Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to a method and compositions for ensuring the extemporaneous treatment of hyperglucose
• HGPP Postprandial Type II Diabetes, thanks to the instantaneous systemic administration of at least one hypoglycemic / insulin secreting active ingredient.
• the invention relates in particular to the process for the production and extemporaneous administration of a pharmaceutical composition exclusive to this application, as well as to its method of preparation and its use.
• Diabetes is an international health scourge that affects more than 300 million people worldwide, with an increase of 10 to 15% per year.
• Type I or insulin proprietary diabetes is characterized by insufficient insulin secretion or lack thereof. It is rapidly fatal without the daily administration of insulin (s) by subcutaneous injection (s).
• Type II Diabetes or maturity is due to the misuse of insulin by the body. It accounts for 90% of Diabetes cases worldwide and results mainly from overweight and lack of physical activity.
• Type II Diabetes associates an abnormality of insulin sensitivity and insulin secretion, particularly a strong alteration of the peak of early insulin secretion. Indeed, an element recently identified as the most actively pathogenic and heavy of vascular, cardiac and organic consequences, in Type II Diabetes, is the existence of a post-hyperglycemia peak.
• HGPP Prandial
• pancreas In healthy adults, the pancreas produces an early peak of insulin that aims to metabolize any saturated amount of glucose absorbed rapidly cumulatively during the meal. This early insulin peak smooths the sudden changes in blood glucose during meals and the inevitable Post-Prandial Hyperglucose. For example, the administration in the non-diabetic of 20 g of Glucose, reflexively induces an insulin peak greater than 120 micrograms per liter of blood within ten minutes.
• Type II Diabetes Today there are several treatment approaches for Type II Diabetes, the goal to be achieved is better control and optimization of blood glucose in a stabilized way, so as not to exceed the thresholds of 1, 20 - 1, 40 g Glucose per liter of blood, especially in the post-meal period.
• Type II Diabetes is usually treated by diet measures and weight loss.
• the goal of treatment is to reduce the mortality, symptoms and complications of Diabetes.
• hypoglycemic sulfonamides including Gliclazide, Glibenclamide and hypoglycemic Biguanides including Metformin.
• Gliclazide is a lipophilic antidiabetic, with a molecular weight of 323 Da, insoluble in water and poorly soluble in alcohol. It acts at the level of the pancreas by stimulating the secretions of islets of Langerhans, increasing the secretion of Insulin or of Peptide C, and also has anti-aggregating type of hematocritic properties.
• Gliclazide is administered in single doses of 30 to 80 mg for 80 to 160 mg day orally. It is extensively metabolized by the first pass through the liver and all its metabolites are devoid of activity. It is 95% bound to plasma-bearing proteins and has a volume of distribution of approximately 30 liters, the peak of which occurs 11-14 hours after dosing, with a half-life of 10-12 hours.
• Glibenclamide is a lipophilic active principle, practically insoluble in water and slightly soluble in ethanol. It is likely to induce hypoglycaemia and is a proven cardiovascular protector.
• Glibenclamide is administered in unit doses of 2.5 to 5 mg per 10 mg / day on average (maximum 15 mg / day). It is highly metabolized by the liver, with a late peak plasma, but with an interesting effect / dose ratio.
• Metformin hydrochloride is a common amphiphilic antidiabetic, of 165 Da molecular weight soluble in water and poorly soluble in alcohol. This active ingredient is a cardiovascular protector that does not affect the pancreatic production of insulin but on the hepatic metabolism of sugar and glycogen, as well as the use of glucose by the tissues.
• Metformin is administered in unit doses of 500 and 1000mg, for 1000 mg to 3000 mg per day, its absorption being 50 to
• Type II Diabetes where it is possible to combine a slow insulin prolonged release over 24 hours and fast insulin, injected before any meal, guaranteeing a peak insulin per and post-prandial adaptable to the unit by each patient, the hypoglycemic treatments proposed for Type II Diabetes do not make it possible to regulate the postprandial glucose so as to keep it close to the physiological requirements and Recommendations of the International Health authorities, ie less than 140 mg of glucose per day. liter of blood (7.8 nmol / l).
