JPH01501708A - Nasal administration of amino acids - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Nasal administration of amino acids Background of the invention The present invention relates to nasal administration of amino acids to mammals. The present invention also provides amino A method of administering acid through the nose to mammals in need of such treatment. Related〇 As is well known, amino acids are the building blocks of the body's proteins. those It also contributes to many other physiological functions well known to those skilled in the art.

There are approximately 20 common amino acids. Their chemical properties and functions are Since it is well known, there is no need to discuss it here. Of these, the most noteworthy ones are amino acids, or at/L essential for the proper functioning of a healthy body. 11m, and is not produced by normal metabolism. These amino acids are It must be obtained from external sources. Other amino acids have therapeutic uses. ing. These are widely used in the treatment of ammonia poisoning due to liver failure, for example. Contains arginine.

For convenience of explaining the present invention, in this disclosure, the amino acids commonly used to represent amino acids are used. Use the abbreviation given. These include: Alanine-ALA Lysine-LYS Asparagi Δ1i-ASP Methionine-MET Special Table Sen1-501708 (2 ) Arginine-ARG Ornithine-0RNT Cystine-CYS Phenyl 75 2 = PHB glutamic acid - GLU proline - PRO glycine - LY 7 N-8DR histidine-Hl5) leonine-THR inleucine-ILE) lipdoa -TRP Leucine-LEU Tyrosine-TYR Valin-VAL However, the present invention is not limited to these common amino IIKs; , synthetic or other less common amino acids, or all these amino acids structurally. It can also be applied to modified versions. Naturally, it is the D- and L-type of amino acids, as well as It can also be applied to seven bodies.

Amino acids that are generally recognized as essential are: ARG MET HIS PHE I LE THR LEU TRP LMS VAL Amino acids that are generally accepted to have therapeutic utility include: Contains: ALA - Used to supplement the diet. - Fasting for 2 weeks after oral administration of 5Cl per day Hypoglycemia and ketosis are abolished and muscle catabolism is reduced in obese patients It was reported that. Additionally, glucagon (gl) in patients with acute and chronic pneumonitis It was also reported to stimulate ucagen) secretion.

ARG-Glutamine and arginine are used to treat ammonia poisoning due to liver failure. used.

GLU - Reduces petit mal seizures and increases mental and physical agility in mentally retarded patients It has been used as an antiepileptic drug.

HIS - Essential for infants and growing children. histidine anemia (histidine) dinanemia), a rare disease caused by a defect in histidine metabolism. used for treatment.

LEU - Used in the diagnosis and treatment of endogenous hyperglycemia in children.

LMS - used orally as soon as oral or vulvar herpes disease appears; Quickly eliminate diseases caused by herpes. Used to supplement regular diet, plasma triglyceride Helps lower cholesterol levels and plasma cholesterol levels.

MET - used to lower urine pH and has been used as a lipotropic factor .

It has been used to treat PHI-5 conditions and Parkinson's disease.

TRP - used to treat depression (in combination with pyridoxine and ascorbic acid) It's here. Used to treat disturbed sleep patterns, migraines, pain, and psychosis. It will be done.

TYR is a precursor of the neurotransmitter 2).

0RN - has been used as an anticholesterolemia drug.

The compositions of the present invention primarily contain amino acids such as those listed above, which may also be used as dietary supplements. It can also be applied to intranasal administration of an effective amount of essential amino acids.

Amino acids intended for the uses listed above can be administered orally and parenterally by injection. It has been available for many years in this form. Although these forms are useful, is not perfect for several reasons.

Oral formulations are not absorbed quickly from the gastrointestinal tract and may not reach high blood levels in a short period of time. There are often Additionally, some desired substances may be excreted before they are absorbed. There is something that is possible.

Injectable solutions and suspensions are more satisfactory for quickly achieving high blood levels. It is something. However, they are usually performed by skilled medical staff in outpatient clinics and hospitals. Must be administered under supervision. Many people strongly dislike injections.

