FR2710529A1 - Aqueous gel for nasal use, pellets, and process for preparing them - Google Patents

Abstract

Aqueous gel for nasal use, which comprises an active principle containing a peptide which is pharmacologically active via the nasal route, or one of its derivatives, a pharmaceutically acceptable surfactant and a gelling agent, and whose pH is in the region of neutrality, preparation process, new pellet and process for preparing it.

Description

 The present invention relates to a new aqueous gel for nasal use, pellets, and a process for their preparation.

 Despite the many efforts and attempts which followed the discovery of insulin over 50 years ago and up to the present day, there is still no pharmaceutical preparation of this hormone capable of being administered without injection to combat effectively pathological hyperglycemia by an easily accessible route, allowing the optimization of insulin therapy without the constraint linked to repeated injections. It is the same for other active ingredients of the same nature.

 The protein nature does not allow the passage of these active ingredients into the bloodstream when they are not administered by injection, unless their absorption is activated by other substances.

 If we take insulin as an example, among the non-injectable routes explored, the nasal route would however be the most promising if its bioavailability and local tolerance to preparations containing it were improved because the anatomical features of the nasal mucosa, in particular its absorption surface and its vascularity, allow obtaining a pharmacokinetic profile and a rapid action of the hormone approaching those of the intravenous route.

 The absorption of insulin by the nasal mucosa and its passage into the systemic circulation through this barrier is only possible if it is associated with a substance activating its absorption from the preparation used, several of these substances known as names of "promoters of nasal absorption" and which allow this passage have been used. They belong to different chemical families such as surfactants, detergents, fatty acids, bile salts, phospholipids and saponins.

 In the specialized literature concerning insulin administered by the nasal route, there are cited, both for the experiments carried out in animals and in tests carried out in humans, several of these promoters showing more or less activity on l nasal absorption of insulin and a more or less good tolerance locally, especially in chronic treatments.

 Insufficient nasal absorption on the one hand, relative local tolerance on the other hand, largely explain the failure of all these trials for the development of a satisfactory nasal insulin preparation which can be used in the treatment of hyperglycaemia.

 EP-A-0 360 340 describes lyophilized powders for nasal use containing an active peptide principle. However, when the powder is inhaled, it is not possible to measure the amount of active ingredient administered; moreover, only a "whiplash" effect is possible, which is not desired in cases where the administration of the active principle should be prolonged over time.

 After extensive research on insulin as an experimental example, the Applicant has been able to demonstrate that, first of all, independently of the preparation used, the bioavailability of the peptide administered by the nasal route, that is to say the amount of the peptide which crosses the mucosa and reaches the circulation from this preparation on contact with the mucosa, essentially depends on the activity of the absorption promoter which is associated with it and on the concentration thereof, these two elements also conditioning the local tolerance of the preparation.

 The bioavailability finally depends on the nature of the preparation used, because mucocilliary clearance, that is to say the physiological mechanism which rapidly clears the nasal cavity of the product introduced towards the esophagus (at most in 20 minutes) to limit the contact time of inappropriate preparations with the mucosa, thereby limiting the absorption of the active product.

 The new compositions for nasal use which are the subject of the present application take advantage of this work and have the characteristics of a gel which, after its preparation, can be used directly, or subjected to rapid freeze-drying which reduces it to pellets of appropriate dimensions allowing its introduction. easy in the human nostrils where by humidification it is reconstituted. The gel is composed of a pharmacologically active peptide by the nasal route, in particular of human insulin, of a surfactant, in particular of sodium glycocholate and of a gelling agent, in particular of methyl cellulose, in aqueous medium of pH around of neutrality.

 This is why the present application relates to an aqueous gel for nasal use, characterized in that it comprises an active principle containing a pharmacologically active peptide by the nasal route or one of its derivatives, a pharmaceutically acceptable surfactant and an agent. gelling agent, and in that its pH is around neutral, namely pH = 7 + 1.5.

 The peptide can be a relatively high molecular weight hormone used for the treatment of endocrine deficiencies or insufficiencies such as for example a water-soluble hormone chosen from luteinizing hormone (LH-RH), gonadotrophin or corticotrophin, and preferably glucagon or in particular insulin, as well as their derivatives. The peptide can also be a product such as interferons used for a preventive or curative purpose to combat certain respiratory pathologies or a vaccine product, from inactivated viruses, such as measles, anti-polio and influenza vaccines. The derivatives can be the salts, esters or polymers (for example commercial insulin is a hexamer), of these peptides.

 The pharmaceutically acceptable surfactant is, for example, a salt of cholic acid or its derivatives, such as sodium cholate, sodium dehydrocholate, sodium (glyco) deoxycholate, and very particularly sodium glycocholate, since glycocholic acid used as promoter is considered to be well tolerated, even for periods of 4 months at very large doses (24 mg per day) which will never be achieved with the present compositions in the form of a gel.