• Drugs currently used for the chronic treatment of Type II Diabetes such as Metformin-based drugs, all administered orally, provide late-onset activity and pharmacological availability that remains linear. They therefore remain unable to reduce at a given moment the sudden and powerful appearance of the post-Prandial Hyperglucose peak.
• the recommendations of the health authorities related to the treatment of Type II diabetes recommend that the change in blood glucose between "fasting glucose” and “postprandial blood glucose” should not present a difference greater than 0.2-0 , 3 g / 1, ie a very small margin of fluctuation, difficult to control with the currently available pharmacological means, all administered orally and some by injection which complicates the therapeutic management by patients.
• Glinides such as Mitiglinide or Nateglinide
• Repaglinide which is an oral hypoglycemic agent which binds to the sulphonylurea receptors of pancreatic beta cells and thus causes rapid and short-term insulin secretion. duration, able to better respond to a hyperglycemic rise.
• Repaglinide a derivative of benzoic acid, is a lipophilic molecule of molecular weight 452.6 administered at a rate of 1 mg per meal. The drug should be taken orally 15 minutes before each meal three times a day, for better postprandial glycemic control.
• Repaglinide thus ingested induced the onset of an insulinotropic response approximately 30 minutes after its intake, but with a large interindividual variability (60%) of its plasma concentration as well as intra-individual variability (35%) requiring frequent adjustments of dosage. Its therapeutic efficacy therefore remains uncertain because of its digestive absorption and especially of its first hepatic passage, elements which alter the immediate pharmacological bioavailability in a variable manner. This treatment is therefore not satisfactory especially since it has been shown that Glinides cause more hypoglycemia and weight gain than conventional treatments like Metformin, which is logical since the latter has no activity insulinosécr réellee.
• Incretins or Gliptins are intestinal hormones, released by endocrine cells of the intestinal epithelium at the arrival of nutrients. They play an important role in potentiating the effect of glucose on pancreatic cells.
• GLP-1 Glucagon Like Peptide-1
• GIP Glucose-dependent Insulinotropic
• GLP-1 has a strong insulinotropic effect in Type II diabetic patients.
• by its ability to stimulate insulin synthesis helps maintain insulin stores pancreatic Beta cells.
• HbAI C hemoglobin is reduced by 1.3%, with an improvement in insulin sensitivity and pancreatic Beta cell function.
• LPG-1 can not be administered orally because of its peptide nature, and its use requires an injection.
• its half-life in vivo is extremely short for about 1 to 2 minutes, due to its rapid degradation by a ubiquitous enzyme, dipeptidylpeptidase, which makes its use impossible.
• Forms of LPG-1 resistant to degradation have been developed, in particular Sitagliptin or Vildagliptin or Saxagliptin.
• Vildagliptin is an amphiphilic molecule soluble in water and organic solvents of molecular weight 303.99 Da with a bioavailability around 85%.
• Sitagliptin is an amphiphilic molecule of molecular weight 407,314 Da, soluble in water and certain organic solvents, whose absolute bioavailability is of the order of 87%. It is related to plasma proteins and the average volume of distribution in the body of a single dose of 100mg of Sitagliptin intravenously is about 198 liters. Saxagliptin with a molecular weight of 315.41 da has a variable bioavailability of 50 to 75% of the dose administered orally; this lipophilic molecule has a high organic distribution volume, close to 180 liters. We can see that these molecules share very similar characteristics.
• Treatment of Type II Diabetes is therefore currently incomplete and does not meet the requirements of the International Recommendations for the Reduction of the Post-Prandial Hyperglucose Peak.
