefore carried out in hydroalcohohc solution with the variable degree of alcohol, preferably between 20 and 95° According to a major characteristic of the invention, the alcohol, present at at least 20% by mass, does not play only the role of solvent, but also that of promoter of an accelerated per-mucous absorption, whose speed increases based on the rise of the degree of alcohol that is used According to a preferred embodiment of the invention, the hydroalcohohc solution is produced based on water and ethanol According to another embodiment, the hydroalcohohc solution is produced with a base of water and isopropyl alcohol The hydroalcohohc solution accordmg to the invention can also comprise one or more adjuvants for dissolution of the active mgredient(s), such as a polymer of the PEG (polyethylene glycol) type with low molecular weight, isopropyl alcohol, a surfactant such as Cremophor, or a polysorbate, and/or alcohol-oil mixtures It can also contain an aroma or a sweetener for sweetening the taste sensation, but only if this proves necessary because any addition of vehicle(s) reduces the ratio of the absorbed dose at the same time that it reduces the per-mucous absorption speed of the active mgredient(s) that is/are being considered According to a particular embodiment, when the active ingredients to be administered contain a carbonyl acid group, the galenical form according to the invention can also comprise a pH-correcting agent and/or a sequestering agent Actually, the active ingredients that contain a carbonyl acid group can react with the primary alcohols and the secondary alcohols for forming an ester This reaction leads to the reduction in the content of active ingredient and to the appearance of impurities, which is incompatible with the preparation of a medication The addition of at least one pH-correcting agent limits the H+ acid ion concentration that induces the estenfication reaction, and the addition of at least one sequestering agent limits the concentration of metal ions that catalyze this reaction, which makes it possible to inhibit the formation of esters from the active ingredients that contain carbonyl ions Preferably, the pH-correcting agent is selected from among sodium carbonates and sodium bicarbonates, monosodium or disodium phosphates, triethanolamine, soda (NaOH) and potash (KOH) The sequestering agent is selected from among ethylene-diamine-tetraacetic acid (EDTA), calcium disodium ethylene diamine tetra-acetate (E385), glucono delta-lactone (E575), sodium gluconate (E576), potassium gluconate (E577) and sodium tnpolyphosphate The galenical form according to the invention allows active ingredients to passively pass through the mucous membranes of the oropharynx in a length of time of less than 20 seconds after administration This very rapid absorption period makes it possible to prevent any stagnation of the solution and of the active mgredient(s) in the buccal atmosphere as well as their inopportune mixing with saliva that can alter them, which would introduce a break in the continuity and the stability of the dissolution of the active mgredient(s) This short length of time also makes it possible to prevent any reflex swallowing of the solution and of the active mgredient(s) that it contains The transmucous passage of an active ingredient shown in the dissolved state according to the invention from the side of the external epithelial membrane, consisting of phospho-lipidic structures that passively absorb the lipophilic molecules by elective affinity, is based on an osmotic demand to the other side of said membrane, in which the concentration of dissolved active ingredient and that of the alcoholic solution being considered participate together The osmotic demand is all the more enduring and powerful since the lipophilic molecule in the dissolved state has a low molecular weight and since the degree of alcohol that is used as an absorption promoter is high The mucous membranes of the mouth and the oropharynx have a very dense, quasi-spongy network of microvessels, so that the molecules, both of alcoholic solvent and dissolved active ingredient, which pass through the lipophilic pores of the epithelial membrane, are instantaneously captured by the blood micro-circulation and collected toward the sublingual veins This phenomenon is accentuated by the presence of alcohol that causes a vasodilatation and an increase of the local microvascular flow rate of the mucous membranes Because of this locally elevated circulatory flow rate, increased by alcohol, there is therefore never equilibrium on either side of the membrane the concentration in the mouth remains higher until the mechanism is exhausted when there are no more molecules to be absorbed Thus, the entirety of the alcohol and the active ingredient that is found dissolved therein according to the invention passes through the mucous membrane The use of the galenical form according to the invention makes it possible to administer an active ingredient dose that is immediately absorbed as soon as it is deposited and upon contact with the mucous membrane to be distributed instantaneously to the entire organism vascularly, without any delay for its pharmacological action and without undergoing the major effects of digestive and hepatic passages The hydroalcohohc solution with an alcohol content of at least 20% by mass according to the invention also has the advantage of solubihzing the active ingredients even if they are slightly soluble and of protecting the pharmaceutical formulation in relation to a microbiological contamination without having to introduce (an) antimicrobial preservation agent(s) It allows the instantaneous systemic administration with reduced and useful doses of pharmacological agents, such as, for example, hormones, anti-hormones, and any active substances on the endocrine glands, cholesterol-lowering agents, anti-infective agents, anti-virals, anti-parasitics, vascular platelet inhibitors, molecules that treat menopause, andropause or sterility, instant contraceptives, analgesic agents, antiinflammatory agents, anti-cancer substances, immunosuppressors, anti-migraine agents, anti-emetic agents, anti-diarrhea agents, anti-spasmodic agents, anti-allergy agents, antiarrhythmic agents, erectogenic agents, anxiolytic agents, anti-diabetic agents, antihypertensives, anti-asthmatic agents, anti-parkmsonian agents and/or antihistamine agents In particular, the galenical form according to the invention can be used for the production of a medication that is intended for the treatment and/or the prevention of migraine attacks, diarrhea syndromes, allergy attacks, vomiting, nauseated symptomatology, supra-ventricular and ventricular arrhythmia, Raynaud's Syndrome, erectile dysfunction, depression, panic disorders, obsessive-compulsive disorders (OCD), anxieties of the social phobia type, problems sleeping or wakmg up, diabetes, pulmonary diseases and asthma attacks, cyclic hormonal insufficiencies and dysmenorrhea, incapacitating, painful inflammatory attacks, Parkinson's disease or neuro-degenerative diseases Advantageously, this invention offers a great simplicity of production and a very good galenical stability the specific regulation for each molecule of the water/alcohol solution ensures the solubilization of the active ingredient while eliminating most of the containers used in the conventional pharmaceutical forms and the traditional sublingual forms It therefore makes it possible both to reduce the production costs and to reduce the risks of intolerance and the possible interactions between active mgredient(s) and vehicles Notably, the action times are very short, in particular compared to the slowness of absorption of medications by the digestive tract The almost-instantaneous pharmacological release makes it possible for a patient to administer to himself a product for an effect that is almost equivalent to the effectiveness of a flash intravenous injection into the circulatory system In addition, since the active ingredient does not encounter any major obstacle to its assimilation and its instantaneous distribution into the organism, the basic administered dose is very low, very close to the useful dose for exerting the required pharmacological activity This dose is preferably less than 300 mg of active ingredient Furthermore, whereby the oropharyngeal mucous membrane has an extremely large total adsorption surface area, scaled down by its nature of folded, villous tissue, the administration of the galenical form according to the invention is free of any risk of lll-timed swallowing or swallowing the wrong way Actually, it allows an extremely fast per-mucous passage that prevents any salivary dissolving or swallowing of the active ingredients that are administered, with the advantage of not destabilizing the mucous membranes, with surfactant derivatives, for example, as is the case of the existing formulations Likewise, the effects of alcohol are insignificant By way of example, 2 to 4 ml of ethanol at 40°C would only produce a blood alcohol level of less than 8 or 16 mg per liter of blood, or, for example, 31 25 to 62 5 times below the legal French tolerances of 0 5 g of alcohol per liter of blood According to one aspect of the invention, the galenical form requires a specific industrial conditioning so as to prevent the degradation of the active mgredient(s) in contact with the air One particular embodiment consists in using an opaque, flexible, metalloplastic packaging that is filled under nitrogen atmosphere for the protection of the stability of the composition and the impermeability to oxygen and to radiation This conditioning ensures the stability over time of the active ingredients that are dissolved in hydroalcoholic solution according to the invention For the comfort of use by the patient, for an easy transport, it is preferably possible to resort to "stick" passages in the form of specific single-dose or multi-dose airtight cases of a maximum capacity of 5 ml, which is the administration volume Still more preferably, the galenical form according to the invention is conditioned in single-dose sticks of 0 25 to 5 ml, able to provide a suitable dose of active ingredient Advantageously, this conditioning is easy to transport and makes possible an easy use of the galenical form at any moment of the day Other characteristics and advantages will emerge from the following examples of the invention I Example of Application to SUMATRIPTAN Sumatriptan is the major anti-migraine agent and market reference However, this molecule from the family of serotonin agonists, when it is administered enterally, has a period of action of about two hours, interminable relative to the waiting of any patient in pain, and an inadequate bioavailability It is possible to use the galenical form according to the invention for the administration of Sumatriptan Such an administration makes it possible to produce effectiveness on the cerebral level m a period of several minutes only for a dosage of between, for example, 5 and 10 mg of basic Sumatriptan It is possible to cite two Sumatriptan example formulations according to the invention 1 - Example Formulation 1 ml per 5 mg of Sumatriptan - Distilled water 0 65 ml - Ethanol, absolute alcohol 0 35 ml - Basic Sumatriptan 5 0 mg - Sweetener, sodium sacchannate 0 3 mg and/or aroma, sufficient quantity 2 - Example Formulation 2 ml per 10 mg of Sumatriptan - Distilled water 1 30 ml - Ethanol, absolute alcohol 0 70 ml - Basic Sumatriptan 10 0 mg - Sweetener, sodium saccharmate 0 5 mg and/or aroma, sufficient quantity 3 - Example Formulation 0 75 ml per 6 mg of Sumatriptan - Distilled water 0 45 ml - Ethanol, absolute alcohol 0 30 ml - Basic Sumatriptan 6 0 mg - Sweetener, sodium