EP0296227A1 - Nasal delivery of amino acids - Google Patents
Nasal delivery of amino acidsInfo
- Publication number
- EP0296227A1 EP0296227A1 EP88901000A EP88901000A EP0296227A1 EP 0296227 A1 EP0296227 A1 EP 0296227A1 EP 88901000 A EP88901000 A EP 88901000A EP 88901000 A EP88901000 A EP 88901000A EP 0296227 A1 EP0296227 A1 EP 0296227A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino acid
- amino acids
- compositions
- usp
- cps
- 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.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Definitions
- This invention is concerned with nasal administration of ammo acids to mammals. It is concerned also with nasal methods of delivery of ammo acids to mammals in need of such treatment.
- Ammo Acids are the building blocks of body protein. Additionally they serve many other physiological functions well known to those skilled in the art.
- ammo acids There are approximately twenty common ammo acids. Their chemistry and functions are so well known that they need not be discussed here. Certain of them are recognized as essential ammo acids, i.e. ammo acids necessary to the proper functioning of a healthy body, and not produced by normal metabolism. These ammo acids must be obtained from an outside source. Other amino acids are utilized therapeutically. These include, for example, argmine which is widely employed in the management of ammonia intoxication due to hepatic failure.
- Vanr.e - VAL The invention, however, is not limited to these common amino acids, but is applicable to other less common amino acids both naturally occurring and synthetic, as well as to structural modifications of all of these amino acids. It is, of course, applicable to D- and L- forms of amino acids as well as racemic mixtures thereof
- amino acids generally recognized as essential are:
- Amino acids which are generally recognized as having therapeutic utility include:
- ARG - Arginine glutamate is used in the management of ammonia intoxication due to hepatic failure.
- HIS HIS - Essential for growth in infants and growing children. Used to treat histidinane ia, a rare disease caused by faulty histidine metabolism. LEU - Used in the diagnosis and treatment of idiopathic hyperglycemia in infancy.
- LYS Used orally as soon as oral or vulval herpes lesions* are apparent and produces rapid resolution of herpes lesions. Used as a dietary supplement to aid in the reduction of plasma- triglyceride and plasma-cholesterol levels.
- compositions of this invention will be principally employed for the nasal delivery of therapeutic quantities of amino acids such as those listed above. They are also applicable to the nasal delivery of useful quantities of the essential amino acids as dietary supplements.
- Amino acids for use as suggested above have been available for a number of years in oral form and in parenteral forms for injection. While useful, these forms are not completely satisfactory for a number of reasons.
- Oral formulations are not rapidly absorbed from the intestinal track and, often do not produce desirably high blood levels in a short time. .Moreover, some of the desired product may be wasted by excretion before it is absorbed. Injectable solutions and suspensions are more satisfactory for producing rapid high blood levels. However, they must normally be administered under the supervision of trained medical personnel in a doctor's office or out-patient department. Many people strongly object to injections.
- the nasal administration process of this invention is significently more convenient than parenteral administration.
- Simple, small containers such as eye droppers, aerosol or other pressurized containers, and tubes which can be easily carried in a pocket or purse can be used for delivery. This should be compared with hypodermic needles which are difficult to use and repugnant to many people. In many jurisdictions it is illegal to transport them.
- Nasal delivery of therapeutic agents has been well known for a number of years. See, for example, U.S. Patents 4,428,883; 4,284,648 and 4,394,390; and PCT application International Publication Number WO83/00286. See also, Hussain et al, J. Phar . Sci.: 68, No. 8, 1196 (1979); _69_ 1240 (1980) and 6_9 (1980).
- Childrey and Essex reported an immediate and marked pressor response upon injection of 1 mg of nicotine in dogs, but little or no effect on injections of the same or larger amounts into the sinus of dogs or cats.
- amino acid containing compositions including gels, sprays and solutions which may be administered in the form of drops all of which are specifically formulated for nasal administration to permit therapeutic delivery of effective amounts of amino acid through the nasal mucous membrane.
- amino acids of course includes pharmaceutically acceptable acid and basic addition salts thereof including organic and inorganic acid addition salts and alkali and alkaline earth addition salts such as hydrochloride, phosphate acetate and sodium, potassium and calcium salts.
- compositions of the invention are for nasal administration and contain a therapeutically effective amount of at least one amino acid. They are conveniently provided as isotonic aqueous compositions which may be buffered to a selected pH.