• the available therapeutic means therefore remain unsuitable, since no medicine that can be easily used by outpatients by hundreds of millions of patients is today able to oppose the HGPP peak in order to contain it within the recommended limits of a maximum blood glucose lower than 1, 4 g / l, throughout the per / post prandial time.
• the objective of the present invention is to overcome the shortcomings and drawbacks of the prior art by providing compositions and a method of administering insulinotropic pharmaceutical compositions of rapid action, easy to use and moderate cost. , to control hyperglycemia peaks at mealtime, a major goal in the treatment of Type II Diabetes.
• the invention aims at a very specific embodiment making it possible to guarantee the instantaneous oral transmucosal administration of an effective dose of at least one insulinotropic hypoglycemic active ingredient, very particularly in the punctual treatment of HyperGlycemia Post. - Prandiale (HGPP) Type II Diabetes in humans or animals, by the implementation of a hydroalcoholic solution in which is dissolved stably and complete at least one hypoglycemic active ingredient.
• HGPP Type II Diabetes in humans or animals
• the invention also provides a method of preparation as well as the use of this drug for the treatment of Type II Diabetes in humans or animals, specifically the point treatment necessary for the reduction of HGPP.
• the method and the compositions according to the invention induce an instant hypoglycemic activity, equivalent to that which could occur by injection.
• an immediate and complete oral trans-mucosal passage in a small volume of a therapeutic preparation based on dosages of hypoglycemic / insulinotropic molecules at least 30 to 50% lower than those usually delivered orally, while limiting any salivary dilution and deglutition of said molecules, these are thus delivered almost instantaneously to the vascular system for a distribution of the whole assay at the specific receptors of their organic pharmacological activity, in order to produce a stimulation of the secretion of insulin or to act on gluconeogenesis
• the formulation is easy to use, inexpensive, readily available and non-invasive. It allows the administration of an immediately bioavailable amount of hypoglycemic / insulinotropic molecules, so that it can prevent the rise of a sudden hyperglycemia, in particular to reduce temporarily the HGPP of Diabetes Type II.
• the already existing hypoglycemic / insulinotropic molecules can be used much more efficiently, at reduced weight doses of 30 to 50% compared to those administered orally, and for the new purpose of clipping the peaks.
• HGPP peaks that no treatment of the prior art can really handle, except by injectable insulin.
• the invention therefore makes it possible to confer on old and known molecules a new and novel therapeutic competence and role, namely to reduce extemporaneously the Post-Prandial Hyperglycemia of Type II Diabetes, an element recognized as eminently pathogenic but currently beyond real control. therapeutic.
• the invention thus meets the international therapeutic demand and the concerns of the State Health authorities, without complicating the therapeutic approach and habits. patient treatment, ie without imposing additional costs or constraints such as repeated injections of insulin used in the treatment of Type I Diabetes.
• the subject of the invention is therefore a pharmaceutical composition in the form of a hydroalcoholic solution in which at least one hypoglycemic / insulinotropic active principle is dissolved in a stable and complete manner, at a dosage reduced by at least 30 to 50%. compared to that used orally, for its application as a drug in the ad hoc treatment of Type II Diabetes HGPP.
• the hydroalcoholic solution at least 30 degrees alcohol.
• transmucosal route any passive crossing of a lipophilic or amphiphilic molecule presented in a state of stable and complete dissolution through the lingual, sublingual, gingival, palatal, jugal mucosa, or any other mucosa provided with a lipophilic epithelium, constitutive of the oral cavity.
• stable and complete dissolution state is meant a state of dissolution restoring the active ingredient in the molecular state and weakly ionized in its dissolution medium, a state of dissolution preventing any eventuality of an untimely recrystallization.
• hydro-alcoholic solution titrating X degrees of alcohol means 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 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 alcohol initial at 100 degrees and a ratio water / alcohol 50/50, the hydroalcoholic solution title 50 degrees of alcohol.
