WO2014007775A1 - A novel formulation having fast dissolution - Google Patents
A novel formulation having fast dissolution Download PDFInfo
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- WO2014007775A1 WO2014007775A1 PCT/TR2013/000203 TR2013000203W WO2014007775A1 WO 2014007775 A1 WO2014007775 A1 WO 2014007775A1 TR 2013000203 W TR2013000203 W TR 2013000203W WO 2014007775 A1 WO2014007775 A1 WO 2014007775A1
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61K31/13—Amines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
Definitions
- the present invention is related to pharmaceutical formulations comprising tricyclo[3.3.1.1 3 ' 7 ]decan-l-amine,3,5-dimethyl hydrochloride that shall be used in the treatment of Alzheimer's disease and dementia. Said formulations are characterized in being in effervescent form.
- Memantine which has the chemical name tricyclo[3.3.1.1 ' ]decan-l amine, 3,5-dimethyl hydrochloride (Formula I), is a non-competitive N-methyl-D-aspartate(NMDA) receptor antagonist neuroprotective agent and it was first disclosed in the application numbered US3391142. In said document, it was indicated that memantine is effective in use for the treatment of Alzheimer's disease and dementia.
- Memantine is marketed in 10 mg and 20 mg tablet and 5 mg and 10 mg oral drop and oral solution forms.
- the tablet dosage forms in the present invention are not preferred due to swallowing problems and low bioavailability.
- Solid dosage forms of this drug (for example tablet) used in the treatment of Alzheimer's disease particularly in patients over 50 years of age are disadvantageous for geriatric patients and people with swallowing difficulties.
- dosage forms such as oral drop and oral solution on the market complicate the adaptation of the patients to the treatment due to the reasons such as their possibility of uncontrolled dose intake, high production costs, bad taste and the problems they pose during use and carrying.
- suspension forms have higher bioavailability than solid dosage forms, they are more inconvenient compared to solid dosage forms when evaluated in terms of stability and shelf life.
- another dosage form provided as an alternative to these dosage forms is fast- dissolving orodispersible dosage forms.
- the patent application WO2009 004440 discloses dosage forms which comprise memantine and dissolve in mouth in less than 60 seconds.
- this dosage form disclosed in the application is not an applicable alternative for an active agent known for its bitter taste like memantine.
- Orodispersible dosage form is not preferred most of the time due to the metallic taste remains in the mouth following the intake of this dosage form.
- the present invention is related to pharmaceutical formulations comprising memantine that shall be used in the treatment of Alzheimer's disease and dementia and are characterized in being in effervescent form.
- formulations of the present invention are in the form of effervescent powder, tablet and granule having the advantages of both tablet and suspension forms; and they eliminate the problems, faced with these dosage forms.
- Effervescent dosage forms are advantageous particularly for patients with dysphagia.
- the pharmaceutical formulations of the present invention comprise effervescent oral dosage forms comprising memantine and at least one pharmaceutically acceptable excipient in addition to the effervescent couple or comprising only memantine and the effervescent couple.
- the present invention is related to effervescent oral dosage forms comprising memantine as the active agent, effervescent couple and at least one pharmaceutically acceptable excipient.
- Memantine in the formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in amorphous or crystalline form or a combination thereof in terms of polymorphic structure.
- Memantine in the formulations of the present invention is preferably in memantine hydrochloride form.
- a characteristic of the effervescent formulations of the present invention is that the amount of memantine in the formulation is in the range of 0.1% and 90%, preferably in the range of 0.1% and 85%, more preferably in the range of 0.1% and 80% by weight.
- the effervescent formulations of the present invention comprise memantine in the range of 1 and 50 mg, preferably in the range of 1 and 45 mg, more preferably in the range of 1 and 40 mg per dosage form.
- effervescent dosage forms of the present invention Another characteristic of the effervescent dosage forms of the present invention is that said formulations are in effervescent powder, tablet and granule form.
- a characteristic feature of the effervescent formulations of the present invention is that said formulations are in effervescent powder, tablet or granule form
- the amount of memantine that said formulations comprise is in the range of 0.1% and
- the inventors have discovered that the highest solubility is obtained when the average particle size of memantine is -smaller than - -50-- ⁇ in the effervescent formulations comprising memantine.
- formulations comprise memantine having an average particle size in the range of 1 ⁇ and 45 ⁇ as the active agent.
