CN103110602A - Disodium adenosine triphosphate troche medical composition - Google Patents
Disodium adenosine triphosphate troche medical composition Download PDFInfo
- Publication number
- CN103110602A CN103110602A CN2013100767254A CN201310076725A CN103110602A CN 103110602 A CN103110602 A CN 103110602A CN 2013100767254 A CN2013100767254 A CN 2013100767254A CN 201310076725 A CN201310076725 A CN 201310076725A CN 103110602 A CN103110602 A CN 103110602A
- Authority
- CN
- China
- Prior art keywords
- tablet
- calcium
- adenosine triphosphate
- remaining rate
- solid composite
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a disodium adenosine triphosphate troche medical composition, and in particular relates to use of calcium salt in preparation of stable triphosadenine or a solid medical composition of officinal salt thereof. The medical composition provided by the invention further stably comprises triphosadenine or the solid medical composition of officinal salt thereof. More specifically, the invention relates to the solid medical composition containing triphosadenine or the officinal salt thereof, wherein even if the medical composition is stored for a long time, the content of the effective components is still highly maintained to ensure the excellent stability. After the solid medical composition provided by the invention is placed at 20+/-2 DEG C for 2 years, the residual ratio of active components, i.e., triphosadenine or officinal salt thereof in the composition is over 80%.
Description
Technical field
The present invention relates to the stable solid composite medicament that contains adenosine triphosphate or its pharmaceutical salts.Even relate more specifically to the solid composite medicament that contains adenosine triphosphate or its pharmaceutical salts of the excellent storage stability that active constituent content also can highly maintain after long preservation.
Background technology
Adenosine triphosphate, be called again ATP, is the compound with energy-rich phosphate bond, emits a large amount of energy while being hydrolyzed into 5 '-adenosine diphosphate (ADP) and phosphoric acid.In vivo, adenosine triphosphate, except the main Power supply source as reaction, also participates in metabolic response as the phosphoric acid donor.Clinical adenosine triphosphate commonly used is its disodium salt (CAS 987-65-5), and structural formula is as follows:
Molecular formula C
10h
14n
5na
2o
13p
3, molecular weight 551.14
Utilization about adenosine triphosphate as medicine, become known for the regulative mechanism of stabilisation such as to(for) injury of head sequela, arrhythmia, accommodative asthenopia, be counted as the curative of the chronic gastritis etc. of digestive tract underactivity.In addition, also become known for increasing moment of muscle power, alleviate the compositions (JP2004-535417) of the adenosine triphosphate that contains effective dose (ATP) of muscle fatigue.Carry out commercially available medicine as the solid preparation that contains adenosine triphosphate, can enumerate for example pharmaceutical salts preparation that particularly for example adenosine triphosphate disodium salt is active component of adenosine triphosphate, common dosage form has adenosine triphosphate disodium salt sheet (20mg/ sheet), injection with adetphos, tribiofosfor injection, injection with adetphos and magnesium chloride etc. clinically.
But, adenosine triphosphate is easily decomposed for water unstable, because the active constituent content time dependent of preserving for a long time in preparation reduces, therefore in the storage of medicine, use the desiccant such as silica gel in the haulage stage, or carry out stored refrigerated, but have the manufacturing cost of following desiccant to use owing to adopting this additional store method to increase, or due to the cold preservation in the process of circulation the such problem of operability variation.In addition, also worry that consumer eats the silica gel as desiccant by mistake.Disclose take in JP49-87684 as the stabilization method of the derivant of ADP etc. and regulated moisture as being the stabilization method of feature below 4.0%, but the method is the moisture contained in the crystallization of the derivant by regulating ADP etc. reaches stabilisation (seeing the embodiment 1 in this JP49-87684), not using the stabilisation of the ATP in solid preparation as purpose.
For this reason, those skilled in the art expect that new method is arranged, and the clinical particularly solid composite medicament of a kind of stable pharmaceutical composition that comprises adenosine triphosphate or its pharmaceutical salts that provides is provided.
