FI111339B - Mfg. liq. pharmaceutical compsn. for intranasal admin. - Google Patents

Abstract

A process for the prepn. of liquid pharmaceutical compsns. for intranasal admin. comprises the dissolution of a effective amt. of calcitonin in a NaCl soln. in depirated water adjusted to pH 3.5-4.5. Also claimed is a spray unit for spray administration of calcitonin by intranasal route.

Description

111339

Method for the preparation of an injection unit for calcitonin syringe delivery Förfarande för framställning av en sprutningsenhet för administrering av calcitonin genom sprutning 5

The present invention relates to a method of preparing an injection unit for intranasal administration of pharmaceutical compositions.

Intranasal administration of polypeptide drugs is extensively described in the literature; 10 See, e.g., Felber et al., Experientia, 1969 page 1195; Gennser et al., Lancet, 1974, page 865; Greenberg et al., Antimicrobial Agents and Chemotherapy, 1978, page 596; Bergquist et al., Lancet, 1979, page 215; Pontiroli et al., British Medical Journal, 1982, page 303, in addition to numerous patents or patent applications for intranasal administration of insulin (EP 94157), vasopressin (Japanese Patent Applications 55066-517, 55055-120), various polypeptides (German Patents 2,256). 445 and 2,758,483, EP 252, Belgian Patent 860,717, South African Patent 68/4241).

The invention provides an injection unit for dispensing formulations such as those set forth above comprising a bottle (1) for adding composition and a dosing pump disposed in the mouth of the bottle, wherein the injection unit is further characterized in that the upper space of said bottle is filled with pressurized nitrogen.

Syringe vials of the above type are known but have a number of drawbacks, for example the problems associated with ensuring the fluid tightness of the liquid contained therein, and in particular of any fat added thereto.

The syringe bottle produced by the method of the invention avoids the above problems, and in particular this is due to the particular design of the pump which has no associated suction / pressure valves (usually BNSDOCID: <111139B1 I> 2 111339) and is designed to passage through the pump in both operating and idle condition.

The features of the process according to the invention are set forth in the claims.

In addition, the pump is uniformly provided with a sealing sleeve which is tightly fitted to the mouth of the bottle to provide a hermetic seal that prevents all gas from being discharged outwards and inwards.

10

The top of the bottle is filled with nitrogen at an excess pressure of 0.2-0.3 bar. This overpressure is intended to compensate for the dehydration during the dosing process, ensuring that the entire contents of the bottle are fully utilized without air flowing back from the outside. This is particularly useful if it is believed that contact of the liquid pharmaceutical composition with the air in the bottle results in degradation of the active ingredient of the composition as well as bacterial contamination of the latter and therefore to the detriment of the person using it.

The bottle has a container bottom with a capacity of about 7 ml and is fed by a pre-compression / 20 dosing pump of approximately 100 microliters at a time, which corresponds to a therapeutically effective dose of the active ingredient.

The pump comprises a hollow housing defining a plurality of chambers of various cross-sections located on the neck of the bottle between said sleeve seal and secured to the bottle by a capsule having a bottom member which is wound around the annular periphery of the neck of the bottle.

The hollow pump housing has a hollow piston that is forced by a spring against a valve seat formed on a piston rod that extends upwardly from the top of the bottle 30.

BNSDOCIO: <EN 111339B1I> i 3 111339 Depressing the crest causes a fluid outlet which is located in the annular chamber which is bounded between the outer surface of the piston and the inside of the largest diameter of the pump casing.

Other features of the syringe assembly produced by the method of the invention will be better understood by reading the following detailed description of one embodiment, which is shown by way of example only in the accompanying drawings, in which Figure 1 is a side view of a bottle according to an embodiment of the invention; and

Fig. 2 is a cross-sectional view showing, on a larger scale, the pump fitted to the neck of the bottle of Fig. 1.

With reference generally to the above figures, the numeral 1 generally denotes a glass bottle having a container bottom 2 and preferably a capacity of about 7 ml.

In a known manner, the bottle 1 has a neck 3 and the neck 3 has an outwardly projecting annular ring 4 at its upper part.

20

Mounted and lined on bottle 1, there is a pre-compression metering pump 5 (Figure 2) designed to release about 100 microliters per application.

The pump 5 comprises a hollow casing 6 disposed in the bottle 1 and supports the lower part of the piston member 7.

25

The hollow housing 6, viewed from the bottom to the top, defines three chambers 8, 9, 10 having increasing sections and the upper of these chambers being imaged to receive the base 11 of the hollow cavity 12, which extends upwardly and protrudes from the top of the bottle 1.

Followed by the pump housing 6 is a piston 13 which is sealingly slidable inside the chamber BNSDOClD: 4 111339 9 and is normally forced upwards by a spring 14 partially located at one end of the recess 15 in the piston 13 and resting at one end on an annular shoulder 12. against the bottom of the lower chamber 8 of the housing 6.