saccharmate 0 5 mg and/or aroma, sufficient quantity The formulations according to the invention show good stability over time The table below presents results of stability studies at 3 months, conducted on the example formulation 3 (Table Removed) II Example of Application to LOPERAMIDE Loperamide is an anti-diarrheal, anti-spasmodic and synthetic digestive analgesic agent of opioid type This molecule is generally metered at 2 mg and comes in gel form or m the form of solution to be taken orally However, when it is administered by the digestive tract, the loperamide undergoes a first digestive passing that leaves available only 40% of the administered dose, and then it undergoes a significant hepatic metabohzation The plasmatic peak is reached only at the end of two hours, and the portion of the effectively bioavailable dose would not be greater than 0 25 mg in the 2 mg administered It is possible to use the galenical form according to the invention for the administration of loperamide Such an administration makes it possible to offer an almost-immediate relief to the patient whose pain and diarrheal syndromes are significantly reduced It is possible to cite two example formulations of loperamide according to the invention 1 - Example Formulation 0 5 ml per 0 25 mg of Loperamide - Distilled water 0 35 ml - Ethanol, absolute alcohol 0 15 ml - Basic loperamide 0 25 mg - Sweetener, sodium saccharmate 0 20 mg and/or aroma, sufficient quantity 2 - Example Formulation 1 ml per 0 50 mg of Loperamide - Distilled water 0 70 ml - Ethanol, absolute alcohol 0 30 ml - Basic loperamide 0 50 mg - Sweetener, sodium saccharmate 0 30 mg and/or aroma, sufficient quantity III Example of Application to Antihistamine Anti-Allergic Agents LORATADINE and CETIRIZINE The antihistamine anti-allergic agents are medications whose purpose is to improve the comfort of allergy patients They act specifically on a molecule that plays a primary role in the mechanisms of inflammation and allergy the histamine Among the commonly-used, non-sedative, antihistamine anti-allergic agents, it is possible to cite loratadine and cetinzine However, for the administration of 10 mg of these molecules by the digestive tract, the plasmatic peaks are reached only at the end of one hour, which does not constitute a suitable treatment for the allergic attack It is possible to use the galenical form according to the invention for the administration of loratadine or cetinzine Such an administration makes it possible to reduce effectively the intensity of attacks in a rather short time, less than 15 minutes, which corresponds to the vascular passage of the active ingredient and then to its peripheral distribution at the tissue level to block the histamine-dependent receptors In addition, whereby the allergic reaction is always accompanied by a local hypervascularization, the galenical form according to the invention allows an easy access of the active ingredients to the affected areas It is possible to cite three example formulations of cetinzine according to the invention, and three example formulations of loratadine according to the invention 1 - Example Formulation 0 5 ml per 1 mg of Cetinzine - Distilled water 0 365 ml - Ethanol, absolute alcohol 0 135 ml - Basic cetinzine 1 0 mg - Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity 2 - Example Formulation 1 ml per 3 mg of Cetinzine - Distilled water 0 675 ml - Ethanol, absolute alcohol 0 325 ml - Basic cetinzine 3 0 mg - Sweetener, sodium saccharinate 0 40 mg and/or aroma, sufficient quantity 3 - Example Formulation 1 ml per 5 mg of Cetirizme - Distilled water 0 575 ml - Ethanol, absolute alcohol 0 425 ml - Basic cetinzine 5 0 mg - Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity 4 - Example Formulation 0 5 ml per 1 mg of Loratadine - Distilled water 0 365 ml - Ethanol, absolute alcohol 0 135 ml - Basic loratadine 1 0 mg - Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity 5 - Example Formulation 1 ml per 3 mg of Loratadine - Distilled water 0 675 ml - Ethanol, absolute alcohol 0 325 ml - Basic loratadine 3 0 mg - Sweetener, sodium saccharinate 0 4 mg and/or aroma, sufficient quantity 6 - Example Formulation 1 5 ml per 5 mg of Loratadine - Distilled water 1 075 ml - Ethanol, absolute alcohol 0 425 ml - Basic loratadine 5 0 mg - Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity IV Example of Application to Anti-Emetic Agents METOPIMAZINE and DOMPERIDONE The anti-emetic agents, such as metopimazme or dompendone, are medications that are commonly used for treating vomiting attacks They are generally administered under dosages of between 10 and 15 mg, in the form of tablets, freeze-dried tablets, syrups, or in the form of solutions to be taken orally However, these forms of administration all have a therapeutic inadequacy, because the molecules are very often rejected by the same vomiting episodes that they have to treat, before having had any effect It is possible to use the galenical form according to the invention for the administration of metopimazme or dompendone Such an administration prevents the problem of the active ingredient being rejected by vomiting and allows an almost immediate therapeutic effect It is possible to cite an example formulation of metopimazme according to the invention, and an example formulation of dompendone according to the invention 1 - Example Formulation 1 ml per 2 mg of Metopimazme - Distilled water 0 675 ml - Ethanol, absolute alcohol 0 325 ml - Basic metopimazme 2 0 mg - Sweetener, sodium sacchannate 0 2 mg and/or aroma, sufficient quantity 2 - Example Formulation 1 ml per 2 mg of Dompendone - Distilled water 0 550 ml - Ethanol, absolute alcohol 0 450 ml - Basic dompendone 2 0 mg - Sweetener, sodium sacchannate 0 20 mg and/or aroma, sufficient quantity V Example of Application to Anti-Nausea Agents DIMENHYDRINATE and DIPHENHYDRAMINE Among the anti-nausea agents that are available on the market, in particular dimenhydrinate and diphenhydramine are known These molecules that are administered by the digestive tract have a strong hepatic metabohzation and a period of action that is delayed relative to the intake, with a poor dose/effectiveness yield It is possible to use the galenical form according to the invention for the administration of dimenhydrinate or diphenhydramine Such an administration makes possible an immediate bioavailability of low active doses and a rapid relief of nauseous symptomatology It is possible to cite an example formulation of dimenhydrinate according to the invention, and an example formulation of diphenhydramine according to the invention 1 - Example Formulation 1 ml per 5 mg of Dimenhydrinate - Distilled water 0 650 ml - Ethanol, absolute alcohol 0 350 ml - Basic dimenhydrinate 5 0 mg - Sweetener, sodium saccharmate 0 3 mg and/or aroma, sufficient quantity 2 - Example Formulation 1 5 ml per 8 mg of Diphenhydramine - Distilled water 0 900 ml - Ethanol, absolute alcohol 0 600 ml - Basic dimenhydnnate 8 0 mg - Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity VI Example of Application to Anti-Arrvthmic Agents Currently, there are two major anti-arrythmic agents, amiodarone and flecainide Amiodarone is known for treating and preventing supraventricular and ventricular arrythmias whether they are supraventricular tachycardias, auricular fibrillations, arrhythmic tachycardias of the Wolff Parkinson White syndrome, severe ventricular arrythmias or else ventricular tachycardias and ventricular fibrillations Amiodarone is also indicated in cardiorespiratory resuscitation in the case of cardiac arrest related to a ventricular fibrillation that is resistant to external electric shocks This previous therapeutic application is effective but produces significant and incapacitating secondary effects, related to excess iodine that is ingested and then released to obtain therapeutic concentrations Actually, m order for the amiodarone to be bioavailable, it is necessary that the entire organism be saturated with it so that it will then release it continuously Emergency treatment is problematic because it is necessary to administer high doses, the pharmacological action is very slow, and the use is limited to administration in a hospital setting so as to be able to monitor the secondary effects that are related to intake It is possible to use the galenical form according to the invention for the administration of amiodarone Such an administration makes it possible to provide an active dose that is immediately absorbed by the endocardium, tissue and organic zone of the heart, which preferably monopolizes amiodarone by the so-called endocytosis mechanism just upon sole contact with the amiodarone-carrying circulating blood for a limited quantity circulating in the vascular network The dose/effect ratio is very good and can allow facilitated and prompt treatment of attacks without hospitalization The invention therefore offers the possibility of administering lower doses that can be adjusted over time and that are adapted to the pathological statue or to the level of therapeutic response from each patient It is possible to cite an example formulation of amiodarone according to the invention Example Formulation 2 ml per 25 mg of Amiodarone - Distilled water 1 ml - Ethanol, absolute alcohol 1 ml - Basic amiodarone 25 0 mg - Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity VII Example of Application to Hormones All of the hormones that are administered by the digestive tract undergo degradations in the digestive tube and then a first-pass hepatic hypermetabolism that both degrades their stereochemical structures and produces metabolites that are capable of generating secondary effect Their residual bioavailability is therefore often very low It is possible to use the galenical form according to the invention for the administration of hormones Such an administration makes possible an issuance and an attachment without delay to tissue hormonal receptors for an effective pharmacological activity with a large reduction of secondary effects Among the various hormones that are used in hormone therapies, it is possible to cite DHEA (DeHydroEpi-Androsteronej This hormone is produced by the organism to be used as a precursor to estrogens and to androgens Its production level greatly decreases with age When it is administered by the digestive tract, the DHEA undergoes a considerable hepatic metabolism that produces metabolites that generate secondary androgenic and even carcinogenic effects This invention makes possible an administration of the dose that is necessary to the DHEA to compensate for the hormonal deficit that is related to age, without running the risk of secondary effects It is possible to cite an example formulation of DHEA according to the invention Example Formulation 2 ml per 10 mg of DHEA - Distilled water 1 2 ml - Ethanol, absolute alcohol 0 8 ml - Basic Sumatriptan 10 0 mg - Sweetener, sodium sacchannate 0 6 mg and/or aroma, sufficient quantity Among the known hormones, it is also possible to cite estradiol, estrogenic hormone, currently administered by the nasal, per-mucous path, with a reduced mean bioavailability, less than 25% of the administered dose It is possible to use the galenical form according to the invention, with rapid vascular and tissue distribution, for administering estradiol Advantageously, such an administration makes it possible to compensate for the sometimes incapacitating problems that arise suddenly, related to periods of insufficient estrogen levels Example Formulation 0 5 ml per 100 ug of Estradiol - Distilled water 0 3 ml - Ethanol, absolute alcohol 0 2 ml - Basic estradiol 100 jag - Sweetener, sodium sacchannate 0 1 mg and/or aroma, sufficient quantity VIII Example of Application to Analgesic