CA1267086A - Method of administering diuretic atrial peptides - Google Patents
Method of administering diuretic atrial peptidesInfo
- Publication number
- CA1267086A CA1267086A CA000508837A CA508837A CA1267086A CA 1267086 A CA1267086 A CA 1267086A CA 000508837 A CA000508837 A CA 000508837A CA 508837 A CA508837 A CA 508837A CA 1267086 A CA1267086 A CA 1267086A
- Authority
- CA
- Canada
- Prior art keywords
- ser
- arg
- phe
- atrial
- ile
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Abstract
Abstract of the Disclosure The disclosure relates to a novel composition for intranasal administration of small atrial peptides having amino acid sequences of about 18 to 28 amino acids.
Description
~;26~7~
This invention relates to a novel composition for administering diuretic atrial peptides and more particularly to the intranasal administration of such peptides.
The atrial peptides comprise a family of closely related peptides originally obtained from the atrial myocardium of mammals. Upon establishment of the amino acid sequences of these peptides, they have been synthetically prepared by conventional solid phase methods of peptide systhesis. For such methods, see Merrifield, J. Amer. Chem. Soc. 85, 2149-54 (1963) and Science 150, 178-85 (1965); Stewart and Young, "Solid Phase Peptide Synthesis," ~.H. Freeman and Company, San Francisco, 1969; the review article by Merrifield in Adv. Enzymol. 32, 291-296, F.F. Nold, Ed., Interscience Publ., New York, I969; and Erickson and Merrifield, The Proteins, Vol. 2, 255, Neurath and ~all, Eds., Academic Press, New York, 1976. U.S. Patent 4,496,544 describes a particularly useful group of small atrial peptides having sequences of from about 18 to about 24 amino acids. These peptides have therapeutic use as diuretics, natriuretics, renal vasodilators and smooth muscle relaxants. As seen from U.S. Patent 4,508,712, these small peptides can be obtained as fragments of a larger peptide having a sequence of 111 amino acids. A
preferred atrial peptide known as atriopeptin-III or AP-III comprises the fragment of amino acids 88-111 and has an internal disulfide ring as follows:
ATRIOPEPTIN III
Ser-ser-cys-phe-gly-gly-arg-ile-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly-cys-asn-ser-phe-arg-tyr Extensions of AP-III have also been described.
Thus, the 28 amino acid peptide ser-leu-arg-arg-AP-III, also known as Cardionatrin I, is disclosed in European Patent Application 116,784, published August 29, 1984.
~.~
67~
The human analog of the 28 amino acid Cardionatrin I having a met12 replacement for ilel2 is described by Kangawa and Matsuo, siochem. Biophys. Res.
Commun. 118 (1), 131-139 (1984).
The 26 amino acid peptide arg-arg-AP-III, also known as atrial natriuretic factor or ANF (8-33), is disclosed as a fragment of a larger 33 amino acid peptide by Seidah et al., Proc. Nat. Acad. Sci. USA 81, 2640-44 (1984).
The 25 amino acid analog of AP-III having an arg extension at the amino acid terminus, also known as auriculin, is described by Yamanaka et al., Nature 309, 719-22 (198~). The relationship of the foregoing small peptides to a common precursor is illustrated by Sagnella and MacGregor, Nature 309, 666-667 (1984).
As reported in the literature, these small atrial peptides have been shown to have potent diuretic activity upon intravenous administration. For example, such effects have been shown in the dog at 10-30 ~g/kg i.v. and at 100 ~g i.v. bolus in humans.
Brief Description of the Invention In accordance with the present invention, it has been found surprisingly that the small atrial peptides can be effectively administered intranasally to produce substantial diuresis using Applicant's composition as defined herein. This discovery was unexpected and arose serendipitously through spontaneous inhalation while the inventors were processing finely particulate atripeptin-III material without the use of face masks.
In accordance with this invention, there is thus provided a composition for producing diurisis in a patient comprising an intranasally therapeutically effective amount of an atrial peptide (as defined ~. . j ~L267~8~
hereinafter), in an intranasally therapeutically effective dosage form of a solution, suspension, ointment or gel.
