MXPA97007899A

MXPA97007899A - Compositions of oxytocin and vasopressin analogues for administration no o

Info

Publication number: MXPA97007899A
Application number: MXPA/A/1997/007899A
Authority: MX
Inventors: Bengtsson Bengt
Original assignee: Ferring Bv
Filing date: 1997-10-14
Publication date: 1999-05-31

Abstract

The present invention relates to an aqueous composition for administering to a patient comprising an oxytocin or vasopressin analog, which retains the disulfide portion in an amount of 1 ug / ml to 250 ug / ml, a disinfectant and / or preservative; of sodium and / or potassium, one or more of the ions selected from the group consisting of (HPO4) 2-, (H2PO4) -, (citrate) -, (HSO4) -, (maleate) -, (glutarate) -, HO2C- (CH2) x -COO- where x is from 4 to 9, HO2C- (CH2) x- (p-phenyl) -COO-, where x is from 1 to 4, HCO3-, (lactate) - , (gluconate) -, (glucoheptanoate) -, (ascorbate) -, (propionate) -, (butyrate) -. The composition may also comprise an effective amount of a protective gas selected from helium, nitrogen, arg.

Description

COMPOSITIONS OF OXYTOCIN AND VASOPRESSIN ANALOGS FOR NON-ORAL ADMINISTRATION FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions for non-oral administration, such as nasal or parenteral administration, of neurohypophysial hormone analogs having a disulfide bond, in particular of vasopressin and oxytocin analogs.

BACKGROUND OF THE INVENTION Various neurohypophysial hormone analogs, in particular vasopressin and oxytocin analogs, are important medicines used to mimic or counteract the effects of natural hormones in patients which, for example, may suffer from hormonal deficiency or overproduction. They are often administered in the form of aqueous compositions, that is, sterile aqueous solutions containing a known amount of peptide. It is important that these compositions are stable enough to be stored at room temperature for a long period of time such as six months or more.

Many neurohypophysial hormone analogues have extremely high activities. Consequently, very small amounts of peptides are required for a single dose. Such diluted solutions of neurohypophysial hormone analogs are not stable enough at room temperature for long periods of time. An important degree of instability is due to the presence of a disulfide bond which can be fractured by oxidative, reductive, electrophilic or nucleophilic attack. In certain analogs, one or both sulfur atoms of the disulfide bridge can be substituted by one or two carbon atoms, respectively. One established form of administration of neurohypophysial hormone analogs in solution is the nasal mucosal route, in particular in the form of an aqueous spray. Various types of intranasal spray delivery devices are known in the art. In general, the peptides in aqueous solution are administered by means of a metered dose spray pumps or via a specially designed graduated plastic tube which is partially filled with an aqueous solution containing a drug. One end of the plastic tube is placed in the mouth and the other end in the desired nose hole. The supply is blowing the solution into the nostril.

Analogs of neurohypophyseal hormones for administration often have an extremely high biological activity, and only a very small amount of peptide is needed in a single dose. However, the particular form of administration may require a minimum volume of liquid for good reproducibility. In this way, the effective concentration ranges for nasally administered peptides are generally very low. For example, a single dose of hormone analogue for nasal administration is typically between 10 μg to 200 μg, but can still be as low as 1 μg and as high as 500 g. Typical dose volumes are from 75 μl to 200 μl.