Anti-Inflammatory Agents Among the commonly used analgesic anti-inflammatory agents, in particular lbuprofene, ketoprofene and diclofenac are known These molecules, when they are administered by the digestive tract, have a period of action that is more than one and one-half hours It is possible to use the galenical form according to the invention for the administration of these analgesic anti-inflammatory agents Such an administration makes it possible to very quickly relieve various pains, be they articular, traumatic, and even migraine-related It is possible to cite an example formulation of diclofenac according to the invention Example Formulation 1 ml per 10 mg of Diclofenac - Distilled water 0 55 ml - Ethanol, absolute alcohol 0 45 ml - Basic diclofenac l00mg - Sweetener, sodium sacchannate 0 5 mg and/or aroma, sufficient quantity IX Example of Application to Erectogenic Agents Three products dominate the erectogenic agent market sildenafil, vardenafil and tadalafil These molecules have a bioavailability by a lesser oral path because of a very significant first hepatic pass The pharmacological effect and the plasmatic peak of these molecules call for a period of 30 to 120 minutes, which involves an anticipated intake relative to the time when the erectogenic effect is anticipated It is possible to use the galenical form according to the invention for the administration of these erectogenic agents Such an administration makes possible an immediate bioavailability of the active ingredient and therefore a very quick erectogenic effect on the order of several minutes It is possible to cite two example formulations of sildenafil according to the invention, and two example formulations of tadalafil according to the invention 1 - Example Formulation 1 ml per 10 mg of Sildenafil - Distilled water 0 55 ml - Ethanol, absolute alcohol 0 45 ml - Basic sildenafil l00mg - Sweetener, sodium sacchannate 0 5 mg and/or aroma, sufficient quantity 2 - Example Formulation 1 5 ml per 20 mg of Sildenafil - Distilled water 0 825 ml - Ethanol, absolute alcohol 0 675 ml - Basic sildenafil 20 0 mg - Sweetener, sodium sacchannate 0 6 mg and/or aroma, sufficient quantity 3 - Example Formulation 0 5 ml per 2 mg of Tadalafil - Distilled water 0 375 ml - Ethanol, absolute alcohol 0 225 ml - Basic tadalafil 2 0 mg - Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity 4 - Example Formulation 1 ml per 5 mg of Tadalafil - Distilled water 0 55 ml - Ethanol, absolute alcohol 0 45 ml - Basic tadalafil 5 0 mg - Sweetener, sodium saccharinate 0 4 mg and/or aroma, sufficient quantity X Example of Application to Anti-Asthmatic Agents The current treatments of asthma by aerosol therapies are effective for ensuring the maintenance of balanced median bronchodilatation, but in the case of a massive, fast-onset bronchospasm, they prove to be totally ineffective Actually, more than half of the anti-asthmatic agents, such as salbutamol, salmeterol, (R) levosalbutamol, etc, administered by inhaled aerosols, do not exceed the oropharyngeal crossing or are absorbed by the esophagus In addition, in the case of an asthma attack, the inspiratory blockage and the peripheral level of the bronchospasm ensure that inhaled treatments fail A sudden and massive asthma attack therefore requires emergency intervention and an injection of anti-asthmatic agents by subcutaneous means It is possible to use the galenical form according to the invention for the administration of anti-asthmatic agents Such an administration makes it possible for the patient to be independent to face the emergency and to halt the attack on his own, by an easy and quick means that requires only a simple gesture The molecules that are administered according to the invention immediately reach the right heart to be immediately distributed via the pulmonary arteries to all of the bronchial tissues inducing the instantaneous end of the bronchospasm It is possible to cite two example formulations of the salbutamol according to the invention 1 - Example Formulation 0 5 ml per 25 mg of Salbutamol - Distilled water 0 275 ml - Ethanol, absolute alcohol 0 225 ml - Basic salbutamol 0 25 mg - Sweetener, sodium sacchannate 0 10 mg and/or aroma, sufficient quantity - Hydrochloric acid or sulfuric acid, sufficient quantity to adjust the pH between 2 and 5 2 - Example Formulation 1 ml per 0 5 mg of Salbutamol - Distilled water 0 575 ml - Ethanol, absolute alcohol 0 425 ml - Basic salbutamol 0 50 mg - Sweetener, sodium saccharinate 0 3 mg and/or aroma, sufficient quantity - Hydrochloric acid or sulfuric acid, sufficient quantity to adjust the pH between 2 and 5 It is possible to cite two example formulations of (R) levosalbutamol according to the mvention 1 - Example Formulation 0 5 ml per 0 25 mg of (R) Levosalbutamol - Purified water sufficient quantity for 0 5 ml - Ethanol, absolute alcohol 0 15ml - Basic (R) levosalbutamol 0 1 g - Hydrochloric acid, sufficient quantity to adjust the pH between 2 and 5 2 - Example Formulation 0 5 ml per 0 5 mg of (R) Levosalbutamol - Purified water sufficient quantity for 0 5 ml - Ethanol, absolute alcohol 0 15 ml - (R) Levosalbutamol 0 5 mg - Sulfuric acid, sufficient quantity to adjust the pH between 2 and 5 - Sufficient quantity of aroma XI Example of Application to Anti-Parkinson Agents APOMORPHINE and SELEGILINE Parkinson's disease is a disease of the extrapyramidal nervous system that is characterized by the triad "trembling, rigidity, akinesia " The treatment is generally the L-DOPA that is combined with a decarboxylase inhibitor This treatment gives rise to pharmacological escapes called "on/off effects During these effects, the patient finds himself in a situation where his dyskinesia reappears with a significant loss of independence There is currently a means of disrupting these episodes by subcutaneous injection of apomorphine chlorohydrate with a period of action of between 2 and 10 minutes and a duration of action of between 45 and 90 minutes Orally, apomorphine is virtually totally metabolized by the liver, with a bioavailability of between 1 and 2% of the dose, whereby all of the metabolites are inactive It is possible to use the galenical form according to the invention for the administration of apomorphine Such an administration makes it possible for the Parkinsonian patient to disrupt his "on/off states, independently, in a period of action that is at least as short as the subcutaneous intake Furthermore, to fight against the symptoms of Parkinson's disease, there is also selegiline, used m monotherapy or in support of the L-DOPA therapy This molecule, a dopamine agonist, has a very short and low absolute bioavailability when taken orally The use of the galenical form according to the invention for the administration of the selegiline makes possible an instantaneous absorption with an almost-immediate and complete pharmacological activity It is possible to cite two example formulations of the apomorphine according to the invention, and two example formulations of selegiline according to the invention 1 - Example Formulation 0 5 ml per 3 mg of Apomorphine - Distilled water 0 275 ml - Ethanol, absolute alcohol 0 225 ml - Basic apomorphine 3 0 mg - Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity 2 - Example Formulation 1 ml per 5 mg of Apomorphine - Distilled water 0 550 ml - Ethanol, absolute alcohol 0 450 ml - Basic apomorphine 5 0 mg - Sodium bisulfite 0 5 mg - Sweetener, sodium saccharinate 0 4 mg and/or aroma, sufficient quantity 3 - Example Formulation 0 5 ml per 0 25 mg of Selegiline - Distilled water 0 275 ml - Ethanol, absolute alcohol 0 225 ml - Basic selegiline 0 25 mg - Sodium bisulfite 0 2 mg - Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity 4 - Example Formulation 1 ml per 0 5 mg of Selegiline - Distilled water 0 275 ml - Ethanol, absolute alcohol 0 225 ml - Basic selegiline 0 5 mg - Sodium bisulfite 0 4mg - Sweetener, sodium saccharinate 0 2mg and/or aroma, sufficient quantity Of course, the invention obviously is not limited to the examples shown and described above, but on the contrary covers all of the variants CLAIMS 1. Galenical form for the administration by transmucous means of at least one active ingredient, characterized in that said active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that comprises at least 20% by mass of alcohol so as to allow rapid absorption of said active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx. 2. Galenical form according to claim 1, wherein at least one active ingredient has a molecular weight that is less than 10,000 Da. 3. Galenical form according to claim 1 or 2, wherein the degree of alcohol of the hydroalcoholic solution is between 20 and 95°. 4. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises between 20 and 95% alcohol and between 5 and 80% by mass of water. 5. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises at least ethanol. 6. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises at least isopropyl alcohol. 7. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises one or more dissolution adjuvants. 8. Galenical form according to claim 6, wherein the dissolution adjuvants are selected from among the polyethylene glycol-type polymers of low molecular weight, the surfactants, isopropyl alcohol and/or alcohol-oil mixtures. 9. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises an aroma and/or a sweetener to sweeten the taste sensation. 10. Galenical form according to one of the preceding claims, wherein the active ingredient contains a carbonyl acid group and wherein the hydroalcoholic solution comprises a pH-correcting agent and/or a sequestering agent. 11. Galenical form according to one of the preceding claims, wherein it allows active ingredient(s) to passively pass through the mucous membranes of the oropharynx in a time period of less than 20 seconds after administration. 12. Galenical form according to any of the preceding claims, wherein the volume for administration is less than 5 ml. 13. Galenical form according to one of the preceding claims, wherein it is packaged by means of a flexible container, ensuring the stability of the active ingredient(s) in its/their dissolving over time. 14. Galenical form according to claim 13, wherein the container comes in the form of a single-dose or multi-dose airtight case with a maximum capacity of 5 ml. 15. Galenical form according to any of the preceding claims, wherein the active ingredient(s) is/are selected from among the hormones, the anti-hormones, and any active agents on the endocrine glands, cholesterol-lowering agents, anti-infective agents, antiviral agents, anti-parasitic agents, vascular platelet inhibitors, molecules that treat menopause, andropause or sterility, instant contraceptives, analgesic agents, antiinflammatory agents, anti-cancer agents, immunosuppressors, anti-migraine agents, antiemetic agents, anti-diarrhea agents, anti-spasmodic agents, anti-allergy agents, anti- arrythmic agents, erectogenic agents, anxiolytic agents, anti-diabetic agents, antihypertensive agents, anti-asthmatic agents, anti-parkinsonian agents and/or antihistamine agents. 16. Use of the galenical form according to one of claims 1 to 15 for the production of a medication that is intended for treatment and/or for preventing migraine attacks, diarrhea syndromes, allergy attacks, vomiting, nauseous symptomatology, supraventricular and ventricular arrythmias, Raynaud's syndrome, erectile dysfunctions, depression, panic disorders, OCD, social phobia-type anxieties, problems sleeping or waking up, diabetes, pulmonary diseases and asthma attacks, cyclic hormonal deficiencies and dysmenorrhea, incapacitating, painful inflammatory attacks, Parkinson's disease or neuro-degenerative diseases.