These small atrial peptides can be represented by the following amino acid sequence:
Rl-cys-phe-gly-gly-arg-X-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly-cys-asn-R2 wherein Rl = H; ser; ser-ser;
R2 = OH; ser; ser-phe;
ser-phe-arg;
ser-phe-arg-tyr;
X = ile; met;
or the physiologically acceptable salts, esters or amides thereof.
The HCl salt is a preferred salt form of the atrial peptide.
Detailed Descri~tion of the Invention The discovery that the small atrial peptides can be effectively administered intranasally provides a novel advantage in the therapeutic administration of these compounds as diuretics.
Although the initial discovery was made by inhalation of finely divided particulate material, the atrial peptides are normally administered intranasally in ~5 dosage forms adapted for nasal administration such as solutions, suspensions, ointments and gels.
In solution dosage form the atrial peptides can be dissolved in a pharmaceutically acceptable solvent such as water and administered as drops or as a spray. The solution form preferably has an acid pH of from about 4 to about 5 for stability purposes.
The preferred concentration of the atrial peptide in solution ranges from about one ~g/ml to about 1000 ~g/ml.
, - . , ' ' 7~6 A convenient method of administering a solution into the nose is through a flexible catheter or plastic nasal tube (rhinyle). From about 0.05 to about 0.5 ml. can be readily applied to the nose in this manner. Solutions of the atrial peptide can also be squirted or sprayed into the nasal cavity such as by means of a squeeze bulb atomizer or spray-mist applicator.
Suspension, ointment and gel dosage forms of the atrial peptide can be prepared by admixing with small amounts of pharmaceutica]ly acceptable gums and jelling agents such as gelatin, dextran, acacia, guar gum, locust bean gum, sodium alginate and cellulose ether gums, for example, methyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose and the like materials.
Other pharmaceutically acceptable additives and carriers can also be included in the intranasal dosage form in small but effective amounts such as surface active agents, for example, Polysorbate 80 (polyethylene oxide sorbitan monooleate), buffering agents such as to maintain physiologic pH 7-7.4, preservatives, stabilizers and the like substances.
Pharmaceutically acceptable carriers and their methods of compounding are well-known and can be selected by reference to a common text such as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 16th edition, 1980.
The amount and frequency of intranasal administration can vary depending upon the condition of the patient under treatment and the degree of therapeutic effect desired.
The following examples will illustrate the invention although it will be understood that the invention is not limited to these specific examples.
.~2~a~
In the peptide structures herein, the amino acid components are designated by conventional abbreviations as follows:
Amino Acid Abbreviated Designation L-Alanine ala L-Arginine arg L-Asparagine asn L-Aspartic Acid asp L-Cysteine cys L-Glutamine gln Glycine gly L-Isoleucine ile L-Leucine leu L-Methionine met L-Phenylalanine phe L-Proline pro L-Serine ser L-Tyrosine tyr .
Example 1 Atriopeptin-III (AP-III) having the following amino acid sequence and containing an internal disulfide ring was prepared by classical Merrifield solid phase peptide synthesis:
ATRIOPEPTIN III
Ser-ser-cys-phe-gly-gly-arg-ile-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly-cys-asn-ser-phe-arg-tyr Pure samples of this peptide in the HCl salt form with about 23~ water were processed by freeze-drying and then transferred from the freeze-drying flasks to bottles. The material was of a finely particulate (powdery) composition. While one of the 67~86 co-inventors was manually making such transfers of about 6~ grams of the material over about a 90 minute period without the use of a protective face mask, small amounts of the powder were spontaneously inhaled. Symptoms of frequent and excessive urination, and a dry and scratchy throat were observed. Since these symptoms did not occur prior to the nasal inhalation of the atriopeptin-III, it was evident that the nasal administration of that compound produced the observed diuretic action.
Example 2 Pure samples of the finely particulate atriopeptin-III in the HCl salt form as in Example 1 were blended in a ball-mill roller jar. During this blending by the other co-inventor who also was not wearing a protective face mask, the sides of the jar were manually scraped down. Some of the sample material, which had a very fine, flour-like consistency, was carried into the air surrounding the jar and spontaneously inhaled. Symptoms of frequent and excessive urination occurred during the succeeding 1-I/2 hours. A slightly sore, scratchy throat condition also was noticed. Since these symptoms did not occur prior to the nasal inhalation of the blended atriopeptin-III, it was concluded that the nasal administration of the atriopeptin-III produced the noted diuretic effect.
