MXPA97000440A - Pharmaceutical composition nasod administrable monodosis and method of application of such composic - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for mono-dose nasal administration, effective and constant, at the plasma level, of an aqueous solution of about 5 to about 75æl, and about 0.2 to about 2.0mg. / ml of desmopressin acetate, a correspondingly molar amount of desmopressin or a pharmaceutically acceptable salt of desmopressin. The composition is useful for the treatment of urinary disorders such as diabetes insipidus, incontinence, and nocturnal enuresis

Description

PHARMACEUTICAL COMPOSITION NASOD ADMINISTRABLE MONODOSIS AND METHOD OF APPLICATION OF SUCH COMPOSITION 5 FIELD OF THE INVENTION The present invention relates to the nasal administration of desmopressin, desmopressin acetate and other pharmaceutically acceptable salts of desmopressin, and to optimal compositions for said administration. BACKGROUND OF THE INVENTION Nasal administration is an attractive route for the delivery of therapeutic peptides. However, in the art optimal conditions for intranasal drug deposition are not achieved peptides, which have to overcome the barrier of the nasal mucosa, enter the systemic circulation and be delivered effectively in the peripheral target organs. In addition, most of the known peptides suitable for nasal administration are expensive, and the current tendency is an "over-delivery", cause of 2 or waste, of said expensive nasal peptides. Therefore, there is a need in the art for improvements in the nasal administration of the peptides. It has been reported that administration of volumes below 50 μl by nasal pump is unacceptable, as it is not assured the accuracy of the dose or the probability of an effective delivery to the - i - target bodies; on the other hand, in the art it is considered that a greater volume, higher than 150 μl, is inadequate, as it is a cause of flooding F. Moren, Aerosols in Medicine, Moren and Other (s), page 346, Elsevier Scientific, Amsterdam (1993). There is a need for an accurate delivery and an economical system for effective nasal administration of the peptides. In particular, there is a need for an accurate and optimal delivery system for the effective nasal administration of desmopressin (hereinafter referred to as "DDAVP"). OBJECTS OF THE INVENTION One of the objects of the invention is to provide a mono-dose pharmaceutical composition of desmopressin, desmopressin acetate or other pharmaceutically acceptable salts of desmopressin, for nasal administration, which composition has to be an improvement that allows an optimal and effective delivery to peripheral objectives. Another object of the invention is to provide an aqueous solution - a raw material of desmopressin, desmopressin acetate or a desmopressin salt. Still another object is to provide a means for nasal administration of an aqueous solution - raw material of desmopressin, desmopressin acetate or other pharmaceutically acceptable salts of desmopressin, for repeated and constant administration of a volume of 5 to 75 μl, more preferably, from a volume of 10 to 50 μl, and in particular a volume of approximately 20 to 45 μl.

And yet another object of the present invention is to provide a method for the nasal administration of desmopressin, desmopressin acetate or other pharmaceutically acceptable salt of desmopressin, in a convenient manner such that in the patients' plasma they are delivered effective and constant concentrations. These objects, amen of others, will be evident to people with expertise in art, thanks to the benefits of the present revelation. SUMMARY OF THE DISCLOSURE For the purposes of this specification, desmopressin (DDAVP) is 1 - (3-mercaptopropionic acid) -8-D-arginine vaso-presin. The expression "nasal" covers the expression "intranasal", which means, in this context, the delivery of drugs through the nasal mucosa. The invention encompasses a single-dose pharmaceutical composition for nasal administration, comprising an aqueous solution having a volume of from about 5 to about 75 μl; the solution contains from about 0.1 to about 2.0 mg / ml of a compound selected from desmopressin, desmopressin acetate or a pharmaceutically acceptable salt of desmopressin. The solution may have a volume of from about 10 to about 50 μl; approximately to about 45 μl; or about 35 μl. The compound is present in the solution, at a concentration of about 0.1 to about 0.5 mg / ml, or about 0.5 to about 2.0 mg / ml.