Full Text

GALENICAL FORM FOR THE ADMINISTRATION OF ACTIVE INGREDIENTS
BY TRANSMUCOUS MEANS
This invention relates to a galenical form for the instantaneous systemic administration by transmucous means of at least one active ingredient The invention also relates to its uses
Currently, there are a large number of pharmaceutical active ingredients that are designed to be self-administered by the patient himself
This self-administration is generally earned out via the digestive tract
However, when they are introduced into the alimentary canal and the stomach, the active ingredients undergo the so-called first digestive pass effect, alterations and losses related to the stomach environment or to variations of intestinal physiologies They are then subjected to a so-called "first hepatic pass" effect, which brings about their metabohzation and/or their more or less intense degradation, with composition of numerous metabolites, for the most part inactive or toxic
The dose of truly bioavailable active ingredients is therefore extremely small only one very residual part of the administered quantity remains valid to produce the pharmacologically expected effect
Thus, by way of example, administered via the digestive tract, certain hormones are destroyed at more than 80% Other substances such as Sumatriptan have a residual bioavailability that is reduced to less than 14% of the administered dose It is also possible to cite analgesic opioids that have a bioavailability that varies between 10 and 40%
In addition, these active ingredients generally have very short half-lives, less than the time it takes to reach plasmatic peaks
It is also known that the beginning of the therapeutic effectiveness for the patient takes place at the earliest 45 minutes after intake, corresponding to the length of time for digestive absorption, metabohzation and vascular diffusion, then tissue and optionally intracellular diffusion
Actually, there are two major problems
The first problem is that it is necessary to administer an adequate dose to the patient, taking into consideration the dilution and the dispersion in the organism, so that the significantly active part that reaches the affected zone is effective
The second is the latency period due to the metabohzation and the diffusion in the organism before the molecule acts and the patient feels its benefits
Another administrative path, the per/sublingual path, which makes it possible to administer medications by passively passing through sublingual, jugal, gingival, lingual, palatine or pharyngeal mucous membranes, then passage into the sublingual veins and distribution to the general circulatory system, thus short-circuiting the digestive passage and the hepatic metabolism, is known
Nevertheless, the existing sublingual formulations are not satisfactory, in particular because of the fact that most of the medications are unstable and consist of molecules that are by nature insoluble in biological liquids such as saliva They are often complex, and a large portion of the molecules generally remains in crystalline form, thus making absorption, and therefore passage into the general circulatory system, impossible
A need therefore persists for a galenical formulation that makes it possible to administer an immediately bioavailable quantity of active ingredient so as to be able to treat painful symptoms or incapacitating problems very promptly and effectively
This is the purpose of this invention in proposing a galenical form for the administration by transmucous means of at least one active ingredient, whereby said active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that comprises at least 20% by mass of alcohol so as to allow rapid absorption of said active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx
Transmucous means is defined as any passive passing-through of a lipophilic or amphiphihc molecule through the lingual, sublingual, gingival, palatine, jugal mucous membranes or any other mucous membranes that constitute the buccal cavity and the oropharynx
The stable and complete dissolved state is defined as a dissolved state that restores the active ingredient to the molecular and weakly ionized state in its dissolved medium, dissolved state that precludes any possibility of an inopportune recrystallization
The active ingredients that are able to be formulated according to the invention are soluble molecules in hydroalcoholic mixtures They are preferably lipophilic or amphiphihc in nature and of low molecular weight, less than 10,000 Da
Preferably, the galenical form according to the invention comes in the form of a hydroalcoholic solution that comprises between 20 and 95% alcohol by mass and a water content of between 5 and 80% The passage in the systemic circulation of the active mgredient(s) formulated according to the invention is therefore carried out in
hydroalcohohc solution with the variable degree of alcohol, preferably between 20 and 95°
According to a major characteristic of the invention, the alcohol, present at at least 20% by mass, does not play only the role of solvent, but also that of promoter of an accelerated per-mucous absorption, whose speed increases based on the rise of the degree of alcohol that is used
According to a preferred embodiment of the invention, the hydroalcohohc solution is produced based on water and ethanol
According to another embodiment, the hydroalcohohc solution is produced with a base of water and isopropyl alcohol
The hydroalcohohc solution accordmg to the invention can also comprise one or more adjuvants for dissolution of the active mgredient(s), such as a polymer of the PEG (polyethylene glycol) type with low molecular weight, isopropyl alcohol, a surfactant such as Cremophor, or a polysorbate, and/or alcohol-oil mixtures It can also contain an aroma or a sweetener for sweetening the taste sensation, but only if this proves necessary because any addition of vehicle(s) reduces the ratio of the absorbed dose at the same time that it reduces the per-mucous absorption speed of the active mgredient(s) that is/are being considered
According to a particular embodiment, when the active ingredients to be administered contain a carbonyl acid group, the galenical form according to the invention can also comprise a pH-correcting agent and/or a sequestering agent Actually, the active ingredients that contain a carbonyl acid group can react with the primary alcohols and the secondary alcohols for forming an ester This reaction leads to the reduction in the
content of active ingredient and to the appearance of impurities, which is incompatible with the preparation of a medication The addition of at least one pH-correcting agent limits the H+ acid ion concentration that induces the estenfication reaction, and the addition of at least one sequestering agent limits the concentration of metal ions that catalyze this reaction, which makes it possible to inhibit the formation of esters from the active ingredients that contain carbonyl ions
Preferably, the pH-correcting agent is selected from among sodium carbonates and sodium bicarbonates, monosodium or disodium phosphates, triethanolamine, soda (NaOH) and potash (KOH) The sequestering agent is selected from among ethylene-diamine-tetraacetic acid (EDTA), calcium disodium ethylene diamine tetra-acetate (E385), glucono delta-lactone (E575), sodium gluconate (E576), potassium gluconate (E577) and sodium tnpolyphosphate
The galenical form according to the invention allows active ingredients to passively pass through the mucous membranes of the oropharynx in a length of time of less than 20 seconds after administration This very rapid absorption period makes it possible to prevent any stagnation of the solution and of the active mgredient(s) in the buccal atmosphere as well as their inopportune mixing with saliva that can alter them, which would introduce a break in the continuity and the stability of the dissolution of the active mgredient(s) This short length of time also makes it possible to prevent any reflex swallowing of the solution and of the active mgredient(s) that it contains
The transmucous passage of an active ingredient shown in the dissolved state according to the invention from the side of the external epithelial membrane, consisting of phospho-lipidic structures that passively absorb the lipophilic molecules by elective
affinity, is based on an osmotic demand to the other side of said membrane, in which the concentration of dissolved active ingredient and that of the alcoholic solution being considered participate together The osmotic demand is all the more enduring and powerful since the lipophilic molecule in the dissolved state has a low molecular weight and since the degree of alcohol that is used as an absorption promoter is high
The mucous membranes of the mouth and the oropharynx have a very dense, quasi-spongy network of microvessels, so that the molecules, both of alcoholic solvent and dissolved active ingredient, which pass through the lipophilic pores of the epithelial membrane, are instantaneously captured by the blood micro-circulation and collected toward the sublingual veins This phenomenon is accentuated by the presence of alcohol that causes a vasodilatation and an increase of the local microvascular flow rate of the mucous membranes