In novel compositions, the compounds discussed above elicit systemic therapeutic responses at low doses. Increases biological effectiveness (bioavailability) and minimizes variation in levels, has a faster onset of action, is easier to administer, Compared to the newest administration methods, it has fewer side effects and can be effectively administered to mammals. It was discovered that it can be done. The method of nasal administration of the present invention is more convenient than parenteral administration. Yes, the difference is significant. Easy to carry in your pocket or purse for administration such as eye drop containers, aerosols, or other pressurized containers and tubes that can be used with Any simple, small container can be used. This is difficult to use and many people feel resistance. It should be compared to a hypodermic needle that uses needles. Many jurisdictions require that they be transported It is illegal to do so.

Intranasal administration of therapeutic agents has been well known for many years. For example, U.S. Patent No. 4.42 8,883; 4,284,648 and 4.394,390 specifications, and P See CT application International Publication WO83/00286. Also, Hu551in et al., J. , Pharm, Sci: 68, A8 r1196 (1979) ;l11240 (1980) and! (1980).

Nasal administration of certain therapeutic agents to mammals, particularly humans, is known; Knowledge does not necessarily imply that all therapeutic agents can be usefully administered by this route. It's not like that. In fact, it has been shown that many drugs cannot be usefully administered via the nose. It has been. It is believed that the compounds of the present invention can be usefully administered intranasally and have higher biological Bio-availability and maintained therapeutic blood levels It is certainly not an indication that this can be achieved.

For example, Zatuchini et al. Chido J (LHRHPeptides as Female and Male Contraceptives), Harper & Row, Pub Lishers (1976), the LHRH peptide was administered intranasally with a volute effect. However, it has been reported that much higher doses are required than for parenteral administration. are doing.

Childrey and Ess ex injected 1 mg nicotine in dogs. Immediate and pronounced pressor response upon injection However, the same or higher amount of nicotine is administered into the nasal cavity of a dog or cat (5i When injected into the nus), there was little or no effect. It was reported that there was no Arch, Otolaryngo+, + upper ma56 4 (1931).

The present invention provides solutions that can be administered in the form of gels, sprays and drops. Amino acid-containing compositions containing liquids, all of which can be administered in effective amounts through the nasal mucosa. Provides compositions specifically formulated for intranasal administration that allow for therapeutic administration of amino acids. Ru. The term ``amino'' naturally refers to organic and inorganic acid addition salts. pharmaceutically acceptable acid and base addition salts thereof (a cid and basic addition 5alt) and alkali and Alkaline earth addition salts, hydrochloride, phosphorus! [, acetate and sodium, potassium and and calcium salts.

Liquid sprays and drops are usually easier to prepare than gels and other viscous compositions. be. In addition, they are difficult to administer, especially in the case of multi-dose This is somewhat convenient. ° On the other hand, viscous compositions provide a longer period of contact with the nasal mucosa. , per dose unit required to achieve the desired result. May be formulated to reduce the amount of amino acids.

More particularly, the compositions of the invention are for nasal administration and contain a therapeutically effective amount. Contains at least - amino acids. They are buffered to a selected pH. 1 sotonic aqueous compo It would be convenient if they were provided as sj-tions). Viscous compositions include gels, waxes, It can take the form of a lotion, cream, etc., and typically has a viscosity of about 2,500 to 2,500. Contains sufficient thickening agent to achieve 6500 cps. However, even more viscosity Compositions as high as up to 10,000 cps can also be used.

A more preferred composition has a viscosity of 2500 to 5000 cps. because This is because if it exceeds this range, administration becomes more difficult.

The amino acids of the present invention pass through the back of the door when the composition is at the isoelectric point of the substance to be absorbed. It is most effectively absorbed when

However, at pH values somewhat below 4 or above 6, irritation of the nasal mucosa becomes a problem. Become. Therefore, it is more preferable to prepare the composition so that the pH value is about 4 to 6. stomach. However, it is not necessary to do so. Values of about 3 to 7 are acceptable. Ru. The pH value is maintained by physiologically acceptable buffers. acetic acid, phosphorus Acid, phthalate or borate buffers are suitable. Acetate due to convenience and economy Buffers are more preferred.

The concentration of active agent in the composition will vary somewhat depending on the amino acid selected. therapeutically The effective amino acid amount varies somewhat between them. However, generally one bulk In bulk or in unit dosage form, the compositions of the present invention typically at a concentration of about 20 to 600 mV-. These are ORN, LYS, ARG or I, which are amino acids particularly applicable to the implementation of This is a more preferable concentration for compositions of the present invention containing .

