CN1827585A - Non-crystalline memantine hydrochloride - Google Patents
Non-crystalline memantine hydrochloride Download PDFInfo
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- CN1827585A CN1827585A CN 200510054603 CN200510054603A CN1827585A CN 1827585 A CN1827585 A CN 1827585A CN 200510054603 CN200510054603 CN 200510054603 CN 200510054603 A CN200510054603 A CN 200510054603A CN 1827585 A CN1827585 A CN 1827585A
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Abstract
The invention relates to a new type of 1-amido-3, 5-dimethyl tricyclic [3, 3, 1, 13, 7] decane hydrochlorate without crystalline phase, a preparing method and its medicinal agent. The material gained by this method is a useful medicine for curing dementia diseases such as Alzheimer's disease and diseases in relation to receptor antagonist of N- methyl-D- aspartate.
Description
Technical field the present invention relates to the memantineHCl of novel noncrystal.The invention still further relates to the memantineHCl of this noncrystal the preparation method, contain the pharmaceutical preparation of this material and in curing the disease as the purposes of medicine.
Technical background memantineHCl (memantine HCl), its chemical name is a 1-amino-3, two methyl three rings [3,3,1,1 of 5-
3,7] decane hydrochloride or 1-amino-3, the two methyl Buddha's warrior attendant hydrochlorides of 5-.Its chemical structure is as follows:
MemantineHCl is treatment senile dementia (Alzheimer's disease, Alzheimer disease, AD) medicine of first novel type of FDA approved.It is a kind of antagonist of noncompetitive N-methyl-D-aspartate (NMDA) acceptor of tool medium tenacity affinity, can significantly improve the senile dementia patient's relevant with nmda receptor memory.Different with first-generation methods of treatment is: memantineHCl demonstrates the effect of its neuroprotective probably at treatment senile dementia one disease, and this sick speed that worsens that can slow down.
Ripple literary composition (Bormann) etc. discloses memantineHCl in United States Patent (USP) (US 5,061,703) be a kind of useful prevention and treatment senile dementia such as Alzheimer's disease, the medicine of diseases such as vascular dementia and the two Combination dementia.The method of the nerve degeneration disease that a kind of nmda receptor that alleviates non local ischemic feature causes is also further disclosed in the United States Patent (USP) (US 5,061,703).
The 6th phase the 6th of pharmaceutical chemistry magazine (Journal of Medicinal Chemistry) volume 1963, has been described preparation 1-amino-3 for 760 to 763 pages, two methyl three rings [3,3,1,1 of 5-
3,7] method of decane hydrochloride (memantineHCl).Method.United States Patent (USP) discloses a kind of method for preparing memantineHCl in (US 4,122,193), and it is by heating 1-chloro-3, and two methyl Buddha's warrior attendants of 5-and urea to 220 (Celsius) degree are made.Heating is normally carried out in a kind of container of sealing, and this container places the oil-bath by the thermostatted regulation and control.After the cooling, reaction product is by the shape of claying into power, water and make paste.The pH value of water is by being adjusted to the 3-5 scope with the mode that drips with dense hydrochloride.Water after the acidifying is regulated the pH value to the 12-13 scope by adding sodium hydroxide solution then with ether extraction twice, water.After the stirring, ether extraction four times of the water of alkalescence.Be merged all extracted with diethyl ether solution, and use the potassium hydroxide drying.The hydrogenchloride hydrogen body of crossing with drying feeds above-mentioned solution and can obtain memantineHCl.Prepared product is the memantineHCl of crystal kenel in this piece file, be heated to always 300 degrees centigrade (℃) it just can dissolve.All above-mentioned files all do not disclose the memantineHCl of noncrystal (or amorphous state).
Chinese patent (CN1400205 A and CN1335299 A) discloses a kind of improved method for preparing memantineHCl.This method is 1-bromo-3, the two methyl Buddha's warrior attendants of 5-and urea place a kind of solvent that is polyol (as 1,2-pair of hydroxyl ethanes, HOCH
2CH
2OH) in, then come the processing reaction thing, use hcl acidifying then with sodium hydroxide solution.There is not memantineHCl open or the description noncrystal in these files yet.