- the amount of memantine that said formulations comprise is in the range of 0.1% and 90%, preferably in the range of 0.1% and 85%, more preferably in the range of 0.1% and 80% by weight.
- the average particle size of memantine comprised in said formulations is smaller than 50 ⁇ , preferably in the range of 1 ⁇ and 50 ⁇ , more preferably in the range of 1 ⁇ and 45 ⁇ .
- the phrase "average particle size" used hereby refers to volumetric average particle diameter and is shown as d 50 in short.
- d 5 o means that volumetric half of a substance has a particle size above the value indicated by d 50 and the other half has a particle size below the value indicated by d 0 .
- D 5 o value can be measured with one of the common devices, e.g. a device measuring particle distribution via laser diffraction (e.g. Malvern Mastersizer etc.).
- a device measuring particle distribution via laser diffraction e.g. Malvern Mastersizer etc.
- effervescent formulations of the present invention comprise at least one pharmaceutically acceptable excipient in addition to memantine and the effervescent couple.
- excipients that can be comprised in the effervescent formulations of the invention can be selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, ' diluents, glidants, wetting agents, oiling agents, pH regulating agents, an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and at least one effervescent base, gel forming agents, flavoring agents, sweeteners, taste regulating agents. emulsifying agents, antifoaming agents, antioxidants, protective agents, solvents or solvent mixtures, coloring agents and complexing agents or combinations thereof.
- excipients that can be used in the effervescent formulations of the present invention comprising memantine are selected from a group comprising binders, disintegrants, filling agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and at least one effervescent base, flavoring agents, sweeteners, solvents or solvent mixtures or combinations thereof.
- the disintegrant that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising carboxyme hyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
- the binder that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch.
- the ratio of at least one pharmaceutically acceptable effervescent acid and the effervescent base used in the effervescent formulations of the present invention comprising memantine is in the range of 0.1 and 10 by weight.
- the surfactant that can be used in the effervescent formulations :of the invention comprising memantine can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
- the stabilizing agents that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
- the drinkable taste which would provide adaptation of the patients in the effervescent formulations comprising memantine -as the active agent has been provided by use of at least one pharmaceutically acceptable sweetener and at least one flavoring agent and adjusting the ratio of the sweetener and the flavoring agent to each other in the range of 3: 1 and 1 :3, preferably in the range of 2.5.T and 1 :2.5, more preferably in the range of 2:1 and 1 :2.
- the effervescent formulations of the present invention comprising memantine can optionally comprise one or more active agents in addition to memantine.
- active agents can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, anti dementia (for instance ginkgo), antineoplastic, antiarrhythmic, antiadrenergic, psychoanaleptic (for instance idebenone), antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidine
- the pharmaceutical formulations of the present invention comprising memantine and a second active agent in addition can be prepared in any of the dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder; in the case that the two active agents are in different formulations but in the same dosage form, said formulations can be prepared in such forms as layered tablet, capsule; when the two active agents are in different formulations and in different dosage forms, the formulations can be prepared in the form of a treatment package where ceftibuten can be in any of the dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder, and the second active agent can be in any of the solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enteric coated tablet, dry powder, granule, capsule, extended- release tablet, modified-release tablet, delayed-
- any production method present in the prior art can be used for formulating the formulations of the invention; wet granulation, dry granulation and dry blending methods are among these production methods.
- the effervescent formulations of the invention- can be produced in accordance with any of the production methods given below; 1. Mixing the active agent memantine and the second active agent, if present, homogeneously with at least one pharmaceutically acceptable excipient and, if necessary, adding at least one of the excipients stated above; treating the mixture- optionally with at least one pharmaceutically acceptable lubricant; giving a desired shape to the obtained mixture,
- the effervescent formulations of the invention are preferably " in the form of tablet. "
- the pharmaceutical formulations of the present invention are used in the prophylaxis and the treatment of Alzheimer's disease and dementia.
- Example I Effervescent formulations comprising memantine
- the effervescent formulation given above is produced according to. any of the methods in the . prior art and explained in the description part in -detail and presented after preparing it in a desired dosage form.
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Abstract
The present invention is related to pharmaceutical formulations comprising tricyclo[3.3.1.13,7 ]decan-1-amine,3,5-dimethyl hydrochloride that shall be used in the treatment of Alzheimer's disease and dementia. Said formulations are characterized in being in effervescent form.