The attending physician or veterinarian will determine the appropriate dose based on factors that he or she can assess. Select. -Dose unit is generally between 0.05 and 0. ．． Contains 3-.

The drug used in the present invention may be used to treat ammonia poisoning or disturbances in sleep patterns. It is usually aimed at addressing one specific problem, such as Therefore The compositions often contain only - therapeutic agents. However, the number of irI There is no reason why it could not contain 2.3 or more amino acids.

The compounds include pharmaceutically acceptable acid or base salts thereof, suitable salts. acid salts, acetates, and alkali metal salts, especially in the form of sodium or potassium salts can be administered at Using - amino acid in its salt form with other - amino acids - For example, glutamine powdered arginine - could be useful in treating ammonia sickness. Ru.

Isotonicity of the composition is determined by sodium chloride, or dextrose, boric acid, sodium tartrate. such as thorium, propylene glycol or other inorganic or organic solutes. Obtained by using other pharmaceutically acceptable agents. sodium ion For the buffer solution contained, sodium chloride is particularly preferred.

The viscosity of the composition is maintained at the selected level using a thickening agent acceptable to the therapist. can be held. Methylcellulose is easily and economically available and easy to handle. Therefore, it is more preferable. Other suitable thickening agents are, for example, xanthan gum, Oxymethyl cellulose, hydroxypropyl cellulose, carbomer (car boomer), etc. The preferred concentration of thickener will depend on the drug selected. Exists. The important point is to use an amount that achieves the selected viscosity. viscosity Compositions are usually prepared from solutions by the addition of such thickening agents.

More preferred compositions within the scope of the present invention include a variety of tolerable moisturizers for mucous membranes. Any lubricant may be used, including sorbitol, propylene glycerin, etc. Contains fur or glycerol. As with thickeners, the concentration is selected Depends on the drug used. However, the presence or absence of these drugs or their concentrations are It is not an essential feature of the invention.

Increased absorption through the abdominal abdomen can be achieved by the use of therapeutically acceptable surfactants. achieved. Typically useful surfactants for these therapeutic compositions include 80, polyoxyl 40 stearate, polyoxyethylene 50 stearate and polyesters of fatty acid partial esters of anhydrous sorbitol, such as octoxynol. Includes lyoxyethylene derivatives. Typical concentrations range from 1% to 10% of total weight. %.

To increase the shelf life of the composition, therapeutically acceptable preservatives are commonly used. . Various preservatives, for example parabens, thimerosal, chlorobutanol or salts However, benzyl alcohol is suitable for use with pensulfonium hydroxide. embalming The appropriate concentration of agent may vary slightly depending on the agent selected, but However, the content ranges from 0.02% to 2%.

Those skilled in the art will recognize that the components of the composition are selected to be chemically inert to the active agent. will recognize that it must be done. This is true for chemical and pharmaceutical sciences. Does not present any problems to those familiar with the principles, or is a reference to standard texts. Problems can be easily circumvented by inspection and simple experimentation.

The therapeutically effective compositions of the invention can be prepared according to generally accepted methods. , prepared by mixing the ingredients. For example, pre-prepare selected components. Simply mix in a blender or other standard machine that produces concentrated mixtures and then The final concentration and viscosity may be adjusted by adding water.

The discovery that amino acids are well absorbed through the nasal mucosa is particularly important for Huss. It is surprising to see the conclusion by Ain et al. that peptides are poorly absorbed. It is important. Transnatal Systemic Medicine ns, Y+W, Chien, Elsevier 5science Pub lishers+ 1985 rp 121 and below (p122) was referred to stomach. However, U.S. Patent No. 4,548,922 discloses that nasal administration of insulin is It should be noted that only the cases in which amphipathic steroids are present are disclosed. It is possible. U.S. Pat. No. 4,476.116 discloses a nasal tube for administering polypeptides. discloses play compositions, but such compositions are clearly not listed as inducers. Requires defined chelating agent.

A typical composition of the invention contains the following components per 100 kg.

Benzyl alcohol NF-1, 50d Sodium chloride, NSP-Q, S.