Summary of the invention
The object of the present invention is to provide a kind of particularly method of solid composite medicament of pharmaceutical composition for preparing adenosine triphosphate or its pharmaceutical salts, expect that this pharmaceutical composition has one or more useful pharmaceutical properties and for example has good stability.The inventor have been surprisingly found that, a certain amount of calcium salt pharmaceutical composition that particularly inorganic calcium salt and adenosine triphosphate or the combination of its pharmaceutical salts are made has good chemical property, the present invention is based on this discovery and is accomplished.
For this reason, first aspect present invention provides a kind of solid composite medicament, wherein comprises adenosine triphosphate or its pharmaceutical salts, calcium salt and optional pharmaceutic adjuvant as active component.
According to the solid composite medicament of first aspect present invention, the pharmaceutical salts of wherein said adenosine triphosphate is adenosine triphosphate disodium salt.
According to the solid composite medicament of first aspect present invention, wherein said calcium salt is inorganic calcium salt.
According to the solid composite medicament of first aspect present invention, wherein said inorganic calcium salt is selected from: calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium sulfate and solvate thereof be hydrate for example.
As everyone knows, its molecular formula of calcium hydrogen phosphate is CaHPO
4, molecular weight approximately 136, every mole of calcium is equivalent to the 136g calcium hydrogen phosphate; Its molecular formula of calcium phosphate Ca
3(PO
4)
2, molecular weight approximately 103, every mole of calcium is equivalent to 103g calcium phosphate; Its molecular formula of calcium carbonate CaCO
3, molecular weight approximately 100, every mole of calcium is equivalent to the 100g calcium carbonate.These calcium salts can be used their hydrate or anhydride, for example can use anhydrous calcium hydrogen phosphate or dicalcium phosphate dihydrate (CaHPO
42H
2o, molecular weight approximately 172, every mole of calcium is equivalent to the 172g dicalcium phosphate dihydrate).But, during in the present invention to these calcium salt meterings, all be converted to its anhydride meter (for example, for dicalcium phosphate dihydrate CaHPO
42H
2o, every mole of calcium is equivalent to the 136g calcium hydrogen phosphate, recipe quantity is counted the 136g calcium hydrogen phosphate, but produces actual interpolation 172g dicalcium phosphate dihydrate while feeding intake).
According to the solid composite medicament of first aspect present invention, wherein comprise adenosine triphosphate or its pharmaceutical salts of 1 molar part, and in the calcium salt of calcium ion 2～60 molar part.
According to the solid composite medicament of first aspect present invention, wherein comprise adenosine triphosphate or its pharmaceutical salts of 1 molar part, and in the calcium salt of calcium ion 5～50 molar part.
According to the solid composite medicament of first aspect present invention, wherein comprise adenosine triphosphate or its pharmaceutical salts of 1 molar part, and in the calcium salt of calcium ion 9～40 molar part.
According to the solid composite medicament of first aspect present invention, wherein comprise adenosine triphosphate or its pharmaceutical salts of 1 molar part, and in the calcium salt of calcium ion 10～40 molar part.
In this article, " adenosine triphosphate that comprises 1 molar part or its pharmaceutical salts; and in the calcium salt of calcium ion 10～40 molar part " mean, for the adenosine triphosphate or its pharmaceutical salts of every 1 molar part, the calcium salt amount comprised in said composition is counted 10～40 molar part with calcium.For example in a compositions, comprise 1 mole of adenosine triphosphate disodium salt, its weight is 551 grams, the calcium salt amount is counted 10～40 moles with calcium, if use calcium hydrogen phosphate be (10～40) * 136 grams=1360g～5440g, if use calcium phosphate be (10～40) * 103 gram ÷ 3=1030g～4120g, if use calcium carbonate be (10～40) * 100 grams=1000g～4000g.When being arranged in this article, similar statement all there is similar meaning.
According to the solid composite medicament of first aspect present invention, wherein said pharmaceutic adjuvant is the acceptable adjuvant of the pharmacy except described calcium salt.