Description
A NOVEL FORMULATION HAVING FAST DISSOLUTION
The present invention is related to pharmaceutical formulations comprising tricyclo[3.3.1.13'7]decan-l-amine,3,5-dimethyl hydrochloride that shall be used in the treatment of Alzheimer's disease and dementia. Said formulations are characterized in being in effervescent form.
• 3 7
Memantine, which has the chemical name tricyclo[3.3.1.1 ' ]decan-l amine, 3,5-dimethyl hydrochloride (Formula I), is a non-competitive N-methyl-D-aspartate(NMDA) receptor antagonist neuroprotective agent and it was first disclosed in the application numbered US3391142. In said document, it was indicated that memantine is effective in use for the treatment of Alzheimer's disease and dementia.
Formula I: Memantine
Memantine is marketed in 10 mg and 20 mg tablet and 5 mg and 10 mg oral drop and oral solution forms. However, the tablet dosage forms in the present invention are not preferred due to swallowing problems and low bioavailability. Solid dosage forms of this drug (for example tablet) used in the treatment of Alzheimer's disease particularly in patients over 50 years of age are disadvantageous for geriatric patients and people with swallowing difficulties.
On the other hand, dosage forms such as oral drop and oral solution on the market complicate the adaptation of the patients to the treatment due to the reasons such as their possibility of uncontrolled dose intake, high production costs, bad taste and the problems they pose during use and carrying. Although suspension forms have higher bioavailability than solid dosage forms, they are more inconvenient compared to solid dosage forms when evaluated in terms of stability and shelf life.
In the prior art, another dosage form provided as an alternative to these dosage forms is fast- dissolving orodispersible dosage forms. The patent application WO2009 004440 discloses dosage forms which comprise memantine and dissolve in mouth in less than 60 seconds. However, this dosage form disclosed in the application is not an applicable alternative for an active agent known for its bitter taste like memantine. Orodispersible dosage form is not preferred most of the time due to the metallic taste remains in the mouth following the intake of this dosage form.
When the prior art is considered, it has been seen that there is need for new dosage forms comprising memantine which have fast dissolution and action; are patient-friendly; suitable for patients experiencing swallowing difficulties; have pleasant taste; have long shelf life.
The inventors have surprisingly discovered that the problems existing in the prior art can be solved with effervescent formulations prepared according to the present invention.
Description of the Invention
The present invention is related to pharmaceutical formulations comprising memantine that shall be used in the treatment of Alzheimer's disease and dementia and are characterized in being in effervescent form.
The characteristic of the formulations of the present invention is that they are in the form of effervescent powder, tablet and granule having the advantages of both tablet and suspension forms; and they eliminate the problems, faced with these dosage forms. Effervescent dosage forms are advantageous particularly for patients with dysphagia.
The pharmaceutical formulations of the present invention comprise effervescent oral dosage forms comprising memantine and at least one pharmaceutically acceptable excipient in addition to the effervescent couple or comprising only memantine and the effervescent couple. In an aspect, the present invention is related to effervescent oral dosage forms comprising memantine as the active agent, effervescent couple and at least one pharmaceutically acceptable excipient.
Memantine in the formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or
combinations thereof in terms of chemical structure; in amorphous or crystalline form or a combination thereof in terms of polymorphic structure.
Memantine in the formulations of the present invention is preferably in memantine hydrochloride form. A characteristic of the effervescent formulations of the present invention is that the amount of memantine in the formulation is in the range of 0.1% and 90%, preferably in the range of 0.1% and 85%, more preferably in the range of 0.1% and 80% by weight.
The effervescent formulations of the present invention comprise memantine in the range of 1 and 50 mg, preferably in the range of 1 and 45 mg, more preferably in the range of 1 and 40 mg per dosage form.
Another characteristic of the effervescent dosage forms of the present invention is that said formulations are in effervescent powder, tablet and granule form.
A characteristic feature of the effervescent formulations of the present invention is that said formulations are in effervescent powder, tablet or granule form
- the amount of memantine that said formulations comprise is in the range of 0.1% and
90%, preferably in the range of 0.1% and 85%, more preferably in the range of 0.1% and 80% by weight.
The effervescent formulations of the present invention are used after dissolved preferably in a glass of water or another suitable liquid. At this point, it is obvious that water solubility of the formulation is a very significant parameter in order to provide an efficient treatment and thus bioavailability.