OBJECTS OF THE INVENTION It is an object of the present invention to solve the stability and storage problems mentioned above, associated with known aqueous solutions of neurohypophyseal hormones analogues, particularly of aqueous solutions containing vasopressin and oxytocin analogues. Another object is to provide a stabilized aqueous solution containing a neurohypophysial hormone analog for oral administration, in particular, nasal or parenteral administration, which can be stored at room temperature for long periods of time, for example, one year, while keeps degradation to a minimum. Yet another object is to provide an oral spray composition for the management of non-normal diseases and conditions, which are mitigated by the administration of neurohypophyseal hormone analogues, particularly of aqueous solutions containing vasopressin and oxytocin analogues. The additional objects of the invention will become apparent from the following description and claims.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, an aqueous composition for administration of neurohypophysial hormones analogues, particularly of aqueous solutions containing vasopressin and oxytocin analogs but not carba or dicarba analogs thereof, which can maintain stability over elongated periods is described. of time, such as six months or more, at room temperature, of the biological active ingredient carried therein. The solution contains, by ccm3 at 25 ° C, from 1 μg / ml to 250 μg / ml of the neurohypophyseal hormone analogue, a disinfectant, sodium and / or potassium ion, one or more selected from the group consisting of (HPO4) 2-, (H2PO4) -, (citrate) -, (HSO4) -, (maieate) -, (glutarate) -, H? 2C- (CH2)? - COO "where x is from 4 to 9, HO2C- (CH2)? - (p-phenyl) -COO-, (glucoheptanoate) -, (ascorbate) -, (propionate) -, (butyrate) -. It is preferred to incorporate an effective amount of a protective gas selected from helium, nitrogen, argon, the effective amount which is from 0.035 cm3 to 0.05 cm3 of argon, from 0.009 cm3 to 0.01 cm3 of helium and from 0.0075 cm3 to 0.02 cm3 of nitrogen. Preferred preservatives and disinfectants include benzyl alcohol, butyl hydroxybenzoate, ethyl hydroxybenzoate, methyl hydroxybenzoate, propyl hydroxybenzoate, dehydroacetic acid, phenethyl alcohol, sorbic acid, benzalkonium chloride, benzethonium chloride, benzododecinium chloride, cetexonium chloride, cetrimide, decualinium chloride, domiphenium bromide, methylbenzethonium chloride, tonzonium bromide, triclobisonium chloride. Most preferred are benzalkonium chloride and benzethonium chloride. Preferred neurohypophyseal hormone analogues include vasopressin and oxytocin analogues. Vasopressin (antidiuretic hormone) has the formula Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-ClyNH2 in which the cysteine residues are connected by a disulfide bond. Oxytocin (the main hormone that contracts the uterus and stimulates lactation) has the formula Cys-Tyr-lle-Gln-Asn-Cys-Pro-Leu-ClyNH2 in which the cysteine residues are bound by a disulfide bond. The preferred vasopressin (VP) analogs are: trapa1, Arg °) VP (go) (ysß) VP (III) d «s-GlyNH ° 2- (ys8 VP (IV) Gly-Glv-Glv- (ysß) VF (V) (Mpa1, D-Arg8) VP (VI) des-GlyN? ° 2- (Mp ?? # TV? Rg9) VP (VII) (Mpa1, Ql 4 / DA * g *) VP (VIII) (Mpa1, Ala4, D-Arg *. VP (ix, (Mpa1, Val4, D-Argß) VP (X) (Mpa1, He4, D ~ A? And B) VF (XI) (Mpa1, Leu4, D-Arg8.}. VP (XII) (Lys °) VP (XIII) D-Hlyft) VP (XIV) and its pharmaceutically acceptable salts, such as its acetates, bromides, chlorides, lactates, sulfates. The most preferred vasopressin analogs are: Gly Gly Gly (Lys8) VP, (Mpa ^, D-Arg8) VP, (Lys8) VP. Preferred oxytocin (OXT) analogs are: (Mpa OXT (XV) (Mpa1, D ~ Tyr (Et) *, Thr4, Ornf) OXT (XVI) (Mpa1, Ile2.} .XXT (XVII) (Mp ** , A *) OXT (XVIII) Gly- (Leu4, Ilßß) OXT (XX) (D-Asn5> OXT (XXI) < DC? S1) OXT (XXII) (Gly4 > OXT (XXIII) (Leu4, D-Ar? R °) OXT (XXIV) ttipa1, eu4, D ~ A? Yft) OXT (XXV) (Arg5)? X ?, (XXVI) (Ile °) OXT (XXVII) and its pharmaceutically acceptable salts, such such as their acetates, bromides, chlorides, lactates, sulfates.The most preferred oxytocin analogues are (pa1, D-Tyr (Et) 2, Thr4, Orn8) OXT, (Arg8) OXT The preferred oxytocin and vasopressin analogs mentioned above are listed in CRC HANDBOOK OF NEUROHIPOPHISEAL ANALOGUES, vol 1 and 2, Jost, K, Lebl, M and Brtnik, F, Eds .; CRC Press, Inc., Boca Raton, 1987, in which primary literature is also cited with respect to the various components, they are formed by the substitution of one or several of their amino acid residues for other amino residues. oacids or structures derived from amino acids. Mpa means deamino-cysteine. HLy means hydroxylysine. It is preferred that the aqueous composition which contains the neurohypophysial hormone analog has a pH between 4.0 and 6.0. A pH of about 5.0 is especially preferred. It is preferred that the solution of the neurohypophysial hormone analogue stabilized according to the invention contains citrate and / or phosphate. Preferred buffer systems according to the invention are citric acid / disodium acid phosphate, diacid sodium phosphate / disodium acid phosphate, and citric acid / e. sodium treatment. Especially preferred is a buffer comprising: citrate-phosphate-sodium atoms in a molar ratio of 1: 3.3: 3.3 to about 1: 0.8: 1.8. It is preferred that the composition according to the invention contains, per ml, from 1 μg / ml to 250 μg / ml, in particular from 1 μg / ml to 20 μg / ml, of a vasopressin analog selected from Gly-Gly- Gly- (Lys8) VP, (Mpa1, D-Arg8) VP, (Lys8) VP including its pharmaceutically acceptable salts or an oxytocin analog selected from (Mpa '', D-Tyr (Et) 2, Thr4, Orn8) OXT and (Arg8 ^ OJCT, which includes its pharmaceutically acceptable salts, from 1.4 to 1.8 mg of citric acid, from 2.0 to 2.85 mg of disodium hydrogen phosphate, and from 0.02 to 0.25 mg of benzalkonium chloride or bencentonium chloride. The invention also discloses the use of an aqueous spray composition for the management of non-normal diseases and conditions which can be treated by nasal administration of a neurohypophysial hormone analogue, in particular, a vasopressin or oxytocin analogue. of the invention are evident from the pref modes eridas and appended claims. The invention will be explained in more detail with reference to a variety of preferred embodiments.