- the viscous compositions may be in the form of gels, lotions, ointments, creams and the like and will typically contain a sufficient amount of a thickening agent so that the viscosity is from about 2500 to 6500 cps, although more viscous compositions even up to 10,000 cps may be employed.
- the preferred compositions have a viscosity of 2500 to 5000 cps, since above that range they become more difficult to administer.
- the amino acids of the invention will be most efficiently absorbed through the nasal membranes if the composition is at the isoelectric point of the material being absorbed. However, at pH values appreciably below 4 or above 6 irritation of the nasal mucosa may become a problem. Therefore it is preferred to prepare the compositions so that the pH is from about 4 to 6, but it is not essential to do so. Values from about 3 to 7 are tolerable.
- the pH is maintained with a physiologically acceptable buffer, suitably an acetate, phosphate, phthalate or borate buffer. Acetate buffers are preferred for convenience and economy.
- compositions of the invention in bulk or unit dosage form will typically contain the selected agent as a concentration of from about 20 to 600 mg/ l. These are the preferred concentrations for compositions of the invention containing ORN, LYS, ARG or TRP; amino acids which are especially applicable to the practice of this invention.
- the physician or veterinarian in attendance will select the proper dosage based on factors which he will be able to evaluate.
- a dosage unit will generally contain 0.05 to 0.3ml.
- compositions will usually contain only one therapeutic agent. However, there is no reason why they may not contain a plurality of amino acids e.g. two, three or even more.
- the compounds may be administered in the form of their pharmaceutically acceptable acid or basic salts, suitable hydrochlorides, acetates, and alkali metal salts, specifically sodium or potsasium. It may be convenient to utilize one amino acid in the form of its salt with another amino acid, for example arginine glutamate to treat ammonia intoxication.
- the isotonicity of the composition may be accomplished using sodium chloride, or other pharmaceutically acceptable agent such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solute.
- sodium chloride is preferred particularly for buffers containing sodium ions.
- Viscosity of the compositions may be maintained at the selected level using a therapeutically acceptable thickening agent.
- Methyl cellulose is preferred because it is readily and economically available and is easy to work with.
- Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickener will depend upon the agent selected. The important point is to use an amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents. Preferred compositions within the scope of this invention will contain a humectant to inhibit drying of the mucous membrane and to prevent irritation.
- humectants any of a variety of therapeutically acceptable humectants can be employed including, for example sorbitol, propylene glycol or glycerol.
- concentration will vary with the selected agent, although the presence or absence of these agents, or their concentration is not an essential feature of the invention.
- Enhanced absorption across the nasal membrane can be accomplished employing a therapeutically acceptable surfactant.
- useful surfactants for these therapeutic compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides such as T een 80, Polyoxyl 40 Stearate, Polyoxyethylene 50 Stearate and Octoxynol. The usual concentration is from 1% to 10% based on the total weight.
- a therapeutically acceptable preservative is generally employed to increase -the shelf life of the compositions.
- Benzyl alcohol is suitable, although a variety of preservatives including, for example, Parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed.
- a suitable concentration of the preservative will be from 0.02% to 2% based on the total weight, although there may be appreciable variation depending upon the agent selected.
- compositions must be selected to be chemically inert with respect to the active agent. This will present no problem to those skilled in chemical and pharmaceutical principles, or can be readily avoided by reference to standard texts or by simple experiment.
- the therapeutically effective compositions of this invention are prepared by mixing the ingredients following generally accepted procedures. For example the selected components may be simply mixed in a blender, or other standard machine to produce a concentrated mixture which is then adjusted to the final concentration and viscosity by the addition of water.
- compositions of this invention contain the following components per 100 ml:
- pH and tonicity will be adjusted q.s. to assure maximum adsorption and miminal local irritation. They will depend on such factors as concentration of the selected amino acid and its isoelectric point.
- compositions are prepared by mixing the named components.
Landscapes
- Health & Medical Sciences (AREA)
- Otolaryngology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Compositions nasales utiles pour l'administration d'aminoacides et de peptides et mode d'administration de ceux-ci par voie nasale.Nasal compositions useful for the administration of amino acids and peptides and method of administration thereof nasally.
Description
NASAL DELIVERY OF AMINO ACIDS
BACKGROUND OF THE INVENTION
This invention is concerned with nasal administration of ammo acids to mammals. It is concerned also with nasal methods of delivery of ammo acids to mammals in need of such treatment.
Ammo Acids, as is well known, are the building blocks of body protein. Additionally they serve many other physiological functions well known to those skilled in the art.