The inventors have discovered that the highest solubility is obtained when the average particle size of memantine is -smaller than - -50-- μηι in the effervescent formulations comprising memantine.
According to this, a characteristic of the effervescent formulations of the present invention is that said formulations comprise memantine having an average, particle size smaller than 50 μπι as the active agent.
In another aspect, another characteristic feature of the present invention is that said formulations comprise memantine having an average particle size in the range of 1 μη and 50 μηι as the active agent.
In another aspect, another characteristic feature of the present invention is that said formulations comprise memantine having an average particle size in the range of 1 μιη and 45 μηι as the active agent.
A characteristic of the effervescent formulations of the present invention is that
- said formulations are in effervescent powder, tablet or granule form
- the amount of memantine that said formulations comprise is in the range of 0.1% and 90%, preferably in the range of 0.1% and 85%, more preferably in the range of 0.1% and 80% by weight.
the average particle size of memantine comprised in said formulations is smaller than 50 μπι, preferably in the range of 1 μιη and 50 μηι, more preferably in the range of 1 μπτ and 45 μηι. The phrase "average particle size" used hereby refers to volumetric average particle diameter and is shown as d50 in short. In this respect, d5o means that volumetric half of a substance has a particle size above the value indicated by d50 and the other half has a particle size below the value indicated by d 0.
D5o value can be measured with one of the common devices, e.g. a device measuring particle distribution via laser diffraction (e.g. Malvern Mastersizer etc.).
Another characteristic feature of the effervescent formulations of the present invention is that said formulations comprise at least one pharmaceutically acceptable excipient in addition to memantine and the effervescent couple.
The excipients that can be comprised in the effervescent formulations of the invention can be selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, ' diluents, glidants, wetting agents, oiling agents, pH regulating agents, an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and at least one effervescent base, gel forming agents, flavoring agents, sweeteners, taste regulating agents.
emulsifying agents, antifoaming agents, antioxidants, protective agents, solvents or solvent mixtures, coloring agents and complexing agents or combinations thereof.
The excipients that can be used in the effervescent formulations of the present invention comprising memantine are selected from a group comprising binders, disintegrants, filling agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, an effervescent couple comprising at least one pharmaceutically acceptable effervescent acid and at least one effervescent base, flavoring agents, sweeteners, solvents or solvent mixtures or combinations thereof.
The disintegrant that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising carboxyme hyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
The diluent that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium-chloride,. sucrose, talc, xylitol.
The glidant that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc.
The binder that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch.
The effervescent formulations of the invention comprising memantine comprise an effervescent couple which is composed of at least one pharmaceutically acceptable effervescent acid and at least one effervescent base in the range of 10% and 95%, preferably in the range of 15% and 95%, more preferably in the range of 20% and 95% in proportion to total formulation weight.
According to this, "effervescent couple" signifies the combination of at least one effervescent acid and at least one effervescent base. Both or any of these two agents can be as combination of different types in the effervescent couple mixture. For example; an effervescent couple comprising two different effervescent acids and one effervescent base; or two , different effervescent acids and two different effervescent bases can be used.
The ratio of at least one pharmaceutically acceptable effervescent acid and the effervescent base used in the effervescent formulations of the present invention comprising memantine is in the range of 0.1 and 10 by weight.
The effervescent acids that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising organic acids such as citric acid and acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or pharmaceutically acceptable hydrates, anhydrates and the like forms thereof or combinations thereof.
The effervescent bases that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising alkali or alkaline earth metal carbonates or bicarbonates or combinations thereof.
The examples of the effervescent bases preferred in the effervescent formulations of the invention comprising memantine can be potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof. The pH regulating agent that can be used in the effervescent formulations of the invention comprising memantine can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts. :
The surfactant that can be used in the effervescent formulations :of the invention comprising memantine can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
The stabilizing agents that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
The sweetener and/or taste regulating agent that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising acesulfame,
aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
The flavoring agent that can be used in the effervescent formulations of the invention comprising memantine can be selected from flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like.
On the other hand, it is a significant necessity to solve the problems resulting from bitter taste of the active agent. In this respect, the invention explains effervescent formulations having a pleasant taste.
