WO1988004926A1 - Administration d'aminoacides par voie nasale - Google Patents

Administration d'aminoacides par voie nasale Download PDF

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Publication number
WO1988004926A1
WO1988004926A1 PCT/US1987/003500 US8703500W WO8804926A1 WO 1988004926 A1 WO1988004926 A1 WO 1988004926A1 US 8703500 W US8703500 W US 8703500W WO 8804926 A1 WO8804926 A1 WO 8804926A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
amino acids
compositions
usp
cps
Prior art date
Application number
PCT/US1987/003500
Other languages
English (en)
Inventor
Jeffrey Wenig
Jason Wenig
Original Assignee
Nastech Pharmaceutical Company, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nastech Pharmaceutical Company, Inc. filed Critical Nastech Pharmaceutical Company, Inc.
Publication of WO1988004926A1 publication Critical patent/WO1988004926A1/fr

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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.
PCT/US1987/003500 1987-01-08 1987-12-28 Administration d'aminoacides par voie nasale WO1988004926A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US144887A 1987-01-08 1987-01-08
US001,448 1987-01-08

Publications (1)

Publication Number Publication Date
WO1988004926A1 true WO1988004926A1 (fr) 1988-07-14

Family

ID=21696066

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1987/003500 WO1988004926A1 (fr) 1987-01-08 1987-12-28 Administration d'aminoacides par voie nasale

Country Status (3)

Country Link
EP (1) EP0296227A1 (fr)
JP (1) JPH01501708A (fr)
WO (1) WO1988004926A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999027905A1 (fr) * 1997-12-02 1999-06-10 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Compositions pour administration nasale
EP1039896A1 (fr) * 1998-09-01 2000-10-04 Charles Hensley Procede et composition permettant d'administrer du zinc ionique a une membrane nasale
WO2004028528A1 (fr) * 2002-09-30 2004-04-08 Riken Compositions d'acides amines destinees a ameliorer les fonctions centrales

Citations (5)

* Cited by examiner, † Cited by third party
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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2666012A (en) * 1950-10-02 1954-01-12 Jr Edgar A Ferguson Nose drops
AU572815B2 (en) * 1982-12-29 1988-05-19 Armour Pharmaceutical Company Pharmaceutical calcitonin compositions for intranasal application

Patent Citations (5)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0296227A4 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999027905A1 (fr) * 1997-12-02 1999-06-10 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Compositions pour administration nasale
US6342251B1 (en) 1997-12-02 2002-01-29 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Compositions for nasal administration
EP1039896A1 (fr) * 1998-09-01 2000-10-04 Charles Hensley Procede et composition permettant d'administrer du zinc ionique a une membrane nasale
EP1039896A4 (fr) * 1998-09-01 2007-08-15 Zicam Llc Procede et composition permettant d'administrer du zinc ionique a une membrane nasale
WO2004028528A1 (fr) * 2002-09-30 2004-04-08 Riken Compositions d'acides amines destinees a ameliorer les fonctions centrales

Also Published As

Publication number Publication date
JPH01501708A (ja) 1989-06-15
EP0296227A1 (fr) 1988-12-28
EP0296227A4 (fr) 1988-11-29

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