Another research person who observed substantial portions of the operations in Examples 1 and
This invention relates to a novel composition for administering diuretic atrial peptides and more particularly to the intranasal administration of such peptides.
The atrial peptides comprise a family of closely related peptides originally obtained from the atrial myocardium of mammals. Upon establishment of the amino acid sequences of these peptides, they have been synthetically prepared by conventional solid phase methods of peptide systhesis. For such methods, see Merrifield, J. Amer. Chem. Soc. 85, 2149-54 (1963) and Science 150, 178-85 (1965); Stewart and Young, "Solid Phase Peptide Synthesis," ~.H. Freeman and Company, San Francisco, 1969; the review article by Merrifield in Adv. Enzymol. 32, 291-296, F.F. Nold, Ed., Interscience Publ., New York, I969; and Erickson and Merrifield, The Proteins, Vol. 2, 255, Neurath and ~all, Eds., Academic Press, New York, 1976. U.S. Patent 4,496,544 describes a particularly useful group of small atrial peptides having sequences of from about 18 to about 24 amino acids. These peptides have therapeutic use as diuretics, natriuretics, renal vasodilators and smooth muscle relaxants. As seen from U.S. Patent 4,508,712, these small peptides can be obtained as fragments of a larger peptide having a sequence of 111 amino acids. A
preferred atrial peptide known as atriopeptin-III or AP-III comprises the fragment of amino acids 88-111 and has an internal disulfide ring as follows:
ATRIOPEPTIN III
Ser-ser-cys-phe-gly-gly-arg-ile-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly-cys-asn-ser-phe-arg-tyr Extensions of AP-III have also been described.
Thus, the 28 amino acid peptide ser-leu-arg-arg-AP-III, also known as Cardionatrin I, is disclosed in European Patent Application 116,784, published August 29, 1984.
~.~
67~
The human analog of the 28 amino acid Cardionatrin I having a met12 replacement for ilel2 is described by Kangawa and Matsuo, siochem. Biophys. Res.
Commun. 118 (1), 131-139 (1984).
The 26 amino acid peptide arg-arg-AP-III, also known as atrial natriuretic factor or ANF (8-33), is disclosed as a fragment of a larger 33 amino acid peptide by Seidah et al., Proc. Nat. Acad. Sci. USA 81, 2640-44 (1984).
The 25 amino acid analog of AP-III having an arg extension at the amino acid terminus, also known as auriculin, is described by Yamanaka et al., Nature 309, 719-22 (198~). The relationship of the foregoing small peptides to a common precursor is illustrated by Sagnella and MacGregor, Nature 309, 666-667 (1984).
As reported in the literature, these small atrial peptides have been shown to have potent diuretic activity upon intravenous administration. For example, such effects have been shown in the dog at 10-30 ~g/kg i.v. and at 100 ~g i.v. bolus in humans.
Brief Description of the Invention In accordance with the present invention, it has been found surprisingly that the small atrial peptides can be effectively administered intranasally to produce substantial diuresis using Applicant's composition as defined herein. This discovery was unexpected and arose serendipitously through spontaneous inhalation while the inventors were processing finely particulate atripeptin-III material without the use of face masks.
In accordance with this invention, there is thus provided a composition for producing diurisis in a patient comprising an intranasally therapeutically effective amount of an atrial peptide (as defined ~. . j ~L267~8~
hereinafter), in an intranasally therapeutically effective dosage form of a solution, suspension, ointment or gel.
These small atrial peptides can be represented by the following amino acid sequence:
Rl-cys-phe-gly-gly-arg-X-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly-cys-asn-R2 wherein Rl = H; ser; ser-ser;
R2 = OH; ser; ser-phe;
ser-phe-arg;
ser-phe-arg-tyr;
X = ile; met;
or the physiologically acceptable salts, esters or amides thereof.
The HCl salt is a preferred salt form of the atrial peptide.
Detailed Descri~tion of the Invention The discovery that the small atrial peptides can be effectively administered intranasally provides a novel advantage in the therapeutic administration of these compounds as diuretics.
Although the initial discovery was made by inhalation of finely divided particulate material, the atrial peptides are normally administered intranasally in ~5 dosage forms adapted for nasal administration such as solutions, suspensions, ointments and gels.