Because of this locally elevated circulatory flow rate, increased by alcohol, there is therefore never equilibrium on either side of the membrane the concentration in the mouth remains higher until the mechanism is exhausted when there are no more molecules to be absorbed
Thus, the entirety of the alcohol and the active ingredient that is found dissolved therein according to the invention passes through the mucous membrane
The use of the galenical form according to the invention makes it possible to administer an active ingredient dose that is immediately absorbed as soon as it is deposited and upon contact with the mucous membrane to be distributed instantaneously to the entire organism vascularly, without any delay for its pharmacological action and without undergoing the major effects of digestive and hepatic passages
The hydroalcohohc solution with an alcohol content of at least 20% by mass according to the invention also has the advantage of solubihzing the active ingredients even if they are slightly soluble and of protecting the pharmaceutical formulation in relation to a microbiological contamination without having to introduce (an) antimicrobial preservation agent(s)
It allows the instantaneous systemic administration with reduced and useful doses of pharmacological agents, such as, for example, hormones, anti-hormones, and any active substances on the endocrine glands, cholesterol-lowering agents, anti-infective agents, anti-virals, anti-parasitics, vascular platelet inhibitors, molecules that treat menopause, andropause or sterility, instant contraceptives, analgesic agents, antiinflammatory agents, anti-cancer substances, immunosuppressors, anti-migraine agents, anti-emetic agents, anti-diarrhea agents, anti-spasmodic agents, anti-allergy agents, antiarrhythmic agents, erectogenic agents, anxiolytic agents, anti-diabetic agents, antihypertensives, anti-asthmatic agents, anti-parkmsonian agents and/or antihistamine agents
In particular, the galenical form according to the invention can be used for the production of a medication that is intended for the treatment and/or the prevention of migraine attacks, diarrhea syndromes, allergy attacks, vomiting, nauseated symptomatology, supra-ventricular and ventricular arrhythmia, Raynaud's Syndrome, erectile dysfunction, depression, panic disorders, obsessive-compulsive disorders (OCD), anxieties of the social phobia type, problems sleeping or wakmg up, diabetes, pulmonary diseases and asthma attacks, cyclic hormonal insufficiencies and dysmenorrhea,
incapacitating, painful inflammatory attacks, Parkinson's disease or neuro-degenerative diseases
Advantageously, this invention offers a great simplicity of production and a very good galenical stability the specific regulation for each molecule of the water/alcohol solution ensures the solubilization of the active ingredient while eliminating most of the containers used in the conventional pharmaceutical forms and the traditional sublingual forms It therefore makes it possible both to reduce the production costs and to reduce the risks of intolerance and the possible interactions between active mgredient(s) and vehicles
Notably, the action times are very short, in particular compared to the slowness of absorption of medications by the digestive tract The almost-instantaneous pharmacological release makes it possible for a patient to administer to himself a product for an effect that is almost equivalent to the effectiveness of a flash intravenous injection into the circulatory system
In addition, since the active ingredient does not encounter any major obstacle to its assimilation and its instantaneous distribution into the organism, the basic administered dose is very low, very close to the useful dose for exerting the required pharmacological activity This dose is preferably less than 300 mg of active ingredient
Furthermore, whereby the oropharyngeal mucous membrane has an extremely large total adsorption surface area, scaled down by its nature of folded, villous tissue, the administration of the galenical form according to the invention is free of any risk of lll-timed swallowing or swallowing the wrong way Actually, it allows an extremely fast per-mucous passage that prevents any salivary dissolving or swallowing of the active
ingredients that are administered, with the advantage of not destabilizing the mucous membranes, with surfactant derivatives, for example, as is the case of the existing formulations
Likewise, the effects of alcohol are insignificant By way of example, 2 to 4 ml of ethanol at 40°C would only produce a blood alcohol level of less than 8 or 16 mg per liter of blood, or, for example, 31 25 to 62 5 times below the legal French tolerances of 0 5 g of alcohol per liter of blood
According to one aspect of the invention, the galenical form requires a specific industrial conditioning so as to prevent the degradation of the active mgredient(s) in contact with the air
One particular embodiment consists in using an opaque, flexible, metalloplastic packaging that is filled under nitrogen atmosphere for the protection of the stability of the composition and the impermeability to oxygen and to radiation This conditioning ensures the stability over time of the active ingredients that are dissolved in hydroalcoholic solution according to the invention
For the comfort of use by the patient, for an easy transport, it is preferably possible to resort to "stick" passages in the form of specific single-dose or multi-dose airtight cases of a maximum capacity of 5 ml, which is the administration volume Still more preferably, the galenical form according to the invention is conditioned in single-dose sticks of 0 25 to 5 ml, able to provide a suitable dose of active ingredient
Advantageously, this conditioning is easy to transport and makes possible an easy use of the galenical form at any moment of the day
Other characteristics and advantages will emerge from the following examples of the invention
I Example of Application to SUMATRIPTAN
Sumatriptan is the major anti-migraine agent and market reference However, this molecule from the family of serotonin agonists, when it is administered enterally, has a period of action of about two hours, interminable relative to the waiting of any patient in pain, and an inadequate bioavailability
It is possible to use the galenical form according to the invention for the administration of Sumatriptan Such an administration makes it possible to produce effectiveness on the cerebral level m a period of several minutes only for a dosage of between, for example, 5 and 10 mg of basic Sumatriptan
It is possible to cite two Sumatriptan example formulations according to the invention
1 - Example Formulation 1 ml per 5 mg of Sumatriptan
- Distilled water 0 65 ml
- Ethanol, absolute alcohol 0 35 ml
- Basic Sumatriptan 5 0 mg
- Sweetener, sodium sacchannate 0 3 mg and/or aroma, sufficient quantity
2 - Example Formulation 2 ml per 10 mg of Sumatriptan
- Distilled water 1 30 ml
- Ethanol, absolute alcohol 0 70 ml
- Basic Sumatriptan 10 0 mg
- Sweetener, sodium saccharmate 0 5 mg and/or aroma, sufficient quantity
3 - Example Formulation 0 75 ml per 6 mg of Sumatriptan
- Distilled water 0 45 ml
- Ethanol, absolute alcohol 0 30 ml
- Basic Sumatriptan 6 0 mg
- Sweetener, sodium saccharmate 0 5 mg and/or aroma, sufficient quantity
The formulations according to the invention show good stability over time The table below presents results of stability studies at 3 months, conducted on the example formulation 3 (Table Removed)
II Example of Application to LOPERAMIDE
Loperamide is an anti-diarrheal, anti-spasmodic and synthetic digestive analgesic agent of opioid type
This molecule is generally metered at 2 mg and comes in gel form or m the form of solution to be taken orally
However, when it is administered by the digestive tract, the loperamide undergoes a first digestive passing that leaves available only 40% of the administered dose, and then it undergoes a significant hepatic metabohzation The plasmatic peak is reached only at
the end of two hours, and the portion of the effectively bioavailable dose would not be greater than 0 25 mg in the 2 mg administered
It is possible to use the galenical form according to the invention for the administration of loperamide Such an administration makes it possible to offer an almost-immediate relief to the patient whose pain and diarrheal syndromes are significantly reduced
It is possible to cite two example formulations of loperamide according to the invention
1 - Example Formulation 0 5 ml per 0 25 mg of Loperamide
- Distilled water 0 35 ml
- Ethanol, absolute alcohol 0 15 ml
- Basic loperamide 0 25 mg
- Sweetener, sodium saccharmate 0 20 mg and/or aroma, sufficient quantity
2 - Example Formulation 1 ml per 0 50 mg of Loperamide
- Distilled water 0 70 ml
- Ethanol, absolute alcohol 0 30 ml
- Basic loperamide 0 50 mg
- Sweetener, sodium saccharmate 0 30 mg and/or aroma, sufficient quantity