According to the solid composite medicament of first aspect present invention, wherein said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, lubricant etc.As everyone knows, for the concrete kind of the diluent of selecting, disintegrating agent, binding agent, lubricant, they may be held concurrently and have several functions, and for example starch has diluent functions and also has the disintegrating agent function.
According to the solid composite medicament of first aspect present invention, it is the pharmaceutical preparation that is tablet, granule or Capsule form.
According to the solid composite medicament of first aspect present invention, its pharmaceutical preparation that is tablet form, this tablet is the tablet of coating.
According to the solid composite medicament of first aspect present invention, its pharmaceutical preparation that is tablet form, this tablet is the tablet of parcel enteric coating.
According to the solid composite medicament of first aspect present invention, wherein said diluent is selected from: one or more of sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, differential silica gel, Pulvis Talci, magnesium stearate etc.In one embodiment, described diluent is selected from: one or more of microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol etc.In one embodiment, described other diluent is selected from: one or more of microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate etc.
Solid composite medicament according to first aspect present invention, wherein said disintegrating agent is selected from: polyvinylpolypyrrolidone, microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, differential silica gel, Pulvis Talci, one or more of magnesium stearate etc.In one embodiment, described disintegrating agent is selected from: one or more of polyvinylpolypyrrolidone, microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone etc.In one embodiment, described disintegrating agent is selected from: one or more of polyvinylpolypyrrolidone, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone etc.
Solid composite medicament according to first aspect present invention, wherein said binding agent is selected from: microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, differential silica gel, Pulvis Talci, one or more of magnesium stearate etc.In one embodiment, described binding agent is selected from: starch, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol and combination thereof.In one embodiment, described binding agent is selected from: starch, polyvinylpyrrolidone, polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, Polyethylene Glycol and combination thereof.
When pharmaceutical composition of the present invention is prepared into to tablet, prepared by its mode that can prepare tablet by many routines, for example it can prepare by the mode of direct powder compression, can also, by the technique preparation of dry granulation tabletting, can also prepare by the mode of conventional wet granule compression tablet.When with direct powder compression or dry granulation tablet forming technique, preparing the pharmaceutical composition of tablet form of the present invention, binding agent wherein adds with dry powder form.And when with wet granule compression tablet technique, preparing the pharmaceutical composition of tablet form of the present invention, binding agent wherein is for example aqueous solution or alcoholic solution of the solution that is mixed with, then join in powder to prepare wet granular, wet granule compression tablet technique prepares tablet routinely; Perhaps, in wet granule compression tablet technique, also can make these binding agents directly with powder type and other mixing of materials, then use wetting agent for example water or aquiferous ethanol wet granular processed, wet granule compression tablet technique prepares tablet routinely.In any case, in wet granule compression tablet technique, the solvent of the wetting agent added or preparation binder solution, after obtaining dry finished granule, these solvents wherein are removed basically.
According to the solid composite medicament of first aspect present invention, wherein said lubricant can be to have lubricated effect, can also be the effect with fluidizer, and term " lubricant " the broad sense Shangdi of using in the present invention comprises lubricant and fluidizer.Lubricant of the present invention is to be selected from following one or more: magnesium stearate, aluminium stearate, calcium stearate, PEG4000 to 8000, Pulvis Talci, castor oil hydrogenated, stearic acid and salt thereof or glyceride, sodium stearyl fumarate etc. and combination thereof, and for example silica sol, magnesium silicate, Pulvis Talci and combination thereof of silicon dioxide.Most preferred lubricant is magnesium stearate, Pulvis Talci, silicon dioxide and combination thereof.