• active ingredient hypoglycemic / insulinotropic reduced dosage any lipophilic or amphiphilic active ingredient capable of decreasing the blood sugar level or preventing the increase of blood sugar level at the peak of Per / Post-Prandial HyperGlycemia (HGPP), this active principle being administered by the oral peri-mucous route under a lower fraction of
• hypoglycemic / insulinotropic active principle is present in base form and / or in salt form, for example in the form of succinate,
• the active ingredient is chosen from all lipophilic or amphiphilic insulinotropic hypoglycemic agents / active principles with a molecular weight of less than 1000 Da.
• hypoglycemic sulfonamides include Gliclazide and Glibenclamide.
• hypoglycemic Biguanides include Metformin.
• Glinides include Mitiglinide, Nateglinide or Repaglinide.
• Suitable Incretins or Gliptins include Sitagliptin, Vildagliptin and Saxagliptin.
• the pharmaceutical composition according to the invention is in the form of a hydroalcoholic solution having a small volume, namely a volume of less than 2 ml, in which is dissolved in a stable and complete manner a small amount of water.
• the formulation according to the invention may optionally also comprise a pH-correcting agent.
• pH corrector agent is meant any acidic agent or any basic agent that does not alter the physicochemical characteristics of the active ingredient (s).
• 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.
• composition or formulation may also comprise, according to the active principles under consideration and their specific dosages, an adjuvant element for potentiating the dissolution of the active ingredient, which will not interfere with the hypoglycemic pharmacodynamic activity of the active antidiabetic agent.
• an adjuvant element for potentiating the dissolution of the active ingredient which will not interfere with the hypoglycemic pharmacodynamic activity of the active antidiabetic agent. It may be, for example, Tocofersolan or TEPGS, an ester combining two chemical structures, those of vitamin E and
• Polyethylene Glycol with low molecular weight between 1000 and 2000 daltons.
• the composition according to the invention is in the form of a hydroalcoholic solution comprising between 30 and 95% alcohol by weight and a water content of between 5 and 70%. Even more preferentially, the formulation according to the invention is in the form of a hydroalcoholic solution comprising between 40 and 85% of alcohol by weight and a water content of between 60 and 15%.
• the hydroalcoholic solution has a degree of alcohol of at least 30 °, preferably between 30 and 90 °, more preferably between 40 ° and 60 °.
• This degree of alcohol is particularly suitable for lipophilic or amphiphilic hypoglycemic / insulinotropic molecules and allows their constant and complete dissolution as well as their almost instantaneous total absorption through the oral mucosa.
• the hydroalcoholic solution is the only organic solvent used in the formulation according to the invention.
• the alcohol of the hydroalcoholic solution acts not only as a solvent, but also as a promoter of an accelerated mucosal absorption of the active principle in question, absorption whose rate increases as a function of the degree of elevation. of alcohol used. This second role becomes the main role of alcohol in cases where the molecules considered are much more water-soluble than alcohol-soluble.
• the hydroalcoholic solution is based on water and ethanol.
• Metformin a complete dissolution of said active ingredient is obtained, for example at a level of 150 mg of Metformin per 1 ml of aqueous alcohol solution at approximately 30 °.
• a formulation allows the passage through mucosal Metformin, a passage that was not conceivable until then.
• this concentration remains illustrative and adaptable according to the subjects and the evolution of Post-Prandial HyperGlycemia of their Type II diabetes, given the great variability of the weighting assays used for this molecule with multiplying coefficients up to to six times the unit dosage.
• the invention makes it possible to obtain complete dissolution of said active ingredient at a level of 1 mg of Glibenclamide per 1 ml of aqueous-alcoholic solution at approximately 50 °.
• the dissolution coefficient of the active ingredients and the useful dosage can therefore be adapted by the means of the invention, modulating them on the one hand as a function of the degree of alcohol desired for a transient passage. mucosal accelerated and secondly according to the preferred weight ratio established for each active ingredient following the water / ethanol equilibrium and possible adjuvants pH or dissolution used.