 It can also be a polyoxyethylene ether such as polyoxyethylene (9) lauryl ether or polyoxyethylene (10) cetyl ether.

 The gelling agent may for example be a vegetable gum, the carboxypolymethylene or a cellulose derivative such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and preferably methyl cellulose. Its association with an aqueous solvent of the active principle and of the surfactant produces a gel.

 The relative proportions of surfactant and active principle can range, for example, from 1.5: 1 to 12.5: 1 by weight, preferably from 4: 1 to 8: 1 and particularly from 5.5: 1.

 The relative proportion of the gelling agent in the gel can range from 1: 1000 to 1:25 by weight, in particular from 1: 500 to 1:50 and particularly from 1: 200 to 1: 100.

 To administer a very precise quantity of the active principle, it is also possible to freeze-dry the gels described above. The pellets thus obtained contain a well-determined amount of active principle and, when they are brought into contact with the nasal mucosa, they have the capacity to rehydrate to reform the gel from which they come. These pellets are a considerable advance compared to the powders to be inspired by the nose, for which one cannot control the amount of active ingredient actually administered.

 In addition, the gel and the pellets provide a prolonged effect of the active ingredient over time.

 The bioavailability of the peptide of this preparation in animals is considerably improved compared to the preparation (solution) which does not have the consistency of gel. As for the local tolerance in chronic administration, it can be expected that it will be at least as good as that of the solutions used so far because the significant improvement in the bioavailability of the peptide allows the reduction of gel uptake in humans. .

 For example, the much better hypoglycemic activity of insulin gel compared to the corresponding solution as well as its improved absorption, demonstrated by much higher concentrations of plasma insulin, are illustrated in the experimental part.

 The drop in blood glucose at an equal dose of insulin is greater in rats treated with the gel 60 and 90 minutes after administration than in animals treated with the solution. Three hours after administration, the drop in blood sugar with the gel remains on the order of minus 50% compared to the initial blood sugar, even though this has already been fully restored in animals treated with the solution.

 The concentration of insulin in the plasma of animals treated 10 and 15 minutes after administration of the gel is twice as high as that of animals treated with the solution. It remains even more important until the sixtieth minute.

 The present application also relates to a process for the preparation of the gels described above, characterized in that an active ingredient containing a pharmacologically active peptide is dissolved nasally in an aqueous solvent, the solution thus obtained is neutralized , a pharmaceutically acceptable surfactant is then added, then a gelling agent, and the whole is stirred to obtain the expected gel.

 The present application also relates to a process for the preparation of the above-described pellets; characterized in that the gel obtained above is divided, and the unit parts thus obtained are subjected to a freeze drying to obtain the expected pellets, rehydratable to transform again into gel by application to the nasal mucosa.

 The gels and pellets described above may also contain one or more conventional excipients or additives such as compatible flavors or preservatives.

 The present application finally relates to a method of treatment of endocrine deficiencies or insufficiencies in humans, characterized in that the patient requiring a supplement of active hormone is administered nasally with a sufficient amount of a gel or 'a pellet defined above to compensate for the aforementioned deficiency or insufficiency.

 The doses to be administered correspond approximately to the well-known doses of the pharmacologically active peptide, usually administered in solution by the parenteral route, or at most twice these doses.

 Compared to the doses of peptides administered hitherto in nasal solution, the gel of the present invention allows their reduction to half or a quarter.

 For example, for a dose of insulin in solution of 10 IU subcutaneously, 10 or 20 IU of gel or pellet according to the invention can be administered. These same doses correspond to 40 IU or more, of insulin in solution administered by spraying or nasal instillations.

 The examples which follow illustrate the present invention, without however limiting it.

EXAMPLE 1 - PREPARATION OF A GEL
The human insulin is weighed and dissolved with stirring in dilute hydrochloric acid, ie 500 IU in 5 ml of 0.1N hydrochloric acid. The solutions are then neutralized with stirring at neutral pH (pH 7.1 + 0, 2) by adding a sufficient volume of 0.05 N sodium hydroxide solution close to 10 ml. 75 mg of sodium glycocholate are weighed and dissolved with stirring in the solution prepared above. The pH is checked again and possibly readjusted. To these solutions are added, with very moderate stirring and at the temperature of 20 "C + 2", 200 mg of finely pulverized methyl cellulose, which thickens the medium uniformly in about one hour of constant stirring. The volume of the solution is made up with distilled water to 20 ml, always with stirring, which is stopped about 15 minutes later.