Solid composite medicament according to first aspect present invention, the relative quantity of wherein said pharmaceutic adjuvant in compositions can change in scope more widely, for example, in solid composite medicament of the present invention, all pharmaceutic adjuvant accounts for 0～95% of composition total weight, for example 5～90%, for example 10～80%, for example 10～70%, for example 10～60%, for example 10～50%.These pharmaceutic adjuvants can add in compositions with its conventional amount used, for example as the adjuvant of lubricant, can add in compositions with the amount of the 1-5% that accounts for composition total weight, for example as the adjuvant of binding agent, can add in compositions with the amount of the 1-10% that accounts for composition total weight, for example as the adjuvant of disintegrating agent, can add in compositions with the amount of the 1-20% that accounts for composition total weight, for example can add in compositions with the amount of the 1-50% that accounts for composition total weight as the adjuvant of diluent.
Solid composite medicament according to first aspect present invention wherein comprises:
Solid composite medicament according to first aspect present invention wherein comprises:
According to the solid composite medicament of first aspect present invention, it is unit dosage form, and for example it is tablet, granule or Capsule form.Term " unit dosage form " refers to that the minimum package unit of compositions or the active dose in minimum medication unit are 1/3,1/2,1,1.5,2,2.5,3,5,10 multiple doses of active component routine dose of the present invention, preferably 1/2 of active component routine dose of the present invention, 1,1.5,2,2.5 multiple doses.For example, the peroral administration preparation of clinical normally used active component of the present invention is tablet at present, comprising adenosine triphosphate disodium salt in its every is 20mg, for this reason, when the present invention's " unit dosage form " is tablet or capsule or granule, the amount (such as labelled amount) that comprises adenosine triphosphate disodium salt in its every tablet tablet, every seed lac wafer or every bag of granule can be about 10mg, about 20mg, about 30mg, about 40mg, about 50mg etc.
According to the solid composite medicament of first aspect present invention, it is tablet, and this is further by coating.The material of described coating can be stomach dissolution type coating or enteric solubility coating, the preferably coating of enteric solubility.In the present invention, the quality of the plain sheet of above preparation is influential for follow-up preparation coating operation, if for example the friability of plain sheet is well-behaved (friability test less loss weight is few), is conducive to follow-up preparation coating operation.
Further, second aspect present invention provides the purposes of calcium salt in the solid composite medicament for preparing stable adenosine triphosphate or its pharmaceutical salts.
According to the described purposes of second aspect present invention, at 20 ± 2 ° of C, (this temperature also can be described as room temperature or room temperature to wherein said solid composite medicament in the present invention, perhaps can be referred to as 20 ° of C), lucifuge, sealing place place after 2 years, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
According to the described purposes of second aspect present invention, wherein said solid composite medicament is at 45 ± 2 ° of C (this temperature high temperature in the present invention, perhaps can be referred to as 45 ° of C), lucifuge, sealing place place after 5 months, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
According to the described purposes of second aspect present invention, it is characterized in that following (i) and/or (ii):
(i) at 20 ± 2 ° of C, (this temperature also can be described as room temperature or room temperature to described solid composite medicament in the present invention, perhaps can be referred to as 20 ° of C), lucifuge, sealing place place after 2 years, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
(ii) described solid composite medicament is at 45 ± 2 ° of C (this temperature high temperature in the present invention, perhaps can be referred to as 45 ° of C), lucifuge, sealing place place after 5 months, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
In above-mentioned calculating, in compositions, the content of active component adenosine triphosphate or its pharmaceutical salts can be measured according to the method for the invention.
According to the described purposes of second aspect present invention, comprise adenosine triphosphate or its pharmaceutical salts, calcium salt and optional pharmaceutic adjuvant as active component in wherein said solid composite medicament.
According to the described purposes of second aspect present invention, the pharmaceutical salts of wherein said adenosine triphosphate is adenosine triphosphate disodium salt.
According to the described purposes of second aspect present invention, wherein said calcium salt is inorganic calcium salt.
According to the described purposes of second aspect present invention, wherein said inorganic calcium salt is selected from: calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium sulfate and solvate thereof be hydrate for example.
According to the described purposes of second aspect present invention, the adenosine triphosphate that comprises 1 molar part in wherein said solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 2～60 molar part.