The molten point of the crystalline of memantineHCl surpasses 300 degree (referring to U.S. Pat 4,122,193) Celsius.Its derivative, for example (its molten point is 360 degree Celsius to the amantadine hydrochloride crystal, referring to Merck Index 13
Th, 389,65 pages) also have a very high lattice energy.The crystal of this class material has very high but is not needed high melting-point, and this high melting-point material but has very important detrimentally affect to its bioavailability when being used as medicine.
Instructed the noncrystal of many medicines to show different dissolution rate features in many files,, also represented different bioavailability [Konne T., Chem Pharm Bull, 38,2003 (1990)] in some cases with the crystal kenel.To some treatment illness, perhaps a kind of bioavailability is better than another kind of bioavailability.The bioavailability that the cephalofruxin fat bioavailability of noncrystal is higher than its crystal kenel is exactly the illustration of classics.
We find that now the memantineHCl of noncrystal can prepare.
Description of drawings Fig. 1: the X-ray powder diffraction of the memantineHCl of noncrystal
Summary of the invention as previously mentioned, memantineHCl is a kind of antagonist of N-methyl-D-aspartate (NMDA) acceptor of moderate avidity intensity, is a prevention and the treatment moderate medicine to serious senile dementia.
On the one hand, the invention provides the 1-amino-3 of novel noncrystal, two methyl three rings [3,3,1,1 of 5-
3,7] decane hydrochloride (memantineHCl).
On the other hand, the present invention further provides a kind of 1-amino-3 for preparing noncrystal, two methyl three rings [3,3,1,1 of 5-
3,7] preparation method of decane hydrochloride (memantineHCl).
Noncrystal among the present invention is meant a kind of solid that does not have the crystal order.The memantineHCl of preferred in the present invention noncrystal contains the memantineHCl that is less than 10 (10%) crystalline form, most preferably is the memantineHCl that is substantially devoid of crystalline form.The memantineHCl that is substantially devoid of crystalline form is meant the memantineHCl that can't detect crystalline form with X-ray powder diffraction method.
On the other hand, the invention provides a kind of two kinds of methods that prepare the memantineHCl of noncrystal.They are: lyophilization and distillation under vacuum.The initial feed that these two kinds of methods are used can be a memantineHCl pure or thick, that make with any method.The described in front patent of method for preparing these initial feed is as having description in the United States Patent (USP) (US4,122,193).The initial feed of using also can be memantineHCl, water or solvate or mixture crystalline form and memantineHCl noncrystal of crystalline form.This mixture is to prepare with above-mentioned any method.
On the one hand, the invention provides a kind of memantineHCl for preparing noncrystal with the vacuum freezedrying method.Step comprises: earlier memantineHCl is dissolved in (the first step) in the solvent, this solution of vacuum freezedrying removes desolvate (second step) then, thereby obtains the memantineHCl of noncrystal.
The vacuum freezedrying of the first step prepares the method for the memantineHCl of noncrystal, pays the utmost attention to be dissolved in the aqueous solution, more preferably considers to be dissolved in the mixed solvent of water and alcoholic solvent, and override considers to be dissolved in a kind of solution of formation in the water.
Special one what carry is that memantineHCl easily is dissolved in the water, and can at room temperature allow memantineHCl all dissolve, and obtains 50 milligrams every milliliter or higher concentration.So the preferential working concentration of the present invention is denseer solution, for example 50 milligrams every milliliter solution relatively.
In second step, also be that the method for a preferred step vacuum freezedrying is: Memantine hydrochloride solution obtains a kind of solid matter by vacuum freezedrying, and this solid-state material of gained is a noncrystal.In the present invention, the vacuum freezedrying step has main two steps: that is exactly freezing and vacuum-drying.
In the first step vacuum freezedrying, the temperature of solution is reduced to and makes all solution all freezing, normally temperature is reduced to negative 50 degree Celsius or prepares the refrigerated mixture to get off.This refrigerative method can make solvent or solute be located away from the solid-state phase material.Common this phase separation can allow solute be in a kind of no crystalline state, but also might produce xln or microcrystal or their mixture.In a preferred embodiment of the present invention, process of cooling is very fast, and solute formation crystalline process will be suppressed like this, thereby produces the material that has only noncrystal.More preferably scheme is that solution cools off with liquid nitrogen, simultaneously the container that contains solution is constantly rotated with the acceleration cooling, and allows them form a frozen coating at container inner wall.In case solution is freezing fully,, so just might allow solvent from the refrigerated mixture, volatilize away by the mode of distillation at this moment as long as slowly heat to the material in the container.
