WO2009025571A1 - Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease - Google Patents
Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease Download PDFInfo
- Publication number
- WO2009025571A1 WO2009025571A1 PCT/RU2007/000446 RU2007000446W WO2009025571A1 WO 2009025571 A1 WO2009025571 A1 WO 2009025571A1 RU 2007000446 W RU2007000446 W RU 2007000446W WO 2009025571 A1 WO2009025571 A1 WO 2009025571A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- succinic acid
- pharmaceutically acceptable
- disease
- sublingual
- treating alzheimer
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the invention relates to sublingual or buccal pharmaceutical compositions comprising succinic acid or pharmaceutically acceptable salts thereof for preventing and/or treating Alzheimer's disease
- Alzheimer's disease is accompanied with central insulin resistance.
- BeA Acta Neuropathol
- US patent 6521665 discloses the method of treating insulin resistance comprising administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof, wherein the succinic acid or a pharmaceutically acceptable salt thereof is administered orally, or parenterally, or topically, or rectally.
- succinic acid does not manifest significant central effects under routes of administration disclosed in US patent 6521665, because of a very low transport capacity for four-carbon dicarboxylates across the blood-brain barrier (BBB).
- BBB blood-brain barrier
- succinic acid manifests central effects under sublingual and buccal administration. It is an object of the present invention to provide a sublingual or buccal pharmaceutical composition for preventing and/or treating Alzheimer's disease comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a sublingual or buccal pharmaceutical composition for preventing and/or treating Alzheimer's disease comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- Succinic acid is a compound of formula HOOCCH 2 CH 2 COOH.
- pharmaceutically acceptable salt refers to non-toxic base addition salts.
- the pharmaceutically acceptable salts of the invention are prepared by a reaction of succinic acid with a pharmaceutically acceptable base by methods well-known from the art.
- Such bases include, but are not limited to, ammonia; sodium base; potassium base; organic amines like as triethylamine, ethanolamine, dimethylethanolamine, diethanolamine, and triethanolamine; 2- ethyl-6-methyl-3-hydroxypiridine; and basic amino acids like arginine, ornithine, and lysine.
- the pharmaceutically acceptable salt of succinic acid is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. More preferably, the pharmaceutically acceptable salt of succinic acid is a compound of Formula (II)
- therapeutically effective amount refers to a nontoxic but sufficient amount of succinic acid or a pharmaceutically acceptable salt thereof to provide the desired therapeutic effect.
- the therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof is from 0.1 to 250 mg per a unit dosage form of the composition of the present invention, more preferably, from 5 to 100 mg per the unit dosage form.
- sublingual dosage form in practicing the invention, can be administered by the intraoral, i.e. sublingual or buccal, routes.
- sublingual means relating to the area of the oral cavity below the tongue.
- uccal means relating to the oral cavity.
- the buccal dosage form is administered by placing in the oral cavity and allowing it to dissolve completely.
- the sublingual dosage form is placed beneath the tongue and allowed to dissolve completely. In all instances, since the absorption of the therapeutic agent is through the oral mucosa, the dosage forms should not be chewed or swallowed before complete dissolution in the mouth.
- pharmaceutically acceptable carrier refers to a one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to any portion of the epithelium of oral cavity of a mammal, preferably a human.
- the carrier may be a solid, liquid, solution, suspension, gel, ointment, lotion, or combinations thereof.
- compositions of the invention can be prepared in a variety of unit dosage forms. Such forms are include, but are not limited to, sublingual tablets, buccal patches, drop, spray, gel, ointment, and powder.
- Preferred pharmaceutical compositions are solid pharmaceutical compositions which rapidly disintegrate in the mouth of a subject, upon insertion into the buccal pouch or upon placement under the tongue. Rapid disintegration means that the pharmaceutical composition is disintegrated within 30 seconds in water at 37 0 C, and preferably within 10 seconds.
- the compositions of the invention are prepared by methods well-known from the art in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, 18th Edition (Ed. A.R. Genaro), 1990.
- the content of succinic acid or a pharmaceutically acceptable salt thereof should be in the range from 0.1 to 90 %, preferably 0.5 to 10 % by the weight of the composition.
- the present invention provides a method of treating Alzheimer's disease comprising sublingually or bucally administering to a mammal in need thereof a pharmaceutical composition comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the term "treating” means treating, controlling, preventing and/or reducing one or more clinical signs (i.e., symptoms) of the disease in a mammal in need thereof.
- the therapeutically effective amount in the method of the invention is 0.1 to 25 mg per kilogram of body weight of the mammal, more preferably, 1 to 5 mg per kilogram.
- the mammal is a human.
