LIQUID PHARMACEUTICAL COMPOSITION FOR NASAL ADMINISTRATION CONTAINING A POLYPEPTIDE AS ACTIVE INGREDIENT

Abstract: A liquid composition for nasal administration of poly­ peptide/s comprising ammonium tartrate and a buffer together with optional adiuvants.

Description: The present invention relates to a liquid pharmaceutical composition for the nasal administration containing salmon calcitonin as active ingredient. It is known that many polypeptides, both of natural and synthetic origin, and derivatives thereof are administered in various dosage forms, said forms comprising liquid or solid nasal spray form. The majority of the liquid nasal spray pharmaceutical compositions contain, besides one or more polypeptides dissolved in a solvent such as water, also an absorption enhancing agent and a buffer to keep the pH of the solution at a physiologically acceptable value, that is at the same time compatible with the nature of the polypeptide, together with other optional adjuvants. As absorption enhancing agents, there are known aromatic carboxyl acids and the ester and amide derivatives thereof, aminoacids, hydroxycarboxylic and polycarboxylic acids, salicylic acids and derivatives thereof, glycirrhizinates, surfactant agents, chelating agents. Nasal spray compositions of the above mentioned types are described, for example, in the following documents: EP-A-115627, BE 897904, EP-A-183527, GB 2127689, JP 294737, EP-A-308725, EP-A-249811, EP-A-067513, EP-A-327756 (corresponding to FR-A-2623090), JP-A-1230530 and US 4,476,116. Tests conducted by the present inventors, have shown that the polypeptides can reach satisfactory and suitable haematic concentrations even without an absorption enhancing agent, and this observation is confirmed by what taught in EP-A-363876, wherein a liquid composition for the nasal administration of a polypeptide merely containing an isotonic agent as adjuvant shows AUC (Area Under Curve) data supersimposable with the ones of a similar composition also containing a known absorption enhancing agent. Furthermore, the same document underlines the undesired effects of some absorption enhancing agents (see page 2, lines 36-38). Anyway an important problem connected with the use of liquid compositions of polypeptides, either with or without an absorption enhancing agent, concerns the stability of such active ingredients as being very prone to degrade, particularly in liquid environment. Said drawback is recognized in literature: see, for example US-A-4,613,500 and EP-A-193372. Such specifications aim to overcoming the stability problems of liquid nasal sprays suggesting the use of powder nasal spray compositions that, however, still exhibit stability and nasal mucose irritation problems due to the presence of water-absorbing, insoluble dispersing agents that are employed to assist the active ingredient in the absorption. Moreover, the powder form can provide for a diffuse, efficient administration of the active ingredient only if this is micronized at differentiated particle size. To this purpose the above-mentioned US-A-4,613,500 and EP-A-193372 use the active ingredients in form of powders comprising mixtures of particles exhibiting different diameters (10 to 250 microns) to provide for a fast absorption of the particles having a diameter of about 10 microns, and a delayed absorption as well due to the particles having a larger diameter to the purpose of maintaining a sufficient plasma concentration for a period of time. It is apparent that the manufacture of said powders having a very fine differentiated particle size is highly complicated and expensive. It has been really surprisingly found that only a composition containing ammonium tartrate and salmon calcitonin is stable and suitable for nasal administration. Accordingly the present invention relates to a liquid pharmaceutical composition for nasal administration buffered at a physiologically pH (3.5 to 7.0), comprising salmon calcitonin as the active ingredient and ammonium tartrate as stabilizing agent, the amount of ammonium tartrate being of from 0.01% to 2.00% w/w with respect to the weight of said composition. In particular the liquid pharmaceutical composition of the present invention has an amount of ammonium tartrate between 0.01% and 0.15%. Such composition is able to guarantee