III Example of Application to Antihistamine Anti-Allergic Agents LORATADINE and CETIRIZINE
The antihistamine anti-allergic agents are medications whose purpose is to improve the comfort of allergy patients They act specifically on a molecule that plays a primary role in the mechanisms of inflammation and allergy the histamine
Among the commonly-used, non-sedative, antihistamine anti-allergic agents, it is possible to cite loratadine and cetinzine However, for the administration of 10 mg of these molecules by the digestive tract, the plasmatic peaks are reached only at the end of one hour, which does not constitute a suitable treatment for the allergic attack
It is possible to use the galenical form according to the invention for the administration of loratadine or cetinzine Such an administration makes it possible to reduce effectively the intensity of attacks in a rather short time, less than 15 minutes, which corresponds to the vascular passage of the active ingredient and then to its peripheral distribution at the tissue level to block the histamine-dependent receptors
In addition, whereby the allergic reaction is always accompanied by a local hypervascularization, the galenical form according to the invention allows an easy access of the active ingredients to the affected areas
It is possible to cite three example formulations of cetinzine according to the invention, and three example formulations of loratadine according to the invention
1 - Example Formulation 0 5 ml per 1 mg of Cetinzine
- Distilled water 0 365 ml
- Ethanol, absolute alcohol 0 135 ml
- Basic cetinzine 1 0 mg
- Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity
2 - Example Formulation 1 ml per 3 mg of Cetinzine
- Distilled water 0 675 ml
- Ethanol, absolute alcohol 0 325 ml
- Basic cetinzine 3 0 mg
- Sweetener, sodium saccharinate 0 40 mg and/or aroma, sufficient quantity
3 - Example Formulation 1 ml per 5 mg of Cetirizme
- Distilled water 0 575 ml
- Ethanol, absolute alcohol 0 425 ml
- Basic cetinzine 5 0 mg
- Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity
4 - Example Formulation 0 5 ml per 1 mg of Loratadine
- Distilled water 0 365 ml
- Ethanol, absolute alcohol 0 135 ml
- Basic loratadine 1 0 mg
- Sweetener, sodium saccharinate 0 2 mg
and/or aroma, sufficient quantity
5 - Example Formulation 1 ml per 3 mg of Loratadine
- Distilled water 0 675 ml
- Ethanol, absolute alcohol 0 325 ml
- Basic loratadine 3 0 mg
- Sweetener, sodium saccharinate 0 4 mg and/or aroma, sufficient quantity
6 - Example Formulation 1 5 ml per 5 mg of Loratadine
- Distilled water 1 075 ml
- Ethanol, absolute alcohol 0 425 ml
- Basic loratadine 5 0 mg
- Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity
IV Example of Application to Anti-Emetic Agents METOPIMAZINE and DOMPERIDONE
The anti-emetic agents, such as metopimazme or dompendone, are medications that are commonly used for treating vomiting attacks
They are generally administered under dosages of between 10 and 15 mg, in the form of tablets, freeze-dried tablets, syrups, or in the form of solutions to be taken orally
However, these forms of administration all have a therapeutic inadequacy, because the molecules are very often rejected by the same vomiting episodes that they have to treat, before having had any effect
It is possible to use the galenical form according to the invention for the administration of metopimazme or dompendone Such an administration prevents the problem of the active ingredient being rejected by vomiting and allows an almost immediate therapeutic effect
It is possible to cite an example formulation of metopimazme according to the invention, and an example formulation of dompendone according to the invention
1 - Example Formulation 1 ml per 2 mg of Metopimazme
- Distilled water 0 675 ml
- Ethanol, absolute alcohol 0 325 ml
- Basic metopimazme 2 0 mg
- Sweetener, sodium sacchannate 0 2 mg and/or aroma, sufficient quantity
2 - Example Formulation 1 ml per 2 mg of Dompendone
- Distilled water 0 550 ml
- Ethanol, absolute alcohol 0 450 ml
- Basic dompendone 2 0 mg
- Sweetener, sodium sacchannate 0 20 mg and/or aroma, sufficient quantity
V Example of Application to Anti-Nausea Agents DIMENHYDRINATE and DIPHENHYDRAMINE
Among the anti-nausea agents that are available on the market, in particular dimenhydrinate and diphenhydramine are known
These molecules that are administered by the digestive tract have a strong hepatic metabohzation and a period of action that is delayed relative to the intake, with a poor dose/effectiveness yield
It is possible to use the galenical form according to the invention for the administration of dimenhydrinate or diphenhydramine Such an administration makes possible an immediate bioavailability of low active doses and a rapid relief of nauseous symptomatology
It is possible to cite an example formulation of dimenhydrinate according to the invention, and an example formulation of diphenhydramine according to the invention
1 - Example Formulation 1 ml per 5 mg of Dimenhydrinate
- Distilled water 0 650 ml
- Ethanol, absolute alcohol 0 350 ml
- Basic dimenhydrinate 5 0 mg
- Sweetener, sodium saccharmate 0 3 mg and/or aroma, sufficient quantity
2 - Example Formulation 1 5 ml per 8 mg of Diphenhydramine
- Distilled water 0 900 ml
- Ethanol, absolute alcohol 0 600 ml
- Basic dimenhydnnate 8 0 mg
- Sweetener, sodium saccharinate 0 6 mg
and/or aroma, sufficient quantity
VI Example of Application to Anti-Arrvthmic Agents
Currently, there are two major anti-arrythmic agents, amiodarone and flecainide
Amiodarone is known for treating and preventing supraventricular and ventricular arrythmias whether they are supraventricular tachycardias, auricular fibrillations, arrhythmic tachycardias of the Wolff Parkinson White syndrome, severe ventricular arrythmias or else ventricular tachycardias and ventricular fibrillations Amiodarone is also indicated in cardiorespiratory resuscitation in the case of cardiac arrest related to a ventricular fibrillation that is resistant to external electric shocks
This previous therapeutic application is effective but produces significant and incapacitating secondary effects, related to excess iodine that is ingested and then released to obtain therapeutic concentrations
Actually, m order for the amiodarone to be bioavailable, it is necessary that the entire organism be saturated with it so that it will then release it continuously
Emergency treatment is problematic because it is necessary to administer high doses, the pharmacological action is very slow, and the use is limited to administration in
a hospital setting so as to be able to monitor the secondary effects that are related to intake
It is possible to use the galenical form according to the invention for the administration of amiodarone Such an administration makes it possible to provide an active dose that is immediately absorbed by the endocardium, tissue and organic zone of the heart, which preferably monopolizes amiodarone by the so-called endocytosis mechanism just upon sole contact with the amiodarone-carrying circulating blood for a limited quantity circulating in the vascular network
The dose/effect ratio is very good and can allow facilitated and prompt treatment of attacks without hospitalization
The invention therefore offers the possibility of administering lower doses that can be adjusted over time and that are adapted to the pathological statue or to the level of therapeutic response from each patient
It is possible to cite an example formulation of amiodarone according to the invention
Example Formulation 2 ml per 25 mg of Amiodarone
- Distilled water 1 ml
- Ethanol, absolute alcohol 1 ml
- Basic amiodarone 25 0 mg
- Sweetener, sodium saccharinate 0 6 mg and/or aroma, sufficient quantity
VII Example of Application to Hormones
All of the hormones that are administered by the digestive tract undergo degradations in the digestive tube and then a first-pass hepatic hypermetabolism that both degrades their stereochemical structures and produces metabolites that are capable of generating secondary effect Their residual bioavailability is therefore often very low
It is possible to use the galenical form according to the invention for the administration of hormones Such an administration makes possible an issuance and an attachment without delay to tissue hormonal receptors for an effective pharmacological activity with a large reduction of secondary effects
Among the various hormones that are used in hormone therapies, it is possible to cite DHEA (DeHydroEpi-Androsteronej This hormone is produced by the organism to be used as a precursor to estrogens and to androgens Its production level greatly decreases with age
When it is administered by the digestive tract, the DHEA undergoes a considerable hepatic metabolism that produces metabolites that generate secondary androgenic and even carcinogenic effects
This invention makes possible an administration of the dose that is necessary to the DHEA to compensate for the hormonal deficit that is related to age, without running the risk of secondary effects It is possible to cite an example formulation of DHEA according to the invention