According to the described purposes of second aspect present invention, the adenosine triphosphate that comprises 1 molar part in wherein said solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 5～50 molar part.
According to the described purposes of second aspect present invention, the adenosine triphosphate that comprises 1 molar part in wherein said solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 9～40 molar part.
According to the described purposes of second aspect present invention, the adenosine triphosphate that comprises 1 molar part in wherein said solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 10～40 molar part.
According to the described purposes of second aspect present invention, pharmaceutic adjuvant described in wherein said solid composite medicament is the acceptable adjuvant of pharmacy except described calcium salt.
According to the described purposes of second aspect present invention, described in wherein said solid composite medicament, pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, lubricant etc.As everyone knows, for the concrete kind of the diluent of selecting, disintegrating agent, binding agent, lubricant, they may be held concurrently and have several functions, and for example starch has diluent functions and also has the disintegrating agent function.
According to the described purposes of second aspect present invention, wherein said solid composite medicament is the pharmaceutical preparation of tablet, granule or Capsule form.
According to the described purposes of second aspect present invention, the pharmaceutical preparation that wherein said solid composite medicament is tablet form, this tablet is the tablet of coating.
According to the described purposes of second aspect present invention, the pharmaceutical preparation that wherein said solid composite medicament is tablet form, this tablet is the tablet of parcel enteric coating.
According to the described purposes of second aspect present invention, described in wherein said solid composite medicament, diluent is selected from: one or more of sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, differential silica gel, Pulvis Talci, magnesium stearate etc.In one embodiment, described diluent is selected from: one or more of microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol etc.In one embodiment, described other diluent is selected from: one or more of microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate etc.
According to the described purposes of second aspect present invention, described in wherein said solid composite medicament, disintegrating agent is selected from: polyvinylpolypyrrolidone, microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, differential silica gel, Pulvis Talci, one or more of magnesium stearate etc.In one embodiment, described disintegrating agent is selected from: one or more of polyvinylpolypyrrolidone, microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone etc.In one embodiment, described disintegrating agent is selected from: one or more of polyvinylpolypyrrolidone, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone etc.
According to the described purposes of second aspect present invention, described in wherein said solid composite medicament, binding agent is selected from: microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, differential silica gel, Pulvis Talci, one or more of magnesium stearate etc.In one embodiment, described binding agent is selected from: starch, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol and combination thereof.In one embodiment, described binding agent is selected from: starch, polyvinylpyrrolidone, polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, Polyethylene Glycol and combination thereof.
When pharmaceutical composition of the present invention is prepared into to tablet, prepared by its mode that can prepare tablet by many routines, for example it can prepare by the mode of direct powder compression, can also, by the technique preparation of dry granulation tabletting, can also prepare by the mode of conventional wet granule compression tablet.When with direct powder compression or dry granulation tablet forming technique, preparing the pharmaceutical composition of tablet form of the present invention, binding agent wherein adds with dry powder form.And when with wet granule compression tablet technique, preparing the pharmaceutical composition of tablet form of the present invention, binding agent wherein is for example aqueous solution or alcoholic solution of the solution that is mixed with, then join in powder to prepare wet granular, wet granule compression tablet technique prepares tablet routinely; Perhaps, in wet granule compression tablet technique, also can make these binding agents directly with powder type and other mixing of materials, then use wetting agent for example water or aquiferous ethanol wet granular processed, wet granule compression tablet technique prepares tablet routinely.In any case, in wet granule compression tablet technique, the solvent of the wetting agent added or preparation binder solution, after obtaining dry finished granule, these solvents wherein are removed basically.
According to the described purposes of second aspect present invention, lubricant described in wherein said solid composite medicament can be to have lubricated effect, can also be the effect with fluidizer, term " lubricant " the broad sense Shangdi of using in the present invention comprises lubricant and fluidizer.Lubricant of the present invention is to be selected from following one or more: magnesium stearate, aluminium stearate, calcium stearate, PEG4000 to 8000, Pulvis Talci, castor oil hydrogenated, stearic acid and salt thereof or glyceride, sodium stearyl fumarate etc. and combination thereof, and for example silica sol, magnesium silicate, Pulvis Talci and combination thereof of silicon dioxide.Most preferred lubricant is magnesium stearate, Pulvis Talci, silicon dioxide and combination thereof.