Also included in the invention is a means for delivery in conjunction with a nasal spray pump or a device for the nasal administration of drops, for the repeated dispensing of a volume of about 5 to about 75 μl of an aqueous solution containing about 0.1 to about 2.0 mg / ml of desmopressin, desmopressin acetate or a pharmaceutically acceptable salt of desmopressin. The solution present in the delivery medium has a volume of from about 10 to about 50 μl; from about 20 to about 45 μl; or about 35 μl. Another aspect of the invention is a method for the delivery of plasma constant levels of desmopressin, desmopressin acetate or a pharmaceutically acceptable salt of desmopressin, administered nasally, at a rate of about 10 to about 75 μl of a solution aqueous containing desmopressin, desmopressin acetate or a pharmaceutically acceptable salt of desmopressin, in the ranges of about 0.1 to about 2.0 mg / ml in the solution. The method is useful for treating urinary disorders such as diabetes insipidus, urinary incontinence, general enuresis and nocturnal enuresis. BRIEF DESCRIPTION OF THE DRAWING The graphic results of an investigation associated with the present invention are described in Figure 1. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, mono-doses of pharmaceutical compositions are provided in the form of aqueous solutions having a volume of 5 to 75 μl and containing from 0.1 to 2.0 mg / ml of desmopressin. , desmopressin acetate or a pharmaceutically acceptable molarly corresponding salt thereof. The compositions of the present invention are useful for the treatment of various urinary disorders such as those associated with diabetes insipidus, incontinence and enuresis, and in particular nocturnal enuresis. It is preferable that the aqueous solution has a volume of 10 to 75 μl. More preferred is a volume of 15 to 50 μl, and in particular, a volume of about 20 to 45 μl. Regardless of the preferred volumes for the aqueous solution, it is preferred that the concentration of desmopressin vary in the range of 0.1 to 0.5 mg per ml, or approximately 0.5 to 2.0 mg per 1. According to With the invention there is provided a sealed container specifically intended to be used with a nasal spray pump or with a device for nasal administration of drops, for the repeated dispensing of a volume of 5 to 75 μl, more preferably a volume of 10 to 50 μl, and in particular a volume of approximately 20 to 45 μl, of an aqueous solution - raw material of desmopressin, desmopressin acetate or another pharmaceutically acceptable salt of desmopressin. The sealed container dispenses constant mono-doses of a solution - raw material containing 0.1 to 0.5 mg per ml or 0.5 to 2.0 mg per ml, of desmopressin acetate or a corresponding molar quantity of desmopressin, or of another suitable, pharmaceutically acceptable salt, of desmopressin. The atomizing pump, or the device for administration drop by drop, can be integrated with the container, and be disposable. It is preferable that the atomizing pump be of the pre-compressed type and that it is designed to deliver a volume in the range of 5 to 75 μl. The mono-dose composition and the raw material solution according to the invention may contain osmotic pressure controlling agents, such as sodium chloride; preservatives such as chlorobutanol or benzalkonium chloride; a buffering agent such as sodium phosphate or sodium citrate buffers, designed to maintain a pH of from about 4 to about 6, preferably about 5; and absorption-enhancing agents, such as bile salts, monolauryl ethers of macrogoles and fusidate derivatives. Within the scope of the present disclosure, other pharmaceutically acceptable solutions and compositions also fall perfectly into sealed containers intended to be used together with a spray pump or with a device for the nasal administration drop by drop of a mono-dose pharmaceutical composition of desmopressin, desmopressin acetate or other pharmaceutically acceptable salts of desmopressin in molar ranges equivalent to those described herein. The invention is based on the discovery that the nasal administration of desmopressin acetate at a concentration of approximately 1.5 μg / μl, gives essentially the same profile of desmopressin concentrations in the plasma, independently of the amount delivered in a range of 25 to 100 μl for adults, and that is also effective with said range of administration. In the case of adults, this pattern extends to even lower volumes, such as a volume of 10 to 15 μl, and for children, to a volume of less than 10 μl, such as a volume of about 5 to 7 μl. Dosing pumps currently available on the market are not useful for the reproducible dispensing of volumes of less than approximately 50 μl. This is due to the lack of incentive to develop and market pumps of this type, since the ratio: volume / concentration level of desmopressin in the plasma, according to the present invention, is disclosed for the first time by means of the present specification. , in a unique way. The following example demonstrates the independence of the effect of desmopressin present in the plasma, with respect to the volume administered of a desmopressin solution having a given concentration of desmopressin acetate. EXAMPLE A solution - raw material containing 0.3 mg of desmopressin acetate per ml in distilled water was prepared. Varied doses of this solution - raw material, were administered to six healthy male volunteers. The administration was done in the form of nasal spray by means of dosing spray pumps, equipped with nebulizer heads. The following doses were administered to each of the nasal windows of each of the male volunteers: 75 μg in 25 μl, 150 μg in 50 μl, 210 μg in 70 μl, and 300 μg in 100 μl. The results, combined, have been consigned in the graph of the Figure 1. While there were individual variations in the profile of desmopressin in the plasma, the ratio: dose / volume / plasma profile was essentially the same for all subjects tested. Figure 1 shows that, within the dose range investigated, the level effect in the plasma does not depend on the volume administered of a desmopressin solution of a given desmopressin acetate concentration (1.5 μg / μl). Said relation is also fulfilled for a wider range of concentrations such as from 0.1 μg / μl to 2 μg / μl, for desmopressin, and for pharmaceutically acceptable salts of desmopressin different from acetate.