Example Formulation 2 ml per 10 mg of DHEA
- Distilled water 1 2 ml
- Ethanol, absolute alcohol 0 8 ml
- Basic Sumatriptan 10 0 mg
- Sweetener, sodium sacchannate 0 6 mg and/or aroma, sufficient quantity
Among the known hormones, it is also possible to cite estradiol, estrogenic hormone, currently administered by the nasal, per-mucous path, with a reduced mean bioavailability, less than 25% of the administered dose
It is possible to use the galenical form according to the invention, with rapid vascular and tissue distribution, for administering estradiol Advantageously, such an administration makes it possible to compensate for the sometimes incapacitating problems that arise suddenly, related to periods of insufficient estrogen levels
Example Formulation 0 5 ml per 100 ug of Estradiol
- Distilled water 0 3 ml
- Ethanol, absolute alcohol 0 2 ml
- Basic estradiol 100 jag
- Sweetener, sodium sacchannate 0 1 mg and/or aroma, sufficient quantity
VIII Example of Application to Analgesic Anti-Inflammatory Agents
Among the commonly used analgesic anti-inflammatory agents, in particular lbuprofene, ketoprofene and diclofenac are known
These molecules, when they are administered by the digestive tract, have a period of action that is more than one and one-half hours
It is possible to use the galenical form according to the invention for the administration of these analgesic anti-inflammatory agents Such an administration makes it possible to very quickly relieve various pains, be they articular, traumatic, and even migraine-related
It is possible to cite an example formulation of diclofenac according to the invention
Example Formulation 1 ml per 10 mg of Diclofenac
- Distilled water 0 55 ml
- Ethanol, absolute alcohol 0 45 ml
- Basic diclofenac l00mg
- Sweetener, sodium sacchannate 0 5 mg and/or aroma, sufficient quantity
IX Example of Application to Erectogenic Agents
Three products dominate the erectogenic agent market sildenafil, vardenafil and tadalafil
These molecules have a bioavailability by a lesser oral path because of a very significant first hepatic pass The pharmacological effect and the plasmatic peak of these molecules call for a period of 30 to 120 minutes, which involves an anticipated intake relative to the time when the erectogenic effect is anticipated
It is possible to use the galenical form according to the invention for the administration of these erectogenic agents Such an administration makes possible an immediate bioavailability of the active ingredient and therefore a very quick erectogenic effect on the order of several minutes
It is possible to cite two example formulations of sildenafil according to the invention, and two example formulations of tadalafil according to the invention
1 - Example Formulation 1 ml per 10 mg of Sildenafil
- Distilled water 0 55 ml
- Ethanol, absolute alcohol 0 45 ml
- Basic sildenafil l00mg
- Sweetener, sodium sacchannate 0 5 mg and/or aroma, sufficient quantity
2 - Example Formulation 1 5 ml per 20 mg of Sildenafil
- Distilled water 0 825 ml
- Ethanol, absolute alcohol 0 675 ml
- Basic sildenafil 20 0 mg
- Sweetener, sodium sacchannate 0 6 mg and/or aroma, sufficient quantity
3 - Example Formulation 0 5 ml per 2 mg of Tadalafil
- Distilled water 0 375 ml
- Ethanol, absolute alcohol 0 225 ml
- Basic tadalafil 2 0 mg
- Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity
4 - Example Formulation 1 ml per 5 mg of Tadalafil
- Distilled water 0 55 ml
- Ethanol, absolute alcohol 0 45 ml
- Basic tadalafil 5 0 mg
- Sweetener, sodium saccharinate 0 4 mg and/or aroma, sufficient quantity
X Example of Application to Anti-Asthmatic Agents
The current treatments of asthma by aerosol therapies are effective for ensuring the maintenance of balanced median bronchodilatation, but in the case of a massive, fast-onset bronchospasm, they prove to be totally ineffective
Actually, more than half of the anti-asthmatic agents, such as salbutamol, salmeterol, (R) levosalbutamol, etc, administered by inhaled aerosols, do not exceed the oropharyngeal crossing or are absorbed by the esophagus In addition, in the case of an asthma attack, the inspiratory blockage and the peripheral level of the bronchospasm ensure that inhaled treatments fail A sudden and massive asthma attack therefore requires emergency intervention and an injection of anti-asthmatic agents by subcutaneous means
It is possible to use the galenical form according to the invention for the administration of anti-asthmatic agents Such an administration makes it possible for the patient to be independent to face the emergency and to halt the attack on his own, by an easy and quick means that requires only a simple gesture
The molecules that are administered according to the invention immediately reach the right heart to be immediately distributed via the pulmonary arteries to all of the bronchial tissues inducing the instantaneous end of the bronchospasm
It is possible to cite two example formulations of the salbutamol according to the invention
1 - Example Formulation 0 5 ml per 25 mg of Salbutamol
- Distilled water 0 275 ml
- Ethanol, absolute alcohol 0 225 ml
- Basic salbutamol 0 25 mg
- Sweetener, sodium sacchannate 0 10 mg and/or aroma, sufficient quantity
- Hydrochloric acid or sulfuric acid, sufficient quantity to adjust the pH between 2 and 5
2 - Example Formulation 1 ml per 0 5 mg of Salbutamol
- Distilled water 0 575 ml
- Ethanol, absolute alcohol 0 425 ml
- Basic salbutamol 0 50 mg
- Sweetener, sodium saccharinate 0 3 mg and/or aroma, sufficient quantity
- Hydrochloric acid or sulfuric acid, sufficient quantity to adjust the pH between 2 and 5
It is possible to cite two example formulations of (R) levosalbutamol according to the mvention
1 - Example Formulation 0 5 ml per 0 25 mg of (R) Levosalbutamol
- Purified water sufficient quantity for 0 5 ml
- Ethanol, absolute alcohol 0 15ml
- Basic (R) levosalbutamol 0 1 g
- Hydrochloric acid, sufficient quantity to adjust the pH between 2 and 5
2 - Example Formulation 0 5 ml per 0 5 mg of (R) Levosalbutamol
- Purified water sufficient quantity for 0 5 ml
- Ethanol, absolute alcohol 0 15 ml
- (R) Levosalbutamol 0 5 mg
- Sulfuric acid, sufficient quantity to adjust the pH between 2 and 5
- Sufficient quantity of aroma
XI Example of Application to Anti-Parkinson Agents APOMORPHINE and SELEGILINE
Parkinson's disease is a disease of the extrapyramidal nervous system that is characterized by the triad "trembling, rigidity, akinesia "
The treatment is generally the L-DOPA that is combined with a decarboxylase inhibitor This treatment gives rise to pharmacological escapes called "on/off effects During these effects, the patient finds himself in a situation where his dyskinesia reappears with a significant loss of independence
There is currently a means of disrupting these episodes by subcutaneous injection of apomorphine chlorohydrate with a period of action of between 2 and 10 minutes and a duration of action of between 45 and 90 minutes
Orally, apomorphine is virtually totally metabolized by the liver, with a bioavailability of between 1 and 2% of the dose, whereby all of the metabolites are inactive
It is possible to use the galenical form according to the invention for the administration of apomorphine Such an administration makes it possible for the Parkinsonian patient to disrupt his "on/off states, independently, in a period of action that is at least as short as the subcutaneous intake
Furthermore, to fight against the symptoms of Parkinson's disease, there is also selegiline, used m monotherapy or in support of the L-DOPA therapy This molecule, a dopamine agonist, has a very short and low absolute bioavailability when taken orally
The use of the galenical form according to the invention for the administration of the selegiline makes possible an instantaneous absorption with an almost-immediate and complete pharmacological activity
It is possible to cite two example formulations of the apomorphine according to the invention, and two example formulations of selegiline according to the invention
1 - Example Formulation 0 5 ml per 3 mg of Apomorphine
- Distilled water 0 275 ml
- Ethanol, absolute alcohol 0 225 ml
- Basic apomorphine 3 0 mg
- Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity
2 - Example Formulation 1 ml per 5 mg of Apomorphine
- Distilled water 0 550 ml
- Ethanol, absolute alcohol 0 450 ml
- Basic apomorphine 5 0 mg
- Sodium bisulfite 0 5 mg
- Sweetener, sodium saccharinate 0 4 mg and/or aroma, sufficient quantity
3 - Example Formulation 0 5 ml per 0 25 mg of Selegiline
- Distilled water 0 275 ml
- Ethanol, absolute alcohol 0 225 ml
- Basic selegiline 0 25 mg
- Sodium bisulfite 0 2 mg
- Sweetener, sodium saccharinate 0 2 mg and/or aroma, sufficient quantity
4 - Example Formulation 1 ml per 0 5 mg of Selegiline
- Distilled water 0 275 ml
- Ethanol, absolute alcohol 0 225 ml
- Basic selegiline 0 5 mg
- Sodium bisulfite 0 4mg
- Sweetener, sodium saccharinate 0 2mg and/or aroma, sufficient quantity
Of course, the invention obviously is not limited to the examples shown and described above, but on the contrary covers all of the variants