The exsiccant step is preferential selects to come in a vacuum dry, just can not dissolved during the refrigerated solvent evaporation like this.The heat energy that is applied is transformed into the solvent of evaporation from the refrigerated solvent, and the solvent of evaporation moves by the refrigerated mixture and further enters in the vacuum beyond the frozen mixture.The solvent of evaporation becomes solution on the refrigerated surface then and reassembles, and becomes solution then in condensation.The temperature that the temperature of condensation remains on frozen mixture drives the exsiccant process to get off.
When solvent is water, the typical vacuum freezedrying condition of memantineHCl of preparation noncrystal comprises that the temperature of frozen mixture spends zero degree from Celsius negative 50, this temperature is before vacuum application, vacuum tightness is preferentially selected 0.01 mmhg or lower vacuum tightness normally at 0.05 mmhg or lower.In the drying step, the temperature of frozen mixture is spent between 20 degree for negative 50.Under these conditions and the situation with standard equipment, what of the character of solute and solvent and its amount the vacuum-drying time depend on.For example, the sample dissolution of 50 gram memantineHCls in water solvent the time, normally 24 to 96 hours vacuum-drying time.
The present invention further provides a kind of method for preparing the memantineHCl of novel noncrystal with distillation method.The method for preparing the memantineHCl of this noncrystal may further comprise the steps.The memantineHCl of mixture thick or pure crystal kenel, water or solvate or crystal type and noncrystal is dissolved in the solvent, under reduced pressure distills the memantineHCl that the evaporative removal solvent obtains noncrystal.
According to a kind of preferred realization preparation method of the present invention, can operate according to following steps: starting raw material is dissolved in adds in the alcoholic solvent of pining for that contains 1 to 4 carbon atom, preferably be heated to the boiling point of solvent, under decompression state, evaporate all solvents then, at last dry gained solid matter under heating (40-60 degree centigrade) state in the vacuum with distillation method.
The first step of distillation method is usually the memantineHCl of mixture thick or pure crystal kenel or crystal type and noncrystal to be dissolved in to add the alcoholic solvent of pining for, and preferably contains the alcoholic solvent of 1 to 4 carbon atom, most preferably in methyl alcohol or the ethanol.MemantineHCl is easily dissolving in methyl alcohol or ethanol, at room temperature just can make denseer complete clear soln.
It is to be noted that especially memantineHCl easily is dissolved in the methyl alcohol, the solution that at room temperature just can to make complete clarifying concentration be 30 mg/ml.The present invention preferably uses denseer methanol solution relatively, as 30 mg/ml.
It is to be noted that especially memantineHCl easily is dissolved in the ethanol, the solution that at room temperature just can to make complete clarifying concentration be 20 mg/ml.Preferred usefulness of the present invention is denseer ethanolic soln relatively, as 20 mg/ml.
Second step of distillation method is to come solvent in the evaporating solns to evaporate to dryness with distillating method commonly used, and obtains the memantineHCl cured article of noncrystal.
Distillation method can be carried out under normal pressure or decompression, and usually at 700 mmhg or more carry out under the low pressure, preferably less than 400 mmhg, more preferably pressure is less than 100 mmhg, and the override selective pressure is the 30-80 mmhg.
According to preparation method of the present invention, can be used as the alcoholic solvent that contains 1 to 4 carbon atom to the butanols of methyl alcohol, ethanol, n-propyl alcohol, b propanol or straight chain.Preferred version is to use the mixture of methyl alcohol, ethanol or these two kinds of solvents.This method also can realize with two kinds or more alcoholic solvent.
The further drying of last resulting solid matter removes last solvent, use the vacuum pan moisture eliminator, thermopnore moisture eliminator or obtain not having the crystalline material with rotary vacuum drier, temperature prioritisedly when dry be chosen in 20 and spend between 80 degree (Celsius), preferred temperature is 20 to 70 degree when coming these materials of drying with vacuum pan, and the preferred time was from 2 hours to 20 hours; Most preferably scheme is that temperature is spent between 50 degree dry about 2-15 hour 35.