- the following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
- This example demonstrates sublingual tablet comprising compound of Formula (II).
- Compound of Formula (II), lactose, microcrystalline cellulose, corn starch, and the magnesium stearate are mixed well in suitable mixer.
- the powder is passed through suitable screen.
- Magnesium stearate is added and tablet is formed by compression. Tablets, when tested according to the USP procedure for sublingual tablets, have a limit of disintegration at most two minutes.
- Example 2 This example demonstrates aqueous composition comprising compound of Formula (II), formulated for administering to the area under the tongue or in the mouth of patient.
- Compound of Formula (II) is dissolved in water for injection to the desired volume, 0.4M disodium phosphate is added to pH 5.0. In this manner, solution with concentration of succinic acid of 20 mg/ml is prepared. The solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into glass vials.
- a disease relevant to human Alzheimer's disease was induced by injection of beta-amyloid peptide 25-35 (beta-amyloid) into nucleus basalis magnocellularis (NBM) of rat brains as described by Harkany T et al. in Behav
- Beta-amyloid was administered bilaterally into
- NBM of male Wistar rats in dose of 2 ⁇ g per each side NBM of male Wistar rats in dose of 2 ⁇ g per each side.
- rats received sublingually or intraperitoneally compositions comprising a water solution of 3 mg/kg of compound of Formula (II) for 7 days singly a day.
- Control rats received saline sublingually.
- passive avoidance performance in rats was tested for two consecutive days.
- a two-compartment, step-through, passive avoidance apparatus consisting of illuminated (25 x 40 x 25 cm) and dark (25 x 40 x 25 cm) compartments attached to an electrified grid floor and separated by a guillotine door (8 x 8 cm) was used.
- the rat was placed in the illuminated compartment in a position its tail directed to the closed door for 2 min to habituate to the apparatus.
- the guillotine door was opened and time to enter to dark compartment was recorded.
- the rat entered to dark compartment completely (four foots in dark compartment)
- the guillotine door was closed and the rat was delivered an electrical shock of 0.8 mA for 3 sec through the grid floor. After the shock, the rat was immediately placed in home cage.
- composition comprising succinic acid
- intraperitoneal administration is much more effective than intraperitoneal administration.
- Sublingually treated rats demonstrate significant improvement in learning and memory as compared to control rats, whereas intraperitoneally treated rats do not.
Abstract
The present invention relates to sublingual or buccal pharmaceutical compositions for preventing and/or treating Alzheimer's disease comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further, the present invention relates to methods for preventing and/or treating Alzheimer's disease with using compositions of the present invention.
Description
SUBLINGUAL OR BUCCAL PHARMACEUTICAL COMPOSITIONS COMPRISING SUCCINIC ACID FOR TREATING ALZHEIMER'S
DISEASE
Field of the Invention
The invention relates to sublingual or buccal pharmaceutical compositions comprising succinic acid or pharmaceutically acceptable salts thereof for preventing and/or treating Alzheimer's disease
Background of the invention
There is grown evidence that insulin acts in brain to regulate a variety of brain functions including learning and memory. Alzheimer's disease is accompanied with central insulin resistance. Craft S. Neurobiol Aging 2005, 26(Suppl D.-65-9. Hover S, Eur J Pharmacol 2004, 490(1 -3): 115-25. Steen E et al., J Alzheimers Pis 2005. 7:63-80. Moroo I et al., Acta Neuropathol (BeA). 1994; 87(4):343-8. Thus, there is the need to improve central insulin sensitivity to treat Alzheimer's disease. US patent 6521665 discloses the method of treating insulin resistance comprising administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof, wherein the succinic acid or a pharmaceutically acceptable salt thereof is administered orally, or parenterally, or topically, or rectally. However, succinic acid does not manifest significant central effects under routes of administration disclosed in US patent 6521665, because of a very low transport capacity for four-carbon
dicarboxylates across the blood-brain barrier (BBB). Hassel B et al, J Neurochem 2002; 82(21:410-9.