There are approximately twenty common ammo acids. Their chemistry and functions are so well known that they need not be discussed here. Certain of them are recognized as essential ammo acids, i.e. ammo acids necessary to the proper functioning of a healthy body, and not produced by normal metabolism. These ammo acids must be obtained from an outside source. Other amino acids are utilized therapeutically. These include, for example, argmine which is widely employed in the management of ammonia intoxication due to hepatic failure.
For convenience m describing tnis invention, the abbreviations normally employed to designate the ammo acids will be used in this disclosure. These include:
Alanine - ALA Lysine - LYS
Aspartic acid - ASP ethiomne - MET
Argmine - ARG Ornitn e - ORNT
Cyste e - CYS Pnenylal e - PHE
Glutamic acid Prol e - PRO
Glyc e - GLY Ser e - SER
Histid e - HIS Tireomne - THR
Isoleuc e - ILE Tryptophan - TRP
Leucine - LEU Tyrosine - TYR
Vanr.e - VAL
The invention, however, is not limited to these common amino acids, but is applicable to other less common amino acids both naturally occurring and synthetic, as well as to structural modifications of all of these amino acids. It is, of course, applicable to D- and L- forms of amino acids as well as racemic mixtures thereof
The amino acids generally recognized as essential are:
ARG MET
HIS PHE
ILE THR
LEU TRP
LYS VA
Amino acids which are generally recognized as having therapeutic utility include:
ALA - Used as a dietary supplement. Oral administration of 50g daily has been reported to reverse hypoglycemia and ketosis and reduced muscle catabolism in obese subjects starved for two weeks. It has also been reported to stimulate glucagen secretion in patients with acute and chronic pancreatitis.
ARG - Arginine glutamate is used in the management of ammonia intoxication due to hepatic failure.
G ' - Has been used as an antiepileptic to reduce petit mal attacks and increase mental and physical alertness in mentally retarded patients.
HIS - Essential for growth in infants and growing children. Used to treat histidinane ia, a rare disease caused by faulty histidine metabolism.
LEU - Used in the diagnosis and treatment of idiopathic hyperglycemia in infancy.
LYS - Used orally as soon as oral or vulval herpes lesions* are apparent and produces rapid resolution of herpes lesions. Used as a dietary supplement to aid in the reduction of plasma- triglyceride and plasma-cholesterol levels.
MET - Has been used to lower pH of urine and has been used as a lipotropic agent.
PHE - Has been used to treat depression and Parkinson's disease.
T RP - Has been used to treat depression (with pyridoxine and ascorbic acid). Used to treat disturbed sleep patterns, migraine, pain and psychosis (mania). TYR is the precursor of the neurotransmitter serotonin.
ORN - Has been used as an anticholesteremic.
The compositions of this invention will be principally employed for the nasal delivery of therapeutic quantities of amino acids such as those listed above. They are also applicable to the nasal delivery of useful quantities of the essential amino acids as dietary supplements.
Amino acids for use as suggested above have been available for a number of years in oral form and in parenteral forms for injection. While useful, these forms are not completely satisfactory for a number of reasons.
Oral formulations are not rapidly absorbed from the intestinal track and, often do not produce desirably high blood levels in a short time. .Moreover, some of the desired product may be wasted by excretion before it is absorbed.
Injectable solutions and suspensions are more satisfactory for producing rapid high blood levels. However, they must normally be administered under the supervision of trained medical personnel in a doctor's office or out-patient department. Many people strongly object to injections.
It has been discovered that the compounds discussed above can be usefully administered to mammals in novel compositions at low dosage levels to elicit a systemic therapeutic response and to provide enhanced bioavailability, minimized variations in blood levels, more rapid onset of activity, ease of administration, and reduced side effects compared to most current methods of administration. The nasal administration process of this invention is significently more convenient than parenteral administration. Simple, small containers such as eye droppers, aerosol or other pressurized containers, and tubes which can be easily carried in a pocket or purse can be used for delivery. This should be compared with hypodermic needles which are difficult to use and repugnant to many people. In many jurisdictions it is illegal to transport them.
Nasal delivery of therapeutic agents has been well known for a number of years. See, for example, U.S. Patents 4,428,883; 4,284,648 and 4,394,390; and PCT application International Publication Number WO83/00286. See also, Hussain et al, J. Phar . Sci.: 68, No. 8, 1196 (1979); _69_ 1240 (1980) and 6_9 (1980).