In solution dosage form the atrial peptides can be dissolved in a pharmaceutically acceptable solvent such as water and administered as drops or as a spray. The solution form preferably has an acid pH of from about 4 to about 5 for stability purposes.
The preferred concentration of the atrial peptide in solution ranges from about one ~g/ml to about 1000 ~g/ml.
, - . , ' ' 7~6 A convenient method of administering a solution into the nose is through a flexible catheter or plastic nasal tube (rhinyle). From about 0.05 to about 0.5 ml. can be readily applied to the nose in this manner. Solutions of the atrial peptide can also be squirted or sprayed into the nasal cavity such as by means of a squeeze bulb atomizer or spray-mist applicator.
Suspension, ointment and gel dosage forms of the atrial peptide can be prepared by admixing with small amounts of pharmaceutica]ly acceptable gums and jelling agents such as gelatin, dextran, acacia, guar gum, locust bean gum, sodium alginate and cellulose ether gums, for example, methyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose and the like materials.
Other pharmaceutically acceptable additives and carriers can also be included in the intranasal dosage form in small but effective amounts such as surface active agents, for example, Polysorbate 80 (polyethylene oxide sorbitan monooleate), buffering agents such as to maintain physiologic pH 7-7.4, preservatives, stabilizers and the like substances.
Pharmaceutically acceptable carriers and their methods of compounding are well-known and can be selected by reference to a common text such as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 16th edition, 1980.
The amount and frequency of intranasal administration can vary depending upon the condition of the patient under treatment and the degree of therapeutic effect desired.
The following examples will illustrate the invention although it will be understood that the invention is not limited to these specific examples.
.~2~a~
In the peptide structures herein, the amino acid components are designated by conventional abbreviations as follows:
Amino Acid Abbreviated Designation L-Alanine ala L-Arginine arg L-Asparagine asn L-Aspartic Acid asp L-Cysteine cys L-Glutamine gln Glycine gly L-Isoleucine ile L-Leucine leu L-Methionine met L-Phenylalanine phe L-Proline pro L-Serine ser L-Tyrosine tyr .
Example 1 Atriopeptin-III (AP-III) having the following amino acid sequence and containing an internal disulfide ring was prepared by classical Merrifield solid phase peptide synthesis:
ATRIOPEPTIN III
Ser-ser-cys-phe-gly-gly-arg-ile-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly-cys-asn-ser-phe-arg-tyr Pure samples of this peptide in the HCl salt form with about 23~ water were processed by freeze-drying and then transferred from the freeze-drying flasks to bottles. The material was of a finely particulate (powdery) composition. While one of the 67~86 co-inventors was manually making such transfers of about 6~ grams of the material over about a 90 minute period without the use of a protective face mask, small amounts of the powder were spontaneously inhaled. Symptoms of frequent and excessive urination, and a dry and scratchy throat were observed. Since these symptoms did not occur prior to the nasal inhalation of the atriopeptin-III, it was evident that the nasal administration of that compound produced the observed diuretic action.
Example 2 Pure samples of the finely particulate atriopeptin-III in the HCl salt form as in Example 1 were blended in a ball-mill roller jar. During this blending by the other co-inventor who also was not wearing a protective face mask, the sides of the jar were manually scraped down. Some of the sample material, which had a very fine, flour-like consistency, was carried into the air surrounding the jar and spontaneously inhaled. Symptoms of frequent and excessive urination occurred during the succeeding 1-I/2 hours. A slightly sore, scratchy throat condition also was noticed. Since these symptoms did not occur prior to the nasal inhalation of the blended atriopeptin-III, it was concluded that the nasal administration of the atriopeptin-III produced the noted diuretic effect.
Another research person who observed substantial portions of the operations in Examples 1 and
2 but who did not come into contact with the particles of the atriopeptin-III material had none of the foregoing symptoms. This finding further confirmed that the atriopeptin-III was the causative agent of the diuresis.
lZ6~7~6 Example 3 Solutions for intranasal administration of the following small atrial peptides are provided by dissolving 0.1 mg of the peptide per ml of distilled water and sterile filtering by passing through a 0.2 micron Millipore filter tBedford, Mass.).
AP-IXI;
Arg-AP-III;
Arg-arg-AP-III;
~des-tyr24]-Ap-III;
~Met8]-AP-III; and [des-phe22-arg23-tyr24]-AP-III.