According to preparation method of the present invention, acetonitrile also can be used as solvent and use.Preparation method of the present invention also comprises and can realize with the mixture of acetonitrile and one or more alcoholic solvents.
According to a kind of preferred realization preparation method of the present invention, can operate according to following steps: starting raw material is dissolved in adds in the alcoholic solvent of pining for that contains 1 to 4 carbon atom, preferably be heated to the boiling point of solvent, under decompression state, evaporate all solvents then, at last dry gained solid matter under heating (35-50 degree) state in the vacuum with distillation method.
By above-described method, can make the memantineHCl of uniform waterless crystallization-free or the memantineHCl hydrate of noncrystal, the memantineHCl of crystalline form of the present invention comprises the memantineHCl of waterless crystallization-free and the memantineHCl hydrate of noncrystal.
We find, by simple and practical and recursive method described above, can make the memantineHCl of uniform waterless crystallization-free or the memantineHCl hydrate of noncrystal.
According to preparation method of the present invention, the memantineHCl of noncrystal can be used for X-ray powder diffraction (X-RPD) method and analyze, and as described in accompanying drawing 1, the X-ray powder diffraction pattern does not show any peak shape.This has shown a kind of feature of the memantineHCl of noncrystal, has shown simultaneously that also products therefrom is the character that belongs to noncrystal.
The present invention further provides a kind of pharmaceutical preparation of memantineHCl of the noncrystal that contains significant quantity, its form is the unit pharmaceutical preparation.This unit pharmaceutical preparation has multiple, can be the pharmaceutical preparation of oral or injection form.That is to say that the compound among the present invention can be by multiple injection form administration such as intravenous or intramuscular.The memantineHCl of the noncrystal among the present invention also can be by the form administration of suction form or external preparation for skin.In addition, the experienced technical staff in the art be it is evident that the pharmaceutical preparation described in the present invention should comprise Memantine hydrochloride and pharmaceutically acceptable other salt thereof of noncrystal.
For the pharmaceutical preparation of the Memantine hydrochloride for preparing no crystallization shape kenel, selected pharmaceutically acceptable carrier is solid or liquid.
The pharmaceutical preparation of solid kenel comprises pulvis, dispersion agent, tablet, pill, capsule, suppository and dispersed particles.Solid-state carrier can be one or more materials.These materials can be thinner, seasonings, solvating agent, lubricant, suspension agent, tackiness agent, sanitas, be used to make the disintegrating agent of tablet or a kind of capsule material of filled type.
For pulvis, its carrier (or auxiliary material) is a kind of scattered very subtly granular solids, and mixes mutually with dispersed active ingredient subtly.For tablet, active ingredient is mixed mutually with the carrier with sticking and character, is pressed into respective shapes and suitably big or small tablet later on according to certain mixed.
In the pharmaceutical preparation of pulvis and tablet, the content of active ingredient preferred one to ten or about weight ratio of 70 percent.Its suitable carriers comprises magnesiumcarbonate, magnesium stearate, and talcum, sugar or lactose, pectin, dextrin, starch, gelatin, tragacanthin, methylcellulose gum, cellulose sodium carboxymethyl, the wax of LMP, cocoa butter and so on, or the like.Here " preparation " speech of usefulness comprises a kind of with active ingredient and the manufacturing of the pharmaceutical preparation of mixed a kind of carrier mutually of inclosure capsule material.Capsule with this carrier is made contains this carrier no matter be with or without in its active ingredient, is closely to link to each other with this carrier all.Tablet, pulvis, capsule, pill and dragee also can be as the solid preparations with oral form administration.
For tablet, can by with one or more auxiliary materials by the compression and molded method make.The production method of compressed tablets is to compress active ingredient and the tackiness agent that exists with powder or particle form with suitable tabletting machine.For example, polyvinylpyrrolidone, gel, Vltra tears sodium, lubricant, inert excipients, sanitas and disintegrating agent (as pyrrolidone, the cellulose sodium carboxymethyl of Explotab, cross bracing) or dispersion agent.The production method of molded tablet is the mixture that comes molded active ingredient that exists with powder or particle form and inert excipients to be formed with suitable moulding machine.That tablet can also make that lid (dressing) form is carried out on the surface and trimmed, also can be formulated as slowly-releasing or controlled release form.