While nasal administration of certain therapeutic agents to mammals, especially humans is known, it is not a necessary conclusion from such knowledge that all therapeutic agents can be usefully administered by this route. In fact is has been shown that many drugs cannot be usefully administered by the nasal
route. It certainly is not a suggestion that the compounds of this invention can be usefully administered nasally to achieve enhanced bioavailability and sustained therapeutic blood levels.
Zatuchini, et al, for example reported in LHRH Peptides as Female and Male Contraceptives, Harper & Row, Publishers (1976) that although LHRH peptides were effective when administered intranasally, a much higher dose was required than with parenteral administration.
Childrey and Essex reported an immediate and marked pressor response upon injection of 1 mg of nicotine in dogs, but little or no effect on injections of the same or larger amounts into the sinus of dogs or cats. Arch. Otolaryngol. , 1_4_ 564 (1931 ).
This invention provides amino acid containing compositions including gels, sprays and solutions which may be administered in the form of drops all of which are specifically formulated for nasal administration to permit therapeutic delivery of effective amounts of amino acid through the nasal mucous membrane. The term "amino acids" of course includes pharmaceutically acceptable acid and basic addition salts thereof including organic and inorganic acid addition salts and alkali and alkaline earth addition salts such as hydrochloride, phosphate acetate and sodium, potassium and calcium salts.
Liquid sprays and drops are normally easier to prepare than gels and other viscous compositions. Additionally, they are somewhat more convenient to administer, especially in multi-dose situations. Viscous compositions, on the other hand can be formulated to provide longer contact periods with the nasal ucosa and reduce the amount of amino acid per dosage unit necessarv to achieve the desired result.
More specifically the compositions of the invention are for nasal administration and contain a therapeutically effective amount of at least one amino acid. They are conveniently provided as isotonic aqueous compositions which may be buffered to a selected pH. The viscous compositions may be in the form of gels, lotions, ointments, creams and the like and will typically contain a sufficient amount of a thickening agent so that the viscosity is from about 2500 to 6500 cps, although more viscous compositions even up to 10,000 cps may be employed. The preferred compositions have a viscosity of 2500 to 5000 cps, since above that range they become more difficult to administer.
The amino acids of the invention will be most efficiently absorbed through the nasal membranes if the composition is at the isoelectric point of the material being absorbed. However, at pH values appreciably below 4 or above 6 irritation of the nasal mucosa may become a problem. Therefore it is preferred to prepare the compositions so that the pH is from about 4 to 6, but it is not essential to do so. Values from about 3 to 7 are tolerable. The pH is maintained with a physiologically acceptable buffer, suitably an acetate, phosphate, phthalate or borate buffer. Acetate buffers are preferred for convenience and economy.
The concentration of active agent in the composition will vary appreciably with the selected amino acid. Therapeutically effective amounts of amino acids vary appreciably amongst themselves. However, as a generalization, the compositions of the invention in bulk or unit dosage form will typically contain the selected agent as a concentration of from about 20 to 600 mg/ l. These are the preferred concentrations for compositions of the invention containing ORN, LYS, ARG or TRP; amino acids which are especially applicable to the practice of this
invention. The physician or veterinarian in attendance will select the proper dosage based on factors which he will be able to evaluate. A dosage unit will generally contain 0.05 to 0.3ml.
The agents used in this invention will normally be targeted to deal with one specific problem such as ammonia intoxication or disturbed sleep patterns. Therefore the compositions will usually contain only one therapeutic agent. However, there is no reason why they may not contain a plurality of amino acids e.g. two, three or even more.
The compounds may be administered in the form of their pharmaceutically acceptable acid or basic salts, suitable hydrochlorides, acetates, and alkali metal salts, specifically sodium or potsasium. It may be convenient to utilize one amino acid in the form of its salt with another amino acid, for example arginine glutamate to treat ammonia intoxication.
The isotonicity of the composition may be accomplished using sodium chloride, or other pharmaceutically acceptable agent such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solute. Sodium chloride is preferred particularly for buffers containing sodium ions.
Viscosity of the compositions may be maintained at the selected level using a therapeutically acceptable thickening agent. Methyl cellulose is preferred because it is readily and economically available and is easy to work with. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickener will depend upon the agent selected. The important point is to use an amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.
Preferred compositions within the scope of this invention will contain a humectant to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of therapeutically acceptable humectants can be employed including, for example sorbitol, propylene glycol or glycerol. As with the thickeners, the concentration will vary with the selected agent, although the presence or absence of these agents, or their concentration is not an essential feature of the invention.