There are several modifications and alterations to the present that can be conceived based on an examination of the present disclosure.

Our intention is that said changes and additions fall within the scope and spirit of this invention, as it is defined by the following claims.

Claims (14)

1. NOVELTY OF THE INVENTION 1.- A nasal administrable single dose pharmaceutical composition, characterized in that it comprises: an aqueous solution, having a volume of approximately 5 to approximately 75 μl; and said solution containing from about 0.1 to about 2.0 mg / ml of a compound selected from the group consisting of desmopressin, desmopressin acetate and a pharmaceutically acceptable salt of desmopressin.
2. 2. The composition according to claim 1, characterized in that said solution has a volume of about 10 to about 50 μl.
3. 3. The composition according to claim 1, characterized in that said solution has a volume of about 20 to about 45 μl.
4. 4. The composition according to claim 1, characterized in that said solution has a volume of approximately 35 μl.
5. 5. The composition according to claim 1, characterized in that said compound is present in said solution at a ratio of about 0.1 to about 0.5 mg / ml.
6. 6. The composition according to claim 1, characterized in that said compound is present in said solution at a rate of about 0.5 to about 2.0 mg / ml.
7. 7. A means characterized in that in combination with a nasal spray pump or a device for administration drop by drop via nasal to dispense respectively a volume of about 5 to about 75 μl of an aqueous solution according to claim 1, comprising about 0.1 to about 2.0 mg / ml of desmopressin, desmopressin acetate or a pharmaceutically acceptable salt of desmopressin.
8. 8. The medium according to claim 7, characterized in that said solution has a volume of about 10 to about 50 μl.
9. 9. The medium according to claim 7, characterized in that said solution has a volume of about 20 to about 45 μl.
10. 10. The medium according to claim 7, characterized in that said solution has a volume of approximately 35 μl.
11. 11. A method for delivering constant levels in the plasma, of a peptide compound, characterized in that it comprises the nasal administration of said compound selected from the group consisting of desmopressin, desmopressin acetate and a pharmaceutically acceptable salt of desmopressin, at a rate of approximately 10. to about 75 μl of an aqueous solution containing said compound in the range of about 0.1 to about 2.0 mg / ml of said solution, according to claim 1.
12. 12. - The method according to claim 11, characterized in that said volume is in the range of about 10 to about 50 μl.
13. 13. The method according to claim 11, characterized in that said volume is in the range of approximately 20 to approximately 45 μl.
14. 14. The method according to claim 11, characterized in that it comprises treating urinary disorders selected from the group consisting of diabetes insipidus, urinary incontinence, general enuresis and nocturnal enuresis. EXTRACT OF THE INVENTION A pharmaceutical composition for the mono-dose nasal administration, effective and constant, at the plasma level, of an aqueous solution of about 5 to about 75 μl, and of about 0.2 to about 2.0 mg / ml of desmopressin acetate, a correspondingly molar amount of desmopressin or a pharmaceutically acceptable salt of desmopressin. The composition is useful for the treatment of urinary disorders such as diabetes insipidus, incontinence, and nocturnal enuresis.