• the pH of the formulation according to the invention is between 4.5 and 9.0, more preferably between 4.5 and 8. These pHs are favorable to optimal absorption of the solution.
• the formulation according to the invention allows the active ingredient passively pass through the oral mucosa in a period of less than 6 seconds after liquid deposition in contact with a given oral mucosal surface.
• the advantage of this very fast absorption time is that it makes it possible to prevent stagnation of the solution and the active ingredient in the oral atmosphere as well as their untimely mixing with saliva capable of altering them, which would introduce a rupture in the continuity and the stability of the dissolution of the active principle (s).
• This short delay also makes it possible to prevent any reflex swallowing of the solution and of the active principle it contains, in the digestive tract.
• the high intravascular concentration of the active ingredient and its distribution without delay have the advantage of conferring on it a concentrated pharmacodynamic effect on its insulin-secreting pancreatic receptor target, so-called "Flash" effect, inaccessible until then.
• the oral trans-mucosal passage of the active principle presented in a 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 the concentration of dissolved active ingredient and that of the alcoholic solution considered together.
• the osmotic appeal is all the more perennial and powerful as the degree of alcohol that serves as an absorption promoter is high.
• a suitable degree of alcohol is between 30 ° and 90 °, preferably between 30 ° and 65 °. This makes it possible simultaneously to obtain and adjust the best dissolution coefficient and specific stabilization for each molecule as well as promoting its trans-mucosal passage within 4 to 6 seconds.
• the invention may be an antidiabetic medicament consisting of a hydroalcoholic solution containing between 30 and 65 ° of alcohol, in which is dissolved between 3 and 10 mg of Gliclazide.
• hydroalcoholic solution containing 50 degrees of alcohol comprising 3.5 mg of gliclazide per ml.
• the antidiabetic medicament according to the invention may consist of a hydroalcoholic solution containing between 40 and 60 ° of alcohol, having a volume of between 0.75 ml and 1.5 ml in which is dissolved between 15 and 225 mg Metformin.
• the hypoglycemic active ingredient may also be Glibenclamide.
• the antidiabetic medicament according to the invention may consist of a hydroalcoholic solution containing between 30 and 65 ° of alcohol, in which is dissolved between 0.25 and 1 mg of Glibenclamide per treatment unit.
• the active ingredient may also be selected from Glinides.
• This may include Repaglinide.
• the antidiabetic medicament according to the invention may consist of a hydroalcoholic solution containing between 30 and 70 degrees of alcohol, in which is dissolved between 0.05 and 1 mg of Repaglinide per treatment unit.
• the active ingredient may be chosen from Gliptins or Incretins. This may include Sitagliptin, Vildagliptin or Saxagliptin.
• the antidiabetic medicament according to the invention may consist of a hydroalcoholic solution containing between 30 and 70 degrees of alcohol, in which is dissolved between 0.25 and 45 mg of Sitagliptin per treatment unit.
• the antidiabetic medicament according to the invention may also consist of a hydroalcoholic solution containing between 30 and 70 degrees of alcohol, in which is dissolved between 0.25 and 25 mg of Vildagliptin per treatment unit.
• the antidiabetic medicament according to the invention can still be constituted by a hydroalcoholic solution containing between 30 and 70 degrees of alcohol, in which is dissolved between 0.25 and 1, 5 mg Saxagliptin.
• the mucous membranes of the mouth have a very dense network of micro-vessels, almost spongy, so that the molecules, both of alcoholic solvent and dissolved active ingredient, which cross the lipophilic pores of the epithelial membrane, are instantly captured by the microcirculation and collected to 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.
• the totality 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 hypoglycemic / insulin stimulant, immediately absorbed as soon as deposited in contact with the mucosa, to be distributed in the instant by the vascular route, without any delay for its pharmacological action and without undergoing the prior destructive effects of the digestive and hepatic passages.