Enhanced absorption across the nasal membrane can be accomplished employing a therapeutically acceptable surfactant. Typically useful surfactants for these therapeutic compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides such as T een 80, Polyoxyl 40 Stearate, Polyoxyethylene 50 Stearate and Octoxynol. The usual concentration is from 1% to 10% based on the total weight.
A therapeutically acceptable preservative is generally employed to increase -the shelf life of the compositions. Benzyl alcohol is suitable, although a variety of preservatives including, for example, Parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed. A suitable concentration of the preservative will be from 0.02% to 2% based on the total weight, although there may be appreciable variation depending upon the agent selected.
Those skilled in the art will recognize that the components of the compositions must be selected to be chemically inert with respect to the active agent. This will present no problem to those skilled in chemical and pharmaceutical principles, or can be readily avoided by reference to standard texts or by simple experiment.
The therapeutically effective compositions of this invention are prepared by mixing the ingredients following generally accepted procedures. For example the selected components may be simply mixed in a blender, or other standard machine to produce a concentrated mixture which is then adjusted to the final concentration and viscosity by the addition of water.
It is suprising to find that amino acids are well absorbed through the nasal mucosa especially in view of the conclusion by Hussain, et al that peptides are poorly absorbed. See Transnasal Systemic Medications, Edited by Y.W. Chien, Elsevier Science Publishers, 1985, page 121 et seq (at page 122). It should be noted, however that U.S. Patent 4,548,922 discloses nasal administration of insulin but only in the presence of amphiphilic steroids. U.S. Patent 4,476,116 discloses nasal spray compositions for the administration of polypeptides, but such compositions require specifically defined chelating agents as inducers.
Typical compositions of this invention contain the following components per 100 ml:
Benzyl alcohol, NF - 1.50ml
Sodium chloride, NSP - q.s. Methyl cellulose, USP (400 cps) 2.00gm
Acetic acid, NF - q.s.
Sodium acetate (anhyd, USP) - q.s.
Sorbitol soln. , USP - 5.00ml
Selected amino acid 2-60gm
Water, purified - qs. 100ml
pH and tonicity will be adjusted q.s. to assure maximum adsorption and miminal local irritation. They will depend on such factors as concentration of the selected amino acid and its isoelectric point.
The following non-limiting examples are given by way of illustration only and are not to be considered limitations of this invention of which many apparent variations of which are possible without departing from the spirit or scope thereof.
EXAMPLE 1
The following compositions are prepared by mixing the named components.
A
Phenylmercuric Acetate NF 0.002g
Boric Acid NF q.s.
Methylcellulose (4000 CPS) USP 2.000g
Acetic Acid NF q.s.
Sodium Acetate (Anhydrous) USP q.s.
Glycerin USP 5.000ml
ARG 2.0g
Water, Purified USP qs 100.000ml
B
Benzalkonium Chloride NF 0.020g
Potassium Chloride USP q.s. Hydroxyethyl Cellulose (3500-4000CPS)NF 1.000g
Acetic Acid NF q.s.
Sodium Acetate (Anhydrous) USP q.s.
Propylene Glycol USP 5.000ml
ORN 20. Og
Water, Purified USP qs 100.000ml
Thi erosal USP 0.002g
Dextrose USP q. s.
Polysorbate 80 USP 10.000g
Methylcellulose (4000 CPS) USP 1.33g
Acetic Acid NF q.s.
Sodium Acetate (Anhydrous) USP q.s.
Glycerin USP 5.000ml
TRP 5.0g
Water, Purified qs 100.000ml
Methylparaben NF 0.020g
Propylparaben NF 0.010g
Sodium Chloride USP 0.820g
Xanthan Gum NF 2.000g
Acetic Acid NF 0.100g
Sodium Acetate (Anhydrous) USP 0.270g
Propylene Glycol USP 5.000g
LYS 50. Og
Water, Purified qs 100.000ml
The viscosities of all of the above compositions are within the viscosity range defined above. Solutions are prepared by omitting the thickening agents.
Claims
1. A therapeutic composition for nasal administration comprising a therapeutically effective amount of an amino acid in an isotonic aqueous buffer at a pH of from about 3 to 7.
2. A therapeutic composition of claim 1 containing a sufficient amount of a therapeutically acceptable thickening agent so that the viscosity is from about 2500 to 6500 cps.