) fh Seyo-su, USF (400cps) 2+oo 9m acetic acid, NF -q, s.

Sodium acetate (anhydrous, USP) -q,s-tulpitot/l/5olo,,U SP-5, OOd selected amino acids 2-609m Purified water-C1,5,100m pH and tonicity to ensure maximum absorption and minimal local irritation. ty) is appropriately manufactured by (q, s,) II. They are the concentration of selected amino acids and It depends on factors such as the temperature and its isoelectric point.

The following non-limiting examples are presented for illustrative purposes only and do not limit the invention. It is not something that should be considered a thing. What is the idea or scope of the invention? Many obvious variations are possible without departing from the above.

Example 1 The following compositions are prepared by mixing the indicated components.

phenylmercuric acetate) NF O, 0029 boric acid N F q, s.

Methyl heptose (4000Cps) USP 2[009 Acetic acid NF q, s. Sodium acetate (anhydrous) USP q,s.

Glycerin U S P 5.000 + dARG 2.09 1fflH water U S P q, s, 100.000 art benzalconi chloride Um N F O, 0209 Potassium chloride U S P q, s.

Hydro#xf7ya-x (3500-4000cps) NF 1.000 9 Acetic acid NF q, s・ Sodium acetate (anhydrous) USP Q,S.

Propylene glycol U S P 5.000 mORN 20.07 Purified water U S P q, S, 100.000 m/Thimerosal USP 05002ri Dextrose U S P q, s.

Polysorbate 80 USF 10.000g Methylcellulose (4000 cps) USP 1.339 Acetic Acid NF q, s.

Sodium acetate (anhydrous) U S P q, S.

・Glycerin USP 5.000 dTRP 5.0g Purified water q, S-100,000- Methyl paraben N F O,0209 Propyl paraben N F O,01 (1 Sodium chloride U S P O, 8209 Xanthan gum N F 1000 g Acetic acid N F O, 1009 Sodium acetate (anhydrous) USP 0.2709 propylene glyph-/L/ USF 5.0009L YS 50.0g Purified water q, s, 100.000 wt The viscosity of any of the above compositions is as defined above. This is the viscosity range. Solutions are prepared by omitting thickening agents.

Handbook supplementary text (spontaneous) October J'1, 1986

Claims (12)

[Claims] 1. consisting of a therapeutically effective amount of an amino acid in an isotonic buffered aqueous solution having a pH of about 3 to 7. A therapeutic composition for nasal administration. 2. a therapeutically acceptable amount sufficient to have a viscosity of about 2,500 to 6,500 cps. The therapeutic composition of claim 1, containing a thickening agent. 3. 20 to 600 mg/ml of amino acids in an isotonic buffered aqueous solution with a pH of about 3 to 7. A therapeutic composition for nasal administration in dosage unit form comprising: 4. a therapeutically acceptable amount sufficient to have a viscosity of about 2500 to 6500 cps; 4. The therapeutic composition of claim 3, further comprising a thickening agent. 5. the amino acid is arginine, ornithine, tryptophan or lysine A therapeutic composition according to claim 1 or 2. 6. Amino acids include arginine, ornithine, tryptophan, and 5. The therapeutic composition of claim 3 or 4, wherein is lysine. 7. Intranasal administration of a therapeutically effective amount of an amino acid in an isotonic buffered aqueous solution having a pH of about 3 to 7. A method of treating a mammal in need of such treatment, comprising: 8. a therapeutically acceptable amount sufficient to have a viscosity of about 2500 to 6500 cps; 8. The method according to claim 7, further comprising a thickening agent which can be used as a thickening agent. 9. 20 to 600 mg/ml of amino acids in an isotonic buffered aqueous solution with a pH of about 3 to 7. requiring such treatment, consisting of nasal administration of a composition in dosage unit form containing Mammalian treatment methods. 10. a therapeutically acceptable amount sufficient to provide a viscosity of approximately 2,500 to 6,500 cps; 10. The method of claim 9, wherein the composition contains a thickening agent that can be mixed. 11. The amino acid is arginine, ornithine, tryptophan or lysine. 9. The method according to claim 7 or claim 8. 12. The amino acid is arginine, ornithine, tryptophan or lysine , the method according to claim 9 or claim 10.