• the pharmaceutical composition according to the invention thus allows an immediacy of complete tissue absorption of hypoglycemic molecules, then their distribution in the central circulation of the body (jugular vein, superior vena cava, right heart, pulmonary arteries, lungs, left heart, then systemic arterial circulation from the Aorta), generating a rapid pharmacodynamic response of "flash" type.
• a galenic form according to the invention made from a composition of 225 mg of Metformin solubilized in 1.5 ml of a 30 ° ethanol hydroalcoholic solution, the whole of this very significant dose of metformin can be administered almost instantaneously and passively.
• This 225 mg dose is close to the theoretically available maximum fraction of a normally administered oral dose (500 mg), which represents at most 50% (250 mg) of the usual oral dose.
• a dosage form according to the invention made from 5 mg of Gliclazide solubilized in 1 ml of a 50 ° ethanol solution, it is possible to administer a dose almost instantaneously and passively (5 mg per liter of blood). greater than the maximum theoretically available fraction of a dose normally administered orally. Indeed, to obtain in the case of an oral dose, a plasma concentration equivalent to 1 mg of Gliclazide per liter of blood as with the composition according to the invention, it would require at least 30 mg of Gliclazide, its average volume. of distribution in the body being 30 liters.
• the bioavailability of the dose administered by the local mucous membrane is complete.
• the hydroalcoholic solution according to the invention titrating at least 30 degrees of alcohol, has not only the advantage of solubilizing the hypoglycemic / insulinotropic molecules, although they are lipophilic, which allows their spontaneous peri-mucous absorption but also protect the pharmaceutical formulation against microbiological contamination without having to introduce antimicrobial preservative (s).
• hydroalcoholic solution according to the invention has a quadruple competence:
• the degree of alcohol doubly increases the rate of mucosal absorption, both by osmotic effect and by causing reflex microvascular vasodilatation, which accelerates the local micro-circulatory flow, and
• the present invention offers a great simplicity of realization and a very good galenic stability: the extremely simplified solution water / alcohol guarantees the solubilization of the active principle and makes it possible to abstract the excipients usually used for the conventional pharmaceutical preparations, including the preservatives .
• the pharmacodynamic action time of the drug according to the invention is very short, compared to the slowness of absorption of hypoglycemic / insulinotropic drugs that require a waiting time of at most 30 minutes for Glinides, between the taking of the drug and the beginning of the hypoglycemic pharmacological action. It allows to act without delay to reduce the peak of Post-Prandial HyperGlycemia.
• the quasi-instantaneous pharmacological delivery can allow a patient to self-administer the drug in per / postprandial period, for an effect equivalent to the effectiveness of a subcutaneous or intravenous injection flash in the circulation , without the inconveniences of skin break-ins and iatrogenic risks related to this type of administration.
• the invention provides a treatment of Post-Prandial Hyperglycemia in the treatment of Type II Diabetes, readily available, effective, immediate, simple and for a reasonable unit and therapeutic cost compared to the current ones of this affection.
• the gain in terms of dose / effect ratio compared to existing antidiabetic drugs is at least 84 to 98% for Gliclazide, 60 to 93.4% for Glibenclamide, 50 to 90% for Gliclazide.
• Repaglinide from 50 to 99.75% for Sitagliptin and from 50 to 99.75% for Vildagliptin, from 85 to 97.5% for Saxagliptin.
• the administration of the pharmaceutical composition according to the invention thus allows a field of economy of dosage effective in the proportions indicated above for each molecule, for a therapeutic effect obtained without delay and which also allows a new therapeutic effect never reached until then, namely, the punctual treatment of Post-Prandial HyperGlycemia in Type II Diabetics.
• the administered hypoglycemic / insulinotropic molecules do not encounter any significant obstacle for their instantaneous arterial delivery to their hepatic or pancreatic target receptors that they gain in a few seconds, the administered basic dose is considerably reduced, comparable to the essential bioavailable dose. to exercise the required instant theoretical pharmacological activity.