Surprisingly, it is demonstrated in the present invention that succinic acid manifests central effects under sublingual and buccal administration. It is an object of the present invention to provide a sublingual or buccal pharmaceutical composition for preventing and/or treating Alzheimer's disease comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Detailed Description of the Invention
The present invention provides a sublingual or buccal pharmaceutical composition for preventing and/or treating Alzheimer's disease comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Succinic acid is a compound of formula HOOCCH2CH2COOH. The term «pharmaceutically acceptable salt" refers to non-toxic base addition salts. The pharmaceutically acceptable salts of the invention are prepared by a reaction of succinic acid with a pharmaceutically acceptable base by methods well-known from the art. Such bases include, but are not limited to, ammonia; sodium base; potassium base; organic amines like as triethylamine, ethanolamine, dimethylethanolamine, diethanolamine, and triethanolamine; 2- ethyl-6-methyl-3-hydroxypiridine; and basic amino acids like arginine, ornithine, and lysine. Preferably, the pharmaceutically acceptable salt of succinic acid is a compound of Formula (I)
or a pharmaceutically acceptable salt thereof. More preferably, the pharmaceutically acceptable salt of succinic acid is a compound of Formula (II)
The term "therapeutically effective amount" refers to a nontoxic but sufficient amount of succinic acid or a pharmaceutically acceptable salt thereof to provide the desired therapeutic effect. Preferably, the therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof is from 0.1 to 250 mg per a unit dosage form of the composition of the present invention, more preferably, from 5 to 100 mg per the unit dosage form.
In practicing the invention, can be administered by the intraoral, i.e. sublingual or buccal, routes. The term "sublingual" means relating to the area of the oral cavity below the tongue. The term "buccal" means relating to the oral cavity. The buccal dosage form is administered by placing in the oral cavity and allowing it to dissolve completely. The sublingual dosage form is placed beneath the tongue and allowed to dissolve completely. In all instances, since the absorption of the therapeutic agent is through the oral mucosa, the dosage forms should not be chewed or swallowed before complete dissolution in the mouth.
The term pharmaceutically acceptable carrier" refers to a one or more compatible solid or liquid filler diluents or encapsulating substances which are
suitable for administration to any portion of the epithelium of oral cavity of a mammal, preferably a human. Typically, the carrier may be a solid, liquid, solution, suspension, gel, ointment, lotion, or combinations thereof.
The compositions of the invention can be prepared in a variety of unit dosage forms. Such forms are include, but are not limited to, sublingual tablets, buccal patches, drop, spray, gel, ointment, and powder. Preferred pharmaceutical compositions are solid pharmaceutical compositions which rapidly disintegrate in the mouth of a subject, upon insertion into the buccal pouch or upon placement under the tongue. Rapid disintegration means that the pharmaceutical composition is disintegrated within 30 seconds in water at 37 0C, and preferably within 10 seconds. The compositions of the invention are prepared by methods well-known from the art in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, 18th Edition (Ed. A.R. Genaro), 1990. The content of succinic acid or a pharmaceutically acceptable salt thereof should be in the range from 0.1 to 90 %, preferably 0.5 to 10 % by the weight of the composition.
Further, the present invention provides a method of treating Alzheimer's disease comprising sublingually or bucally administering to a mammal in need thereof a pharmaceutical composition comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
As used herein, the term "treating" means treating, controlling, preventing and/or reducing one or more clinical signs (i.e., symptoms) of the disease in a mammal in need thereof.
Preferably, the therapeutically effective amount in the method of the invention is 0.1 to 25 mg per kilogram of body weight of the mammal, more preferably, 1 to 5 mg per kilogram.
Preferably, the mammal is a human. The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Example 1.
This example demonstrates sublingual tablet comprising compound of Formula (II).
Compound of Formula (II), lactose, microcrystalline cellulose, corn starch, and the magnesium stearate are mixed well in suitable mixer. The powder is passed through suitable screen. Magnesium stearate is added and tablet is formed by compression. Tablets, when tested according to the USP procedure for sublingual tablets, have a limit of disintegration at most two minutes.
Example 2.
This example demonstrates aqueous composition comprising compound of Formula (II), formulated for administering to the area under the tongue or in the mouth of patient.
Compound of Formula (II) is dissolved in water for injection to the desired volume, 0.4M disodium phosphate is added to pH 5.0. In this manner, solution with concentration of succinic acid of 20 mg/ml is prepared. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into glass vials.
Example 3.