The effervescent formulations of the present invention comprise at least one pharmaceutically acceptable sweetener in the range of 1% and 5%, preferably in the range of 1% and 4.5%, more preferably in the range of 1% and 4% by weight. and. at -least me. pharmaceutically acceptable flavoring agent in the range of 1% and 5%, preferably in the range of 1 % and 4%, more preferably in the range of 1% and 3.5% by weight in order to suppress the bitter taste of the active agent. The ratio of the sweetener and the flavoring agent used in the effervescent formulations of the present invention to each other is in the range of 3: 1 and 1 :3, preferably in the range of 2.5: 1 and 1 :2.5, more preferably in the range of 2: 1 and 1 :2.
In other words, the drinkable taste which would provide adaptation of the patients in the effervescent formulations comprising memantine -as the active agent has been provided by use of at least one pharmaceutically acceptable sweetener and at least one flavoring agent and adjusting the ratio of the sweetener and the flavoring agent to each other in the range of 3: 1 and 1 :3, preferably in the range of 2.5.T and 1 :2.5, more preferably in the range of 2:1 and 1 :2.
The lubricants that can be used in the effervescent formulations of the invention comprising memantine can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, talc, stearic acid, zinc stearate or combinations thereof.
The effervescent formulations of the present invention comprising memantine can optionally comprise one or more active agents in addition to memantine.
These active agents can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, anti dementia (for instance ginkgo), antineoplastic, antiarrhythmic, antiadrenergic, psychoanaleptic (for instance idebenone), antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha- glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B1; vitamin C, vitamin E, vitamin B6> vitamin B2> vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
In the case that the two active agents are in the same formulation, the pharmaceutical formulations of the present invention comprising memantine and a second active agent in addition can be prepared in any of the dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder; in the case that the two active agents are in different formulations but in the same dosage form, said formulations can be prepared in such forms as layered tablet, capsule; when the two active agents are in different formulations and in different dosage forms, the formulations can be prepared in the form of a treatment package where ceftibuten can be in any of the dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder, and the second active agent can be in any of the solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film-coated tablet, enteric coated tablet, dry powder, granule, capsule, extended- release tablet, modified-release tablet, delayed-release tablet. The preparation method for the formulations of the invention comprises the steps of formulating the active agent with an appropriate excipient composition and giving a desired shape to said formulation.
Any production method present in the prior art can be used for formulating the formulations of the invention; wet granulation, dry granulation and dry blending methods are among these production methods.
More specifically, the effervescent formulations of the invention- can be produced in accordance with any of the production methods given below;
1. Mixing the active agent memantine and the second active agent, if present, homogeneously with at least one pharmaceutically acceptable excipient and, if necessary, adding at least one of the excipients stated above; treating the mixture- optionally with at least one pharmaceutically acceptable lubricant; giving a desired shape to the obtained mixture,
2. Wet-granulating the mixture obtained through mixing the active agent memantine and the second active agent, if available, homogeneously with at least one pharmaceutically acceptable excipient with the granulation solution optionally comprising at least one excipient; drying the obtained granules; adding at least one pharmaceutically acceptable excipient in to the dry granules and giving a desired shape to the obtained granules,
3. Wet-granulating at least one of the excipients stated above with the granulation solution optionally comprising at least one excipient; drying the obtained granules; adding memantine, the second active agent, if available, and optionally at least one excipient to the dry granules and mixing them together; giving a desired shape to the obtained granules,
4. Dry-granulating the mixture obtained through adding the active agent memantine, the second active agent, if available, and at least one of the excipients stated above and giving a desired shape to the obtained granules. To obtain a desired dosage form after the formulations of the invention are prepared according to any one of the methods above, the formulations
• can be compressed into tablets,
• can be filled into sachets.
The effervescent formulations of the invention are preferably "in the form of tablet. " The pharmaceutical formulations of the present invention are used in the prophylaxis and the treatment of Alzheimer's disease and dementia.
The examples below are given to explain the pharmaceutical compositions of the invention and the preparation methods thereof; the scope of the invention cannot be restricted to these examples.
EXAMPLES
Example I: Effervescent formulations comprising memantine
The effervescent formulation given above is produced according to. any of the methods in the . prior art and explained in the description part in -detail and presented after preparing it in a desired dosage form.
Claims
1. A pharmaceutical formulation comprising memantine as the active agent, characterized in that said formulation is in effervescent form.
2. The formulation according to claim 1, characterized in that the amount of memantine in said formulation is in the range of 0.1% and 90% by weight.