Example 1 Preparation of buffer solutions. The stock solutions (0.1 M) are prepared by dissolving the sodium or potassium salt or acid in distilled water, after which they are diluted to 0.01 M. From a few sparingly soluble salts, the 0.01 M solutions are prepared directly. Data for acid solutions for the preparation of buffers are given in Table 1.

Table 1. Acid solutions for buffer preparations * very low solubility prepare strong solutions Data for salt solutions for buffer preparation are given in Table 2. Table 2. Salt solutions for buffer preparation.

The acid solutions (25 ml) are titrated with saline to prepare buffers of pH 4.9 and 5.3. The results are given in Table 3; the buffer solutions of this form are used to prepare the aqueous compositions according to the invention. Table 3. Buffer solutions of pH 4.9 and 5.3 prepared by the titration of acid solution with saline.

Example 2 Preparations of the compositions according to the invention. A number of compositions according to the invention are prepared by dissolving the analogues (I) - (XXIV) of vasopressin and oxytocin (as acetates) in one or more of the buffers described in Table 3. The compositions are illustrated in the Tables 4 (vasopressin analogs) and 5 (oxytocin analogues). Table 4/1. Aqueous compositions of vasopressin analogues Table 4/2. Aqueous compositions of vasopressin analogues Table 4/3. Aqueous compositions of vasopressin analogues Table 5. Aqueous compositions of oxytocin analogues For comparison of the aqueous compositions, a number of compounds of the invention are prepared in sodium acetate / acetic acid or phosphate buffers (sodium ion of pH 7.0 as a solvent and benzethonium chloride or benzaiconium chloride as preservative / disinfectant (Table 6 ).

Table 6. Aqueous comparative compositions.

As is evident from the Figures, the stability of the compositions of the invention is superior to the comparative compositions.

Example 3 Stability test to detect peptide degradation. The compositions prepared in Example 2 are stored in 10 ml glass bottles provided with airtight plastic caps in the dark at 65 ° C. Samples are taken after 2, 5, 8, and 12 weeks and analyzed for the respective vasopressin or oxytocin analogs by CLAP [Varian Star System; L¡chrospher® PR-18 5 μm column (50 x 4 mm); gradient elution with various proportions of acetonitrile / phosphate buffer 0.0667 of pH 7.