3. A therapeutic composition for nasal administration in dosage unit form containing from 20 to 600 mg/ml of an amino acid in an isotonic aqueous buffer at a pH of from about 3 to 7.
4. A therapeutic composition of claim 3 containing a sufficient amount of a therapeutically acceptable thickening agent so that the viscosity is from about 2500 to 6500 cps.
5. A therapeutic composition of claim 1 or 2 wherein the amino acid is arginine, ornithine, tryptophane or lysine.
6. A therapeutic composition of claim 3 or 4 wherein the amino acid is argine, ornithine, tryptophane or lysine.
7. A method of treating a mammal in need of such treatment which comprises nasal administration of a therapeutically effective amount of an amino acid in an isotonic aqueous buffer at a Ph of from about 3 to 7.
8. A method as in claim 7 wherein the composition contains a sufficient amount of a therapeutically acceptable thickening agent so that the viscosity is from about 2500 to 6500 cps.
9. A method of treating a mammal in need of such treatment which comprises nasal administration of a composition in disage unit form containing from 20 to 600 mg/ml of an amino acid in an isotonic aqueous buffer at a pH of from about 3 to 7.
10. A method as in claim 9 wherein the composition contains a sufficient amount of a therapeutically acceptable thickening agent so that the viscosity is from about 2500 to 6500 cps.
11. A method as in claim 7 'or 8 wherein the amino acid is arginine, ornithine, tryptophaneor"lysine.
12. A method as in claim 9 or 10 wherein the amino acid is argine, ornithine, tryptophane or lysine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US144887A | 1987-01-08 | 1987-01-08 | |
| US1448 | 1995-07-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0296227A4 EP0296227A4 (en) | 1988-11-29 |
| EP0296227A1 true EP0296227A1 (en) | 1988-12-28 |
Family
ID=21696066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP88901000A Withdrawn EP0296227A1 (en) | 1987-01-08 | 1987-12-28 | Nasal delivery of amino acids |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0296227A1 (en) |
| JP (1) | JPH01501708A (en) |
| WO (1) | WO1988004926A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1035833B1 (en) | 1997-12-02 | 2005-08-31 | Archimedes Development Limited | Compositions for nasal administration |
| US6080783A (en) * | 1998-09-01 | 2000-06-27 | Gum Tech International, Inc. | Method and composition for delivering zinc to the nasal membrane |
| JP2004123564A (en) * | 2002-09-30 | 2004-04-22 | Inst Of Physical & Chemical Res | Amino acid composition for improving central neural function |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2666012A (en) * | 1950-10-02 | 1954-01-12 | Jr Edgar A Ferguson | Nose drops |
| EP0115627A1 (en) * | 1982-12-29 | 1984-08-15 | Armour Pharmaceutical Company | Enhancement of intranasal absorption of calcitonin by formulation with surfactants |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4284648A (en) * | 1979-08-03 | 1981-08-18 | The University Of Kentucky Research Foundation | Nasal administration of propranolol |
| US4414202A (en) * | 1980-02-19 | 1983-11-08 | Silvetti Anthony N | Composition for treatment of wounds |
| US4428883A (en) * | 1981-03-06 | 1984-01-31 | The University Of Kentucky Research Foundation | Novel method of administering β-blockers and novel dosage forms containing same |
| US4476116A (en) * | 1982-12-10 | 1984-10-09 | Syntex (U.S.A.) Inc. | Polypeptides/chelating agent nasal compositions having enhanced peptide absorption |
| US4604286A (en) * | 1984-09-17 | 1986-08-05 | Daigo Nutritive Chemicals, Ltd. | Infusion solution for parenteral nutrition |
-
1987
- 1987-12-28 EP EP88901000A patent/EP0296227A1/en not_active Withdrawn
- 1987-12-28 JP JP50134288A patent/JPH01501708A/en active Pending
- 1987-12-28 WO PCT/US1987/003500 patent/WO1988004926A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2666012A (en) * | 1950-10-02 | 1954-01-12 | Jr Edgar A Ferguson | Nose drops |
| EP0115627A1 (en) * | 1982-12-29 | 1984-08-15 | Armour Pharmaceutical Company | Enhancement of intranasal absorption of calcitonin by formulation with surfactants |
Non-Patent Citations (1)
| Title |
|---|
| See also references of WO8804926A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0296227A4 (en) | 1988-11-29 |
| WO1988004926A1 (en) | 1988-07-14 |
| JPH01501708A (en) | 1989-06-15 |
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