3. The formulation according to claims 1-2, characterized in that the amount of memantine in said formulation is in the range of 0.1% and 85% by weight.
4. The formulation according to claims 1-3, characterized in that the amount of memantine in said formulation is in the range of 0.1% and 80% by weight.
5. The formulation according to claim 1, characterized in that said formulation comprises memantine in the range of 1 and 50 mg per unit dosage form.
6. The formulation according to claim 5, characterized in that said formulation comprises memantine in the range of 1 and 45 mg per unit dosage form.
7. The formulation according to claims 5-6, characterized in that said formulation comprises memantine in the range of 1 and 40 mg per unit dosage form.
8. The formulation according to claim 1, characterized in that the active agent is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof; in the form of amorphous or crystalline form or a combination thereof in terms of polymorphic structure.
9. The formulation according to claim 8, characterized- in that the active agent is in the form of memantine hydrochloride salt.
10. The formulation according to any preceding claims, characterized in that said formulation is in effervescent powder, tablet and granule form.
1 1. The formulation according to any preceding claims, characterized in that the average particle size of the active agent in said formulations is smaller than 50 μηι.
12. The formulation according to claim 1 1 , characterized in that the average particle size of the active agent in said formulations is in the range of 1 μπι and 50 μπι.
13. The formulation according to claims 1 1-12, characterized in that the average particle size of the active agent in said formulations is in the range of 1 μπι and 45 μηι.
14. The formulation according to any preceding claims, characterized in that said formulation comprises at least one pharmaceutically acceptable excipient.
15. The formulation according to claim 14, characterized in that the excipients that can be comprised in said formulation are selected from a group comprising binders,
disintegrants, viscosity enhancing agents, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulating agents, an effervescent - couple comprising _ at least , one pharmaceutically acceptable effervescent acid and at least one effervescent base, gel forming agents, flavoring agents, sweeteners, taste regulating agents, emulsifying agents, antifoaming agents, antioxidants, protective agents,, solvents -or - solvent mixtures, coloring agents and complexing agents or combinations thereof.
16. The formulation according to claim 15, characterized in that the excipients that can be comprised in said formulation are selected from a group comprising binders, disintegrants, filling agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, effervescent acids, effervescent bases, flavoring agents, sweeteners, solvents or solvent mixtures or combinations thereof.
17. The formulation according to claims 14-16, characterized in that said formulation comprises an effervescent couple composed of at least one pharmaceutically acceptable effervescent acid and at least one effervescent base in the range of 10% and 95% in proportion to total weight of the formulation.
18. The formulation according to claims 14-17, characterized in that said formulation comprises an effervescent couple composed of at least one pharmaceutically acceptable effervescent acid and at least one effervescent base in the range of 15% and 95% in proportion to total weight of the formulation.
19. The formulation according to claims 14-18, characterized in that said formulation comprises at least one pharmaceutically acceptable effervescent acid and at least one effervescent base in the range of 20% and 95% in proportion to total weight of the formulation.
20. The formulation according to claims 14-19, characterized in that the ratio of at least one pharmaceutically effervescent acid and at least one effervescent base to each other is in the range of 0.1 and 10.
21. The formulation according to claims 14-20, characterized in that the effervescent acids that can be used in said formulations are selected from a group comprising organic acids such as citric acid_and acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or pharmaceutically acceptable hydrates, anhydrates and the' like forms thereof or combinations thereof.
22. The formulation according to claims 14-20, characterized in that the effervescent bases that can be used in said formulation are selected from a group comprising alkali or alkaline earth metal carbonates or bicarbonates or combinations thereof.
23. The formulation according to claim 22, characterized in that the effervescent bases that can be used in said formulation are selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof.
24. The formulation according to claim 16, characterized in that said formulation comprises at least one pharmaceutically acceptable sweetener in the range of 1% and 5% in proportion to total weight of the formulation.
25. The formulation according to claim 24, characterized in that said formulation comprises at least one pharmaceutically acceptable sweetener in the range of 1% and 4.5% in proportion to total weight of the formulation.
26. The formulation according to claims 24-25, characterized in that said formulation comprises at least one pharmaceutically acceptable sweetener in the range of 1% and 4% in proportion to total weight of the formulation.
27. The formulation according to claim 16, characterized in that said formulation comprises at least one pharmaceutically acceptable flavoring agent in the range of 1% and 5% in proportion to total weight of the formulation.