CLAIMS
1. Galenical form for the administration by transmucous means of at least one active ingredient, characterized in that said active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that comprises at least 20% by mass of alcohol so as to allow rapid absorption of said active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx.
2. Galenical form according to claim 1, wherein at least one active ingredient has a molecular weight that is less than 10,000 Da.
3. Galenical form according to claim 1 or 2, wherein the degree of alcohol of the hydroalcoholic solution is between 20 and 95°.
4. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises between 20 and 95% alcohol and between 5 and 80% by mass of water.
5. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises at least ethanol.
6. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises at least isopropyl alcohol.
7. Galenical form according to one of the preceding claims, wherein the hydroalcoholic solution comprises one or more dissolution adjuvants.
8. Galenical form according to claim 6, wherein the dissolution adjuvants are selected from among the polyethylene glycol-type polymers of low molecular weight, the surfactants, isopropyl alcohol and/or alcohol-oil mixtures.
9. Galenical form according to one of the preceding claims, wherein the
hydroalcoholic solution comprises an aroma and/or a sweetener to sweeten the
taste sensation.
10. Galenical form according to one of the preceding claims, wherein the active ingredient contains a carbonyl acid group and wherein the hydroalcoholic solution comprises a pH-correcting agent and/or a sequestering agent.
11. Galenical form according to one of the preceding claims, wherein it allows active ingredient(s) to passively pass through the mucous membranes of the oropharynx in a time period of less than 20 seconds after administration.
12. Galenical form according to any of the preceding claims, wherein the volume for administration is less than 5 ml.
13. Galenical form according to one of the preceding claims, wherein it is packaged by means of a flexible container, ensuring the stability of the active ingredient(s) in its/their dissolving over time.
14. Galenical form according to claim 13, wherein the container comes in the form of a single-dose or multi-dose airtight case with a maximum capacity of 5 ml.
15. Galenical form according to any of the preceding claims, wherein the active ingredient(s) is/are selected from among the hormones, the anti-hormones, and any active agents on the endocrine glands, cholesterol-lowering agents, anti-infective agents, antiviral agents, anti-parasitic agents, vascular platelet inhibitors, molecules that treat menopause, andropause or sterility, instant contraceptives, analgesic agents, antiinflammatory agents, anti-cancer agents, immunosuppressors, anti-migraine agents, antiemetic agents, anti-diarrhea agents, anti-spasmodic agents, anti-allergy agents, anti-
arrythmic agents, erectogenic agents, anxiolytic agents, anti-diabetic agents, antihypertensive agents, anti-asthmatic agents, anti-parkinsonian agents and/or antihistamine agents.
16. Use of the galenical form according to one of claims 1 to 15 for the production of a medication that is intended for treatment and/or for preventing migraine attacks, diarrhea syndromes, allergy attacks, vomiting, nauseous symptomatology, supraventricular and ventricular arrythmias, Raynaud's syndrome, erectile dysfunctions, depression, panic disorders, OCD, social phobia-type anxieties, problems sleeping or waking up, diabetes, pulmonary diseases and asthma attacks, cyclic hormonal deficiencies and dysmenorrhea, incapacitating, painful inflammatory attacks, Parkinson's disease or neuro-degenerative diseases.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=kDhf6E3huyGjMd8BM8sxMg==&loc=+mN2fYxnTC4l0fUd8W4CAA==

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Patent Number

279984

Indian Patent Application Number

2606/DELNP/2009

PG Journal Number

06/2017

Publication Date

10-Feb-2017

Grant Date

06-Feb-2017

Date of Filing

21-Apr-2009

Name of Patentee

PHILIPPE PEROVITCH

Applicant Address

2 ROUTE DE LA POSTE, F-33680 LE TEMPLE, FRANCE.

Inventors:

#	Inventor's Name	Inventor's Address
1	PHILIPPE PEROVITCH	2 ROUTE DE LA POSTE, F-33680 LA POSTE, F-33680 LE TEMPLE, FRANCE.

PCT International Classification Number

A61K 47/10

PCT International Application Number

PCT/FR2007/051993

PCT International Filing date

2007-09-21

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0653899	2006-09-22	France