This example demonstrates methods for treating Alzheimer's disease. A disease relevant to human Alzheimer's disease was induced by injection of beta-amyloid peptide 25-35 (beta-amyloid) into nucleus basalis magnocellularis (NBM) of rat brains as described by Harkany T et al. in Behav
Brain Res. 1998 90(2): 133-45. Beta-amyloid was administered bilaterally into
NBM of male Wistar rats in dose of 2 μg per each side. On day 16th after the amyloid injection, rats received sublingually or intraperitoneally compositions comprising a water solution of 3 mg/kg of compound of Formula (II) for 7 days singly a day. Control rats received saline sublingually. On day next to the last day of the treatment, passive avoidance performance in rats was tested for two consecutive days. A two-compartment, step-through, passive avoidance apparatus consisting of illuminated (25 x 40 x 25 cm) and dark (25 x 40 x 25 cm) compartments attached to an electrified grid floor and separated by a guillotine door (8 x 8 cm) was used. In the acquisition trial, the rat was placed in
the illuminated compartment in a position its tail directed to the closed door for 2 min to habituate to the apparatus. The guillotine door was opened and time to enter to dark compartment was recorded. When the rat entered to dark compartment completely (four foots in dark compartment), the guillotine door was closed and the rat was delivered an electrical shock of 0.8 mA for 3 sec through the grid floor. After the shock, the rat was immediately placed in home cage. In the retention trial, conducted 24 h after the acquisition trial, the rat was placed in the illuminated compartment and the retention latency to enter into the dark compartment was recorded until 180 s had elapsed. The latency was accepted for 180 s, if the rat did not enter the dark compartment for 180 s. Data are presented as retention latency mean ± SEM (n=8).
*Differs significantly of control (PO.05).
Thus, sublingual administration of composition comprising succinic acid is much more effective than intraperitoneal administration. Sublingually treated rats demonstrate significant improvement in learning and memory as compared to control rats, whereas intraperitoneally treated rats do not.
Claims
1. A sublingual or buccal pharmaceutical composition for preventing and/or treating Alzheimer's disease comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
2. The composition of Claim I3 wherein the pharmaceutically acceptable salt of succinic acid is a compound of Formula (I)
CH3
\ + CH2 COOH
CH, — N — CH2 — CH2 — OH • I _ Formula (1)
6 / CH2 COO
CH3 or a pharmaceutically acceptable salt thereof.
3. The composition of Claim 2, wherein the compound of Formula (I) is the compound of Formula (II)
Formula (II) 
4. A method of treating Alzheimer's disease comprising sublingually or buccally administering to a mammal in need thereof a pharmaceutical composition comprising a therapeutically effective amount of succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA201000118A EA201000118A1 (en) | 2007-08-15 | 2007-08-15 | SUBLINGUAL OR TRANSBUCKCAL COMPOSITIONS CONTAINING AMBER ACID AND INTENDED FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
| PCT/RU2007/000446 WO2009025571A1 (en) | 2007-08-15 | 2007-08-15 | Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2007/000446 WO2009025571A1 (en) | 2007-08-15 | 2007-08-15 | Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009025571A1 true WO2009025571A1 (en) | 2009-02-26 |
Family
ID=39429279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU2007/000446 WO2009025571A1 (en) | 2007-08-15 | 2007-08-15 | Sublingual or buccal pharmaceutical compositions comprising succinic acid for treating alzheimer's disease |
Country Status (2)
| Country | Link |
|---|---|
| EA (1) | EA201000118A1 (en) |
| WO (1) | WO2009025571A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124061A (en) * | 1991-04-01 | 1992-06-23 | Geary Sr Robert J | Systemic plant cryoprotection with choline salts |
| WO2003026686A1 (en) * | 2001-09-27 | 2003-04-03 | Pomytkin Igor A | Potentiating the therapeutic effects of interferons |
| WO2005000340A1 (en) * | 2003-06-27 | 2005-01-06 | Pomytkin Igor A | Synergistic compositions comprising erythropoietin and succinic acid (salt) |
| US20060002989A1 (en) * | 2004-06-10 | 2006-01-05 | Ahmed Salah U | Formulations of sumatriptan for absorption across biological membranes, and methods of making and using the same |
| US20060199862A1 (en) * | 2005-03-04 | 2006-09-07 | Pomytkin Igor A | Method for enhancing cognitive function |
-
2007
- 2007-08-15 EA EA201000118A patent/EA201000118A1/en unknown
- 2007-08-15 WO PCT/RU2007/000446 patent/WO2009025571A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124061A (en) * | 1991-04-01 | 1992-06-23 | Geary Sr Robert J | Systemic plant cryoprotection with choline salts |
| WO2003026686A1 (en) * | 2001-09-27 | 2003-04-03 | Pomytkin Igor A | Potentiating the therapeutic effects of interferons |
| WO2005000340A1 (en) * | 2003-06-27 | 2005-01-06 | Pomytkin Igor A | Synergistic compositions comprising erythropoietin and succinic acid (salt) |
| US20060002989A1 (en) * | 2004-06-10 | 2006-01-05 | Ahmed Salah U | Formulations of sumatriptan for absorption across biological membranes, and methods of making and using the same |
| US20060199862A1 (en) * | 2005-03-04 | 2006-09-07 | Pomytkin Igor A | Method for enhancing cognitive function |
Also Published As
| Publication number | Publication date |
|---|---|
| EA201000118A1 (en) | 2010-06-30 |
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