Claims

CLAIMS 1 . An aqueous composition for administration to a patient of an oxytocin or vasopressin analog preserving the disulfide portion, characterized in that it comprises: the analogue in an amount of 1 μg / ml to 250 μg / ml; a disinfectant and / or preservative; a sodium / potassium ion; one or more of the groups consisting of (H P? 4) 2-, (H2PO4) -, (citrate) -, (HSO4) -, (maieate) -, (glutarate) -, HO2C- (CH2) x -COO- where x is from 4 to 9, H? 2C- (CH2) ? - (p-phenyl) -COO ", where x is from 1 to 4, HCO3-, (lactate) -, (gluconate)" (glucoheptanoate) ", (ascorbate) -, (propionate) -, (butyrate) -.
2. The composition according to claim 1, characterized in that it comprises an effective amount of a protective gas selected from helium, nitrogen, argon, such as 0.035 cm3 to 0.05 cm3 of argon, 0.009 cm3 to 0.01 cm3 of helium or 0.0075 cm3. cm3 to 0.02 cm3 of nitrogen.
3. The composition according to claim 1 or 2, characterized in that the preservative and / or disinfectant is selected from benzyl alcohol, butyl hydroxybenzoate, ethyl hydroxybenzoate, methyl hydroxybenzoate, propyl hydroxybenzoate, dehydroacetic acid, phenethyl alcohol, sorbic acid, benzalkonium chloride, benzethonium chloride, benzododecinium chloride, cetexonium chloride, cetrimide, dequalinium chloride, domiphenium bromide, methylbenzethonium chloride, tonzonium bromide, triclobisonium chloride.
4. The composition according to claim 3, characterized in that the disinfectant and / or preservative is benzethonium chloride.
5. The composition according to claim 3, characterized in that the disinfectant and / or preservative is benzalkonium chloride.
6. The composition according to any of claims 1 to 5, characterized in that the vasopressin analog (VP) is selected from: (l? h. «> * r A * r-gß) VP (I) (Lyse) VP (III) d« s-GlyNH ° a- (Ly88) VP (TV) eiy-Gly-Giv- (? »Ysß) vf (V) (Hpa1, DAt? R8) F (VI) de-GlyNH ° 2- (Mp ?? f D-Argß) VF (VII) (Kpa1, oxy *, r > - -? - ? cg *) V? »(VIII) (Mpaa, Al * 4, D-Arg *) VP (IX) (Mpa1, Val4, D-Argß) VP (X) - (Mpa1, llt; 4, D-Aryfl ) VP (XI) (Up 1, Leu4, D-Arg8) VP (XII) (Lys °) VP (XIII) (Mpd1, D-Hlyß) VP (XIV) and their pharmaceutically acceptable salts.
7. The composition according to claim 6, characterized in that the vasopressin analogue is Gly-Gly-Gly- (Lys ^) VP.
8. The composition according to claim 6, characterized in that the vasopressin analogue is (Mpa ", D-Arg8) VP.
9. The composition according to claim 6, characterized in that the vasopressin analogue is (Lysd) VP.
10. The composition according to any of claims 1 to 5, characterized in that the oxytocin analog is selected from: (Mpa1) oxt (xv> (Mpaa, D-Ty tEt) *, Thr *, Orn) OXT (XVI) (Mp »1, Ile2) OXT (XVII) (Mp» 1, Al **) OXT (XVIII) Gly- (Leu4, Ileß) OXT (XX) < D-AsnD) OXT (XXI) (DC? S1) OXT (XXII) (Gly4) OXT (XXII 1) (Leu4, D-Arg °) OXT (XXIV) (Mpa1, Leu *, D ~ Ai and *) OXT (XXV) (Arcje &? X? (XXVI) (Ilß °) OXT (XXV I) and their pharmaceutically acceptable salts.
11. The composition according to claim 10, characterized in that the oxytocin analogue is (Mpa1, D-Tyr (Et) 2, Thr4, Orn8) OXT.
12. The composition according to claim 10, characterized in that the oxytocin analogue is (Arg8) OXT.
13. The composition according to any of claims 1-12, characterized in that the composition has a pH between 4.0 and 6.0.
14. The composition according to claim 13, characterized in that the pH is about 5.0.
15. The composition according to claim 13 or 14, characterized in that the pH is stabilized by a citrate buffer.
16. The composition according to claim 13 or 14, characterized in that the pH is stabilized by a phosphate buffer.
17. A container filled with the composition according to any of claims 1-16, arranged to be placed under permanent or intermittent pressure.
18. The composition according to claim 17, characterized in that the container is made of a polymer material.
19. The composition according to claim 17, characterized in that the container is unible to a pressure measuring pump.
20. A sealed container, adapted to be attached to a pressure measuring pump containing the composition according to any of claims 1-16. twenty-one .
The container in accordance with the claim 20, uses air as pressurized dispensing fluid.
22. An aqueous pharmaceutical composition containing, per ml, from 1 μg / ml to 20 μg / ml, of a vasopressin analog selected from Gly-Gly-Gly- (Lys8) VP, (Mpa1, D-Arg8) VP, (Lys8 ) VP including its pharmaceutically acceptable salts or an oxytocin analog selected from (Mpa1, D-Tyr (Et) 2, Thr4, Orn8) OXT and (Arg8) OXT, which includes their pharmaceutically acceptable salts, from 1.4 to 1 .9 mg of citric acid monohydrate, 2.0 to 4.0 mg of disodium hydrogen phosphate dihydrate, and 0.01 to 0.25 mg of a preservative selected from benzalkonium chloride or benzethonium chloride.
23. The composition according to claim 22, characterized in that the preservative is benzalkonium chloride.
24. The composition according to claim 23, characterized in that the vasopressin analogue is Gly-Gly-Gly- (Lys) VP.
25. The composition according to claim 23, characterized in that the vasopressin analogue is Mpa1, D-Arg8) VP.
26. The composition according to claim 23, characterized in that the vasopressin analogue is (Lys8) VP.
27. The composition according to claim 23, characterized in that the oxytocin analog is (Mpa1, D-Tyr (Et) 2, Thr4, Orn8) OXT.
28. The composition according to claim 23, characterized in that the oxytocin analogue is (Arg8) OXT.
29. The composition according to any of claims 22-28, characterized in that it contains a protective gas in an amount from 0.035 cm3 to 0.05 cm3 of argon, of 0.009 cm3 to 0.01 cm3 of helium or from 0.0075 cm3 to 0.02 cm3 of nitrogen.
30. The composition according to any of claims 22-29, characterized in that it contains from 3.0 to 7.0 mg of Na + per ml.