28. The formulation according to claim 27, characterized in that said formulation comprises at least one pharmaceutically acceptable flavoring agent in the range of 1% and 4% in proportion to total weight of the formulation.
29. The formulation according to claims 26-27, characterized in that said formulation comprises at least one pharmaceutically acceptable flavoring agent in the range of 1% and 3.5% in proportion to total weight of the formulation.
30. The formulation according to claims 24-29, characterized in that the ratio of at least one pharmaceutically acceptable sweetener and at least one flavoring agent comprised in said formulation to each other is in the range of 3: 1 and 1 :3.
31. The formulation according to claim 30, characterized in that the ratio of at least one pharmaceutically acceptable sweetener and at least one flavoring agent comprised in said formulation to each other is in the range of 2.5: 1 and 1 :2.5.
32. The formulation according to claims 30-31 , characterized in that the ratio of at least one pharmaceutically acceptable sweetener and at least one flavoring agent comprised in said formulation to each other is in the range of 2: 1 and 1 :2.
33. The effervescent formulation comprising memantine as the active agent according to any preceding claims, wherein said formulation comprises at least a second active agent in addition to memantine selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, anti dementia (for instance ginkgo), antineoplastic, antiarrhythmic, antiadrenergic, psychoanaleptic (for instance idebenone), antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B[; vitamin C, vitamin E, vitamin B6j vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
34. A method for production of the formulation according to any preceding claims, characterized in that said method comprises the steps of wet granulation, dry granulation, dry blending or combinations thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201207631 | 2012-07-02 | ||
| TR2012/07631 | 2012-07-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014007775A1 true WO2014007775A1 (en) | 2014-01-09 |
Family
ID=49170842
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2013/000203 WO2014007775A1 (en) | 2012-07-02 | 2013-07-02 | A novel formulation having fast dissolution |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2014007775A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9750705B2 (en) | 2012-08-31 | 2017-09-05 | The Regents Of The University Of California | Agents useful for treating obesity, diabetes and related disorders |
| US10420718B2 (en) | 2014-07-02 | 2019-09-24 | University Of Bradford | Effervescent compositions containing co-crystals of the acid part |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3391142A (en) | 1966-02-09 | 1968-07-02 | Lilly Co Eli | Adamantyl secondary amines |
| CN1742711A (en) * | 2005-09-23 | 2006-03-08 | 北京阜康仁生物制药科技有限公司 | Menantine hydrochloride effervescent tablet and preparing method thereof |
| WO2007113856A2 (en) * | 2006-03-31 | 2007-10-11 | Rubicon Research Private Limited | Directly compressible composite for orally disintegrating tablets |
| WO2009004440A2 (en) | 2007-06-29 | 2009-01-08 | Orchid Chemicals & Pharmaceuticals Limited | Quick dissolve compositions of memantine hydrochloride |
| WO2012026902A1 (en) * | 2010-08-25 | 2012-03-01 | Mahmut Bilgic | Combinations comprising donepezil, memantine and gingko biloba extract |
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2013
- 2013-07-02 WO PCT/TR2013/000203 patent/WO2014007775A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3391142A (en) | 1966-02-09 | 1968-07-02 | Lilly Co Eli | Adamantyl secondary amines |
| CN1742711A (en) * | 2005-09-23 | 2006-03-08 | 北京阜康仁生物制药科技有限公司 | Menantine hydrochloride effervescent tablet and preparing method thereof |
| WO2007113856A2 (en) * | 2006-03-31 | 2007-10-11 | Rubicon Research Private Limited | Directly compressible composite for orally disintegrating tablets |
| WO2009004440A2 (en) | 2007-06-29 | 2009-01-08 | Orchid Chemicals & Pharmaceuticals Limited | Quick dissolve compositions of memantine hydrochloride |
| WO2012026902A1 (en) * | 2010-08-25 | 2012-03-01 | Mahmut Bilgic | Combinations comprising donepezil, memantine and gingko biloba extract |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9750705B2 (en) | 2012-08-31 | 2017-09-05 | The Regents Of The University Of California | Agents useful for treating obesity, diabetes and related disorders |
| US10420718B2 (en) | 2014-07-02 | 2019-09-24 | University Of Bradford | Effervescent compositions containing co-crystals of the acid part |
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