• This dose is of course dependent on the active ingredient administered and the patient targeted. It is preferably between 0.025 mg and 250 mg of active principle, depending on said active ingredient considered, for volumes of hydroalcoholic solution ranging from 0.25 ml to 2 ml.
• the administration of the medicinal product according to the invention may be situated between 5 and 15 minutes after the start of a meal, so as to simulate the first physiological insulin secretion phase still deficient in diabetic patients. II, a phase normally located a few minutes after the start of the meal but delayed up to 30 minutes and 3 times less important in Type II diabetics.
• the dose of hypoglycemic / insulinotropic active ingredient administered according to the invention has the advantage of being directly active by inducing an instantaneous stimulation of insulin production close to secretion. physiological normal for some or an action on hepatic metabolism of sugar and the use of glucose by the tissues for others.
• the instantaneous stimulation of induced insulin production is very close to a normal physiological insulin production, which allows an infinitely more dynamic regulation of Post-Prandial Hyperglycemia peaks, adapted to the patient considered. compared with Glinide-based drugs of the prior art.
• this insulinotropic competence of the drug according to the invention is close to that of a rapid injection of insulin that the Type I diabetic is administered subcutaneously, a few moments before the meal.
• the invention for insulin secretory hypoglycemics and in particular for Glinides, allows a release at once rapid (a few minutes) and short (1 to 2 hours) of insulin, corresponding specifically to the duration recognized peak post-Prandial Hyperglycemia, without risk of iatrogenic hypoglycemia.
• the oral mucosa having a total surface of extremely broad absorption, multiplied by its character of pleated villous tissue
• the administration of the drug according to the invention is devoid of any risk of inadvertent swallowing or false route . 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, with various elements or excipients.
• the formulation according to the invention is particularly suitable for punctual ambulatory treatment of Post-Prandial Hyperglycemia Type II Diabetes which must be taken several times a day, namely for each meal.
• an aqueous alcohol solution of 0.75 ml of ethanol at 50 ° can produce only a circulating theoretical alcohol concentration of less than 0.017 g per liter of blood, according to the official Widmark reference formula, ie one thirtieth the legal tolerance in France established at 0.5 g per liter of blood.
• Oral mucosal administration is almost completely premature and spontaneously exhaled through the alveolar surfaces of the lung tissue where it was immediately driven by the pulmonary artery. Therefore, another significant advantage of the method of administration of the invention, there is virtually no systemic alcoholic administration.
• the invention relates to a process for preparing the formulation.
• a method of manufacturing the product according to the invention, particularly adapted, comprises the following steps:
• the method comprises the following steps:
• the process may optionally comprise the following steps before filtration:
• the present invention can be used in the context of a Type II diabetes treatment, for the instantaneous administration at reduced and useful doses of hypoglycemic agents, especially hypoglycemic sulphonamides, hypoglycemic Biguanides, Glibenclamide, Glinides or
• Incretins in particular Metformin, Gliclazide, Gibenclamide, Repaglinide, Sitagliptin or Vildagliptin or Saxagliptin.
• the present invention can be used for producing a medicament with oral transmucosal administration to counter the appearance of Post-Prandial Hyperglucose peaks in the treatment of
• Type II diabetes and prevent all associated risks.
• Such a drug is a simple, effective, exclusive and moderately costly answer to the problem of therapeutic management of Post-Prandial Hyperglycemia peaks, hitherto impossible to treat or very marginally, with the advantage of being able to use inter alia molecules already known in their conventional oral application, thus extensively evaluated for most of them for decades on populations of tens of millions of subjects.
• the invention allows for a previously unbalanced rebalancing of Type II Diabetes treatment, by administration of an oral hypoglycemic molecule to conventional background therapy, combined with the administration of extemporaneous spot treatment of HyperGlycemia Post. -Prandiale
• HGPP HGPP
• HGPP a product according to the invention dedicated to specifically compensate for the post-Prandial Hyperglucose peak. It is thus possible to treat simultaneously the two determining aspects of the affection.