For preparation suppository, with a kind of wax of low solubility,, earlier it is dissolved as the mixture of fatty acid glycerine fat and cocoa butter, then active ingredient is disperseed wherein equably with stirring means.Uniform mixture after dissolving is poured in the molding of suitable size, and cooling and solid state promptly make.
Oral liquid described in the present invention can be by making uniform solution and suspension, for example water or water and propylene glycol solution.Also can make water and polypropylene glycol solution to injection liquid.This oral liquid can be by ordinary method with pharmaceutically acceptable carrier such as suspension reagent: as sorb (sugar) alcohol slurry, edible fat after derivatived cellulose or the hydrogenation, emulsifying agent (as Yelkin TTS), nonaqueous carrier and sanitas (methyl or propyl group ethylbenzene acid esters) prepare.Oral liquid formulations also can contain pigment, sweeting agent and buffering salt.
The oral liquid made from aqueous suspension can prepare with following method: with the dispersive active ingredient is soluble in water equably, add higher material of viscosity such as natural or synthetic glue again, resin, methylcellulose gum, the suspension agent that Vltra tears sodium etc. are commonly used.
Oral liquid described in the present invention also comprises uses water dissolution after making uniform dry powder doses before use again.
Pharmaceutical preparation preferred unit pharmaceutical preparation described in the present invention, the preparation of this form can also further divide the unit formulation of the active ingredient that is converted into appropriate amount.The unit pharmaceutical preparation can be that the form of packing places phial or peace bottle, and it contains a certain amount of pharmaceutical preparation such as tablet, capsule or pulvis etc.In addition, the unit pharmaceutical preparation can be a tablet, capsule or pulvis or any formulation that places packing.
In the unit pharmaceutical preparation content of active ingredient 0.5 milligram to 50 nanogram ranges, and be variable or adjustable, preferred 2 milligrams to 20 milligrams, and decide according to the intensity and the concrete purposes of active ingredient.In addition, also can contain the active medicinal matter that other is complementary in the pharmaceutical preparation of the Memantine hydrochloride of noncrystal.
Another program of the present invention is: a kind of in preparation treatment senile dementia illness, to warm-blooded animal, particularly the people with the memantineHCl of the noncrystal of significant quantity as the use of medicine in curing the disease.As a kind of N-methyl-D-aspartate (antagonist of (NMDA) acceptor, the memantineHCl of novel noncrystal is a kind of prevention and treatment senile dementia such as Alzheimer's disease, useful medicine in the disease relevant with N-methyl-D-aspartate (NMDA) receptor antagonist such as vascular dementia and the two Combination dementia.
In curing the disease, treat the senile dementia illness as the antagonist of N-methyl-D-aspartate (NMDA) acceptor, the drug dose of the memantineHCl of the noncrystal among the present invention is to begin every day with 0.5 milligram to 50 milligrams, 5 to 20 milligrams of preferred every days, these dosage can and depend on employed compound to regulate according to patient's situation and disease serious degree, are variable.Proper dosage is decided by concrete case.The general therapeutic method is from few dosage, adds to the most effective dosage then.For convenience, every purpose dosage can also be divided into administration several times.
Though described the concrete scheme of the present invention, also should be included within this scope to conspicuous some modification of experienced technical staff in the art or the situation that is equal to.
Following examples are used for illustrating concrete scheme of the present invention, and embodiment does not limit the scope of the invention.
Embodiment
Example one: the preparation of the memantineHCl of noncrystal (lyophilization)
The memantineHCl of 2.0g crystal type is contained in milliliter round-bottomed flask, add 40 ml waters and allow solute all be dissolved in the water, prepared solution is transferred in 2 liters of vials with special heavy sheet glass layer, solution in the vial with special heavy sheet glass layer cools off rapidly with liquid nitrogen, simultaneously the vial that contains solution is constantly rotated to quicken cooling, and allow them form a frozen coating at the vial inwall, freezing until all solution.Allow lyophilizer be evacuated to the vacuum tightness about 0.01 mmhg then and kept 5 hours, treat all water evaporates and make solid-state memantineHCl (1.8g, productive rate 90%).The prepared solid-state memantineHCl of X-ray powder diffraction methods analyst shows a smooth diffracting spectrum (seeing accompanying drawing 1) that does not have peak shape, has proved that products therefrom belongs to the memantineHCl of noncrystal.