Various other examples will be apparent to the person skilled in the art after read.ng the present disclosure without departing from the spirit and scope of the invention and it is intended that all such examples be included within the scope of the appended claims. Thus, other examples for modulating the extracellular volume, sodium and vascular resistance by intranasal administration of these small atrial peptides are included within the scope of the appended claims.
* Trademark
lZ6~7~6 Example 3 Solutions for intranasal administration of the following small atrial peptides are provided by dissolving 0.1 mg of the peptide per ml of distilled water and sterile filtering by passing through a 0.2 micron Millipore filter tBedford, Mass.).
AP-IXI;
Arg-AP-III;
Arg-arg-AP-III;
~des-tyr24]-Ap-III;
~Met8]-AP-III; and [des-phe22-arg23-tyr24]-AP-III.
Various other examples will be apparent to the person skilled in the art after read.ng the present disclosure without departing from the spirit and scope of the invention and it is intended that all such examples be included within the scope of the appended claims. Thus, other examples for modulating the extracellular volume, sodium and vascular resistance by intranasal administration of these small atrial peptides are included within the scope of the appended claims.
* Trademark
Claims (10)
1. A composition for producing diuresis in a patient comprising an intranasally therapeutically effective amount of an atrial peptide of the following amino acid sequence:
wherein R1 = H; ser; ser-ser;
R2 = OH; ser; ser-phe;
ser-phe-arg;
ser-phe-arg-tyr;
X = ile; met;
or the physiologically acceptable salts, esters or amides thereof; in an intranasally therapeutically effective dosage form of a solution, suspension, ointment or gel.
wherein R1 = H; ser; ser-ser;
R2 = OH; ser; ser-phe;
ser-phe-arg;
ser-phe-arg-tyr;
X = ile; met;
or the physiologically acceptable salts, esters or amides thereof; in an intranasally therapeutically effective dosage form of a solution, suspension, ointment or gel.
2. The composition of Claim 1 in which R1 is ser-ser, R2 is ser-phe-arg-tyr and X is ile.
3. The composition of Claim 2 in which the atrial peptide is in the HC1 salt form.
4. The composition of Claim 2 in which the atrial peptide is in solution with a pharmaceutically acceptable solvent.
5. The composition of Claim 4 in which the solvent is water.
6. Use of an atrial peptide of the following amino acid sequence:
wherein R1 = H; ser; ser-ser; arg-ser-ser;
arg-arg-ser-ser; leu-arg-arg-ser-ser;
ser-leu-arg-arg-ser-ser;
R2 = OH; ser; ser-phe;
ser-phe-arg;
ser-phe-arg-tyr;
X = ile; met;
or the physiologically acceptable salts, esters or amides thereof, as a diuretic agent.
wherein R1 = H; ser; ser-ser; arg-ser-ser;
arg-arg-ser-ser; leu-arg-arg-ser-ser;
ser-leu-arg-arg-ser-ser;
R2 = OH; ser; ser-phe;
ser-phe-arg;
ser-phe-arg-tyr;
X = ile; met;
or the physiologically acceptable salts, esters or amides thereof, as a diuretic agent.
7. Use as claimed in Claim 6, in which R1 is ser-ser, R2 is ser-phe-arg-tyr and X is ile.
8. Use as claimed in Claim 7, in which the atrial peptide is in the HC1 salt form.
9. Use as claimed in Claim 7, in which the atrial peptide is in solution with a pharmaceutically acceptable solvent.
10. Use as claimed in Claim 9, in which the solvent is water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA508837A CA1267086C (en) | 1985-05-10 | 1986-05-09 | Method of administering diuretic atrial peptides |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73278185A | 1985-05-10 | 1985-05-10 | |
| US732,781 | 1985-05-10 | ||
| CA508837A CA1267086C (en) | 1985-05-10 | 1986-05-09 | Method of administering diuretic atrial peptides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA1267086A true CA1267086A (en) | 1990-03-27 |
| CA1267086C CA1267086C (en) | 1990-03-27 |
Family
ID=24944933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA508837A Expired CA1267086C (en) | 1985-05-10 | 1986-05-09 | Method of administering diuretic atrial peptides |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1267086C (en) |
-
1986
- 1986-05-09 CA CA508837A patent/CA1267086C/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1267086C (en) | 1990-03-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 19940927 |