• the invention thus provides the therapeutic response hitherto deficient or insufficient, that of the treatment of post-Prandial Hyperglucose (HGPP).
• HGPP post-Prandial Hyperglucose
• the pharmaceutical composition according to the invention corresponding to a very small fluid volume, is very easy to administer.
• a patient can easily deposit it in his mouth in direct contact with a specific area of mucosa, reduced surface.
• the patient must deposit the formulation according to the invention in a mucosal territory protected from salivary secretions, for example the juvenile gutter, bounded on the one hand by the lower and outer gingival crown and on the other by the mucous wall of the lower and inner faces of the cheeks and lower lip.
• This channel represents on average a closed reservoir about 18 cm long and 1 to 1.5 cm deep, a mucosal absorption surface of 35 to
• the formulation according to the invention requires a specific industrial packaging, in order to allow its safe, simple and ergonomic use and to prevent any degradation of the active ingredient in contact with air or light.
• a particular embodiment consists in using a packaging, preferably of small size, plastic or flexible metalloplastic or 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.
• a packaging preferably of small size, plastic or flexible metalloplastic or 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 comprise a cannula allowing the precise and easy deposition of the solution according to the invention in contact with an adequate mucosal area.
• the galenic form according to the invention is packaged in single-dose packages of 0.1 to 2 ml, capable of providing a precise adequate dose of active ingredient, adaptable to each patient.
• this packaging is easy to transport and allows easy use of the dosage form at any time of the day.
• Formulation 1 Gliclazide 5mg for 1, 5ml at about 50 ° of Ethanol
• Formulation 2 Gliclazide 3mg for 0.9ml at about 50 ° of Ethanol
• Formulation 4 Glibenclamide 1 mg for 1 ml at about 50 ° of Ethanol
• Formulation 5 Metformin 150 mg for 1 ml of alcohol at 30 °:
• Formulation 7 Repaglinide 0.125 mg per 0.25 ml of 50 ° hydroxyl alcohol solution:
• This seventh example of formulation can be obtained by the implementation of the method described by following:
• Formulation 8 Repaglinide 0.25 mg per 0.5 ml of 50 ° hydroalcoholic solution:
• Formulation 9 Repaglinide 0.5 mg per 1 ml of 50 ° hydroxyl alcohol solution:
• Formulation 10 Sitagliptin 5 mg per 0.5 ml of 50 ° hydroxyl alcohol solution: - Sitagliptin 5 mg
• Formulation 11 Sitagliptin 10 mg per 0.5 ml of 50 ° hydroxyl alcohol solution:
• Formulation 13 Vildagliptin 2.5 mg per 0.5 ml of 50 ° hydroxyl alcohol solution:
• Formulation 15 Vildagliptin 10 mg per 1 ml of 50 ° hydroxyl alcohol solution:
• Formulation 16 Vildaqliptin 15 mq for 1 ml of 50 ° hydroxyl alcohol solution:
• Formulation 17 Saxaqliptin 1.5 mq for 0.5 ml of 50 ° hydroxyl alcohol solution:
• Formulation 18 Saxagliptin 0.75 mg per 0.5 ml of 50 ° hydroxyl alcohol solution:
• This eighteenth example formulation can be obtained by implementing the method described as follows:
• Formulation 19 Saxagliptin 0.5 mg per 0.5 ml of 50 ° hydroxyl alcohol solution:
• Formulation 20 Saxaqliptin 0.25 mg for 0.25 ml of 50 ° hydroalcoholic solution:
• This twentieth example of formulation can be obtained by the implementation of the method described by following:
• the invention is also applicable to the animal, in particular to the treatment of overweight pets suffering from type II diabetes, such as dogs for example.

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• 2009
  • 2009-07-10 FR FR0954819A patent/FR2947729B1/fr not_active Expired - Fee Related
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