The bottom 17 of the piston 13 functions as a valve and is normally forced by a spring 14 against the valve seat 18 formed on the base 11 of the piston rod 12.

The seal 19 of silicone rubber is placed in the pump casing 6 and the mouth of bottle 1 and serves as hermetic barrier, in addition, it prevents the fluid flow 10 Masta out of the bottle, but also prevents possible interactions with the outside of the gas-exchange in either direction.

The bottle 1 has a plastic capsule 20 fitted to its mouth, this capsule being centrally provided with a hole for passage of the piston rod 12 and secured to the bottle 15 with an aluminum base 21 wrapped around the annular rising ring 4 of the bottle.

The top space in bottle 1 is filled with nitrogen to an excess pressure of 0.2-0.3 bar.

The purpose of this overpressure is to compact the reversible liquid during use to ensure that the entire contents of the bottle are used without airflow from the outside and thus also to ensure that the nitrogen atmosphere is maintained during use without time limit.

The nitrogen atmosphere of the flask is obtained by spraying the empty flask with nitrogen, dividing the solution, evacuating the gas from the flask and replacing it with nitrogen, installing and sheathing the pump which produces excess pressure through the pump. All these operations are carried out under a nitrogen atmosphere.

30 In this way, almost all of the air is removed from the top of the bottle, which in practice consists only of nitrogen, which is maintained throughout the product's useful BNSDOCID: <111339B1 I> 5 111339.

To operate the syringe bottle made by the method of the invention, the hollow piston rod 12 is pressed down, thereby causing the piston 13 to move down 5 against the force of the spring 14.

The downward movement of the piston 13 causes the volume of the annular chamber 10 to decrease so that the liquid therein tends to flow to the bottom 17 of the piston 13 and the valve seat 18 then acts as a syringe from the bypass 22 22 of the piston rod 12.

When the piston rod 12 is released, this causes the piston 13, and thus the piston rod 12, to be forced upwardly by the spring 14 to the position shown in Fig. 2, which results in more fluid flowing into the annular chamber 10.

15

The amount of fluid pumped with each release, which is almost equal to the volume of the annular chamber 10, is about 100 microliters.

From the foregoing, it should be clear that the particular design of the illustrated pump, which does not have a suction / pressure valve (typically a ball type), prevents the contents of the bottle from flowing through the pump in both operating and idle condition.

The following non-limiting examples illustrate the invention in more detail.

Example 1

Salchatonin (500,000 I.U.) is dissolved in 850 ml of purified water containing 9 mg of analytically pure sodium chloride; The pH was adjusted to 4.0 with analytically pure 1N HCl and the solution was diluted to 1000 mL by addition of 30 purified water. Filter the solvent into a 0.2 μιη: η filter and dispense into 5 ml containers as shown in the attached figures with a dispenser which BNSDOCID: <111139B1 I> 6 111339 releases 0.1 ml portions each time corresponding to 501. U. salkatoniinia.

Example 2 The procedure of Example 1 was repeated, however, using twice the amount of Salvatone (1,000,000 I.U.). The solution is dispensed into suitable 2.5 ml containers as shown in the figures in the appendix which release doses of 0.1 ml each time corresponding to 100 U.I. salkatonia.

BNSDOCID: <FI 111339B1 I>

Claims (4)

A method of preparing a spray unit for administering by spraying calcitonin, said spray unit comprising a bottle (1) containing a liquid composition of calcitonin and a pump (5) mounted and enclosed in said bottle, the pump (5) comprising a hollow case (6) formed by a plurality of sections, a plunger (13) arranged to act against the force of a spring (14) and a plunger rod (12) projecting from the bottle (1) Upper portion, characterized in that , that an annular chamber (10) has been defined between the cow (13) and the hollow case (6), the decrease of the vagina volume, as a result of the piston rod (12) being pushed, causing the liquid in said chamber (10) to pass between the piston bottom ( 17) and a valve connection (18) formed in a base (11) of the piston rod (12), the liquid being then allowed to flow through a passage (22) in the hollow piston rod (12), and of the upper space of fla the shoe (1) is filled with nitrogen under pressure. 2. A method according to claim 1, characterized in that said upper space in the bottle (1) is filled with nitrogen to an overpressure of 0.2-0.3 bar. 20 3. A method according to claim 1 or 2, characterized in that a sleeve gasket (19) is arranged between the hollow case (6) of the pump (5) and the bottle mouth (1) and serves as a hermetic closure to prevent gas from flowing in and out. out of the bottle. 25 4. A method according to any one of claims 1-3, characterized in that the bottle (1) has a capacity of about 7 ml and the dosing pump (5) releases about 100 microliters each, which corresponds almost to the volume of the annular chamber ( 10). BNS DOCID: <FI 111339B1 I>