Example two: the preparation of the memantineHCl of noncrystal (distillation under vacuum)
The memantineHCl of 1.2g crystal type all is dissolved in the 40 ml methanol solvents.The solution that makes therefrom further is heated to boiling state, under decompression state (80 mmhg) and evaporate all solvents and obtain the exsiccant solid with distillation method under 20-50 degree centigrade.The drying solid that makes places 60 degrees centigrade of vacuum maintenances following dry 2 hours.X-ray powder diffraction (seeing accompanying drawing 1) has proved that products therefrom belongs to the memantineHCl of noncrystal.
Example three: the preparation of the memantineHCl of noncrystal (distillation under vacuum)
The memantineHCl of 1.0g crystal type all is dissolved in 50 milliliters of alcohol solvents.The solution that makes therefrom further is heated to boiling state, under decompression state (80 mmhg) and evaporate all solvents and obtain the exsiccant solid with distillation method under 20-60 degree centigrade.The drying solid that makes places 60 degrees centigrade of vacuum maintenances following dry 2 hours.X-ray powder diffraction (seeing accompanying drawing 1) has proved that products therefrom belongs to the memantineHCl of noncrystal.
Claims (13)
1. the 1-amino-3 of a noncrystal, two methyl three rings [3,3,1,1 of 5-
3,7] decane hydrochloride (memantineHCl).
2. the memantineHCl of noncrystal according to claim 1 is characterized in that having and the substantially the same feature of X-ray powder diffraction (seeing accompanying drawing 1).
3. the memantineHCl of noncrystal according to claim 1 is characterized in that containing the memantineHCl that is less than 10% crystalline form.
4. the memantineHCl of noncrystal according to claim 1 is characterized in that being substantially devoid of the memantineHCl of crystalline form.
5. 1-amino-3 for preparing noncrystal, two methyl three rings [3,3,1,1 of 5-
3,7] method of decane hydrochloride (memantineHCl), it is characterized in that may further comprise the steps: the memantineHCl of crystalline form is dissolved in forms solution in the solvent, remove the solvent in the solution, vacuum and heating drying and make the memantineHCl of noncrystal.
6. according to the preparation method of the memantineHCl of the described noncrystal of claim 5, it is characterized in that removing and desolvate with the vacuum freezedrying method.
7. the preparation method of the memantine hydrochloride of noncrystal according to claim 5 is characterized in that with decompression (30-400 mmhg) distillating method except that desolvating.
8. according to the preparation method of the memantineHCl of claim 5 or 6 described noncrystals, it is characterized in that used solvent is a water solvent.
9. according to the preparation method of the memantineHCl of claim 5 or 7 described noncrystals, it is characterized in that used solvent is to contain 1 alcoholic solvent to 4 carbon atoms.
10. the preparation method of the memantine hydrochloride of noncrystal according to claim 9 is characterized in that used alcoholic solvent is methyl alcohol or ethanol.
11. a 1-amino-3 that contains the noncrystal of significant quantity, two methyl three rings [3,3,1,1 of 5-
3,7] decane hydrochloride (memantineHCl) and pharmaceutically acceptable carrier such as thinner, auxiliary material, additive, filler, lubricant, solvent, the pharmaceutical preparation of tackiness agent or stablizer.
12. pharmaceutical preparation according to claim 11 is characterized in that its formulation is a tablet, lozenge, pulvis, syrup, fritter sheet, liposome, injection liquid, dispersion agent, suspension, solution, capsule, paste, ointment, sprays.
13. the memantineHCl of claim 1 or 2 or 3 or 4 described noncrystals in preparation treatment senile dementia (Alzheimer's disease), in the disease relevant such as vascular dementia and the two Combination dementia with N-methyl-D-aspartate (NMDA) receptor antagonist as the purposes of medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510054603 CN1827585A (en) | 2005-03-04 | 2005-03-04 | Non-crystalline memantine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510054603 CN1827585A (en) | 2005-03-04 | 2005-03-04 | Non-crystalline memantine hydrochloride |
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