long stability and good absorption of the active ingredient, thereby avoiding the use of irritant absorption enhancing agents or complicated preparation and delivery techniques. The above stated range of ammonium tartrate concentration was chosen in view of the following considerations. Ammonium tartrate is effective as stabilizing agent even at low concentration close to the lower limit stated hereabove, and any further addition of ammonium tartrate over the upper limit of 2% not only does not increase its stabilizing activity, but it can cause toleration problems too. The following examples are provided for illustrative purposes only, and are not intended as limiting the invention. EXAMPLE 1 Salmon calcitonin 55000 I.U. Ammonium tartrate 600 mg Citric acid, anhydrous 655 mg Sterile degassed water q.s. to 100 ml EXAMPLE 2 Salmon calcitonin 55000 I.U. Ammonium tartrate 600 mg Citric acid, anhydrous 655 mg Sodium merthiolate 10 mg Sterile degassed water q.s. to 100 ml EXAMPLE 3 Salmon calcitonin 55000 I.U. Ammonium tartrate 600 mg Citric acid, anhydrous 344,5 mg Sodium chloride 500 mg Sodium merthiolate 10 mg Sterile degassed water q.s. to 100 ml EXAMPLE 4 Salmon calcitonin 55000 I.U. Ammonium tartrate 309.5 mg Citric acid, anhydrous 304.5 mg Methyl p-hydroxybenzoate 80 mg Propyl p-hydroxybenzoate 20 mg Sterile degassed water q.s. to 100 ml EXAMPLE 5 Salmon calcitonin 55000 I.U. Ammonium tartrate 600 mg Citric acid, anhydrous 393 mg Sodium chloride 500 mg Methyl p-hydroxybenzoate 80 mg Propyl p-hydroxybenzoate 20 mg Sterile degassed water q.s. to 100 ml It can be seen that in some of the foregoing Examples citric acid is mentioned: it is however to be noted that citric acid was not used as an absorption enhancing agent, but it is merely the acidic component of the buffer. Stability tests The stability of the formulation of example 1 has been evaluated against the following preparation: Comparison formulation Calcitonin 55000 I.U. Sodium chloride 700 mg Sodium citrate dihydrate 618.5 mg Citric acid, anhydrous 609 mg Benzalkonium chloride 22 mg Sterile degassed water q.s. to 100 ml The tests have been carried out by HPLC titration under the following conditions: Reagents Ammonium phosphate, dybasic, R Phosphoric acid, R Acetonitrile, HPLC grade Tetrahydrofurane, HPLC grade Solvent buffer: thoroughly weigh and dissolve 1 g of glacial acetic acid, 1 g of sodium acetate trihydrate, R, and 3.75 g of sodium chloride, R, into a 550 ml volumetric flask with water (pH = 4.0). Mobile phase 0.2 M dibasic ammonium phosphate/acetonitrile/tetrhahydrofurane = 720:260:20, adjusted to pH 5.3 with phosphoric acid, R grade. Reference substance Salmon calcitonin working standard. Apparatus High pressure liquid chromatograph with variable wavelenght UV detector, connected to a recorder and a computer. Column: Whatman Partisphere Ca 5u (125x4) conditions Column temperature : ambient Flow rate : 1 ml/min Detector : UV 220 nm Injected amount : 10 ul The results of the experiments are shown in Tables 1 and 2.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, NL A liquid pharmaceutical composition for the nasal administration buffered at a physiologically acceptable pH of 3.5 to 7.0, characterized in that it comprises salmon calcitonin as the active ingredient and ammonium tartrate as stabilizing agent, the amount of ammonium tartrate being of from 0.01% to 2.00% w/w with respect to the weight of said composition. A liquid pharmaceutical composition as claimed in claim 1, characterized in that the amount of ammonium tartrate is between 0.01% and 0.15%. Claims for the following Contracting State : ES A process for the preparation of a liquid pharmaceutical composition for the nasal administration buffered at a physiologically acceptable pH of 3.5 to 7.0, characterized in that salmon calcitonin as the active ingredient is admixed with ammonium tartrate as stabilizing agent, the amount of ammonium tartrate being of from 0.01% to 2.00% w/w with respect to the weight of said composition. A process as claimed in claim 1 characterized in that the ammonium tartrate is added in an amount between 0.01% and 0.15% w/w.

Inventors: CESCHEL, GIANCARLO, RONCHI, CELESTINO, SEGU, ANTONELLA MARIA
Applicants: PHIDEA S.P.A.
Application year: 1990
Main classification: A61K47
IPC codes: A61K47, A61K9, A61K38