EXAMPLE 2 - PREPARATION OF PELLETS
Freeze-dried pellets are obtained by distributing volumes ranging from 0.1 to 0.3 ml of gel from Example 1 in cylindrical glass containers having a diameter of 5 mm which are cooled to 80 "C for 24 hours The final product is then obtained by subjecting the tubes to a freeze-drying process in an apparatus
CHRIST ALPHA 1-4, in several stages under pressure reduced to 0.03 mbar according to a cycle of 22 H at -40 C, 3 H at 10 C, 2 H at 0 C, and 1 H at +10 "C.

EXAMPLE 3
The procedure is as in Example 1, but with 2000 IU of insulin and 300 mg of sodium glycocholate to obtain the gel and the corresponding pellets.

EXAMPLE 4 - PHARMACOLOGICAL STUDY
The tests carried out to test the various products were carried out on batches of male rats weighing close to 300 g., Deprived of food for 12 hours and under pentobarbital anesthesia.

 Intranasal administration was done using a precision syringe connected to a flexible catheter inserted into the nostril where the same volume (0.05 ml) of each product was deposited.

 Before administration of the products and at regular intervals thereafter, venous blood samples were taken and analyzed for the determination of - blood glucose (blood sugar) and plasma insulin (insulinemia) - blood sugar alone in the second.

 If we plot on a graph the curves giving the percentage drop in blood glucose observed compared to basal blood sugar as a function of time in minutes by administration of the same dose of insulin and glycocholic acid (AGC), namely 10 units of insulin and 2 mg of AGC / kg, on the one hand in a nasal solution and on the other hand in a nasal gel containing 1% methylcellulose, it can be seen that the drop in blood sugar at an equal dose of insulin is more important in rats treated with the gel, 60 and 90 minutes after administration, than in animals treated with the solution.

 Three hours after administration, the decrease in glycemia with the gel remains in the order of 50% compared to the initial glycemia, while the latter is restored to its initial level in animals treated with the solution.

 If the insulinemia expressed in micro-units / ml as a function of time in minutes is also plotted on a graph, it is observed that the concentration of insulin in the plasma of the animals treated with the gel, 10 and 15 minutes after administration under the same conditions as above, is twice as large as that of animals treated with the solution. It remains even more important until the sixtieth minute.

 These results show, on the one hand, that the same doses of insulin and glycocholic acid in intranasal administration in the form of a solution are clearly less active in lowering blood sugar as a function of time than the gel according to the invention, and d On the other hand, that the gel allows better absorption of insulin by the nasal mucosa, since its administration approximately doubles the insulinemia at 10 minutes.

 If we finally report on a graph the results expressed as a percentage drop in blood sugar as a function of time in minutes, in the form of curves comparing a nasal solution administered at the rate of 10 units of insulin and 2 mg / kg of glycocholate , compared to the gel form, at 1% methylcellulose administered respectively at a rate of 5 units and 1 mg / kg, or half in doses of insulin and glycocholate, it is noted that the two curves representing the drop in blood sugar , due to the action of insulin in relation to blood sugar before treatment, are not significantly different; they are practically superimposable both at the level of the maximum effect between 30-45 minutes and 90 minutes during the rise in blood sugar.

 These results show that the gel form makes it possible to obtain the same hypoglycemic efficacy as a double dose of insulin and glycocholate, and more generally of peptide and surfactant, administered in nasal solution.

 As has been explained above, in particular with regard to the tolerance of glycocholate, the reduction in the doses to be administered which the gel form allows, thanks to the increased pharmacological activity of the peptide, provides better local and general tolerance of the preparations according to the invention especially during necessarily long treatments such as those with insulin.

Claims (9)

RIVINDICATIONS  1. Aqueous gel for nasal use, characterized in that it comprises an active principle containing a pharmacologically active peptide by the nasal route or one of its derivatives, a pharmaceutically acceptable surfactant and a gelling agent, and in that its pH is around neutrality.  2. Gel according to claim 1, characterized in that the surfactant is a salt of cholic acid or one of its derivatives.  3. Gel according to claim 1 or 2, characterized in that the surfactant is a salt of glycocholic acid.  4. Gel according to one of claims 1 to 3, characterized in that the gelling agent is a derivative of cellulose.  5. Gel according to one of claims 1 to 4, characterized in that the gelling agent is methyl cellulose.  6. Gel according to one of claims 1 to 5, characterized in that the weight proportion of the gelling agent in the gel is between 1: 1000 and 1:25.  7. A method of preparing a gel according to claim 1, characterized in that an active ingredient containing a pharmacologically active peptide is dissolved by the nasal route in an aqueous solvent, the solution thus obtained is neutralized, then add a pharmaceutically acceptable surfactant, then a gelling agent, and stir the whole to obtain the expected gel.  8. Pellet characterized in that it consists of a gel according to one of claims 1 to 6, freeze-dried.  9. A method of preparing a pellet as defined in claim 8, characterized in that the gel is divided as defined in one of claims 1 to 6 and subjected the unit parts thus obtained to a freeze-drying for obtain the expected rehydratable pellets.