According to the described purposes of second aspect present invention, the relative quantity of pharmaceutic adjuvant described in wherein said solid composite medicament in compositions can change in scope more widely, for example, in solid composite medicament of the present invention, all pharmaceutic adjuvant accounts for 0～95% of composition total weight, for example 5～90%, for example 10～80%, for example 10～70%, for example 10～60%, for example 10～50%.These pharmaceutic adjuvants can add in compositions with its conventional amount used, for example as the adjuvant of lubricant, can add in compositions with the amount of the 1-5% that accounts for composition total weight, for example as the adjuvant of binding agent, can add in compositions with the amount of the 1-10% that accounts for composition total weight, for example as the adjuvant of disintegrating agent, can add in compositions with the amount of the 1-20% that accounts for composition total weight, for example can add in compositions with the amount of the 1-50% that accounts for composition total weight as the adjuvant of diluent.
According to the described purposes of second aspect present invention, in wherein said solid composite medicament, comprise:
According to the described purposes of second aspect present invention, in wherein said solid composite medicament, comprise:
A kind of typical diluent is dextrin in the present invention.
According to the described purposes of second aspect present invention, wherein said solid composite medicament is unit dosage form, and for example it is tablet, granule or Capsule form.Term " unit dosage form " refers to that the minimum package unit of compositions or the active dose in minimum medication unit are 1/3,1/2,1,1.5,2,2.5,3,5,10 multiple doses of active component routine dose of the present invention, preferably 1/2 of active component routine dose of the present invention, 1,1.5,2,2.5 multiple doses.For example, the peroral administration preparation of clinical normally used active component of the present invention is tablet at present, comprising adenosine triphosphate disodium salt in its every is 20mg, for this reason, when the present invention's " unit dosage form " is tablet or capsule or granule, the amount (such as labelled amount) that comprises adenosine triphosphate disodium salt in its every tablet tablet, every seed lac wafer or every bag of granule can be about 10mg, about 20mg, about 30mg, about 40mg, about 50mg etc.
According to the described purposes of second aspect present invention, wherein said solid composite medicament is tablet, and this is further by coating.The material of described coating can be stomach dissolution type coating or enteric solubility coating, the preferably coating of enteric solubility.In the present invention, the quality of the plain sheet of above preparation is influential for follow-up preparation coating operation, if for example the friability of plain sheet is well-behaved (friability test less loss weight is few), is conducive to follow-up preparation coating operation.
Further, third aspect present invention relates to the method for the pharmaceutical composition in the preparation described solid composite medicament of the arbitrary embodiment of first aspect present invention or the described purposes of second aspect present invention any one, and it comprises the following steps:
(i) each crushing material is become can pass through 60 purpose fine powders;
(ii) adenosine triphosphate or its salt are fully mixed homogeneously with calcium salt;
(iii) step (ii) the gained mixture pharmaceutic adjuvant optional with other mixed homogeneously, by the preparation technology of tablet, capsule or granule, be prepared into tablet, capsule or granule;
(iv) optionally step (iii) gained tablet is carried out to coating for example enteric coated.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Below with characteristics, be further described to various aspects of the present invention.
All documents that the present invention quotes from, their full content is incorporated to this paper by reference, and if, when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to explain, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In addition, the inventor have been surprisingly found that, when pharmaceutical composition of the present invention is pressed into to tablet, adenosine triphosphate or its pharmaceutical salts in every 20 weight portions, add wherein 5-80 weight portion (10～60 weight portions for example, 10～50 weight portions for example) dextrin is during as diluent, for the performance of the tablet weight variation that improves tablet and friability two aspects, is very favourable (although relevant with the friability aspect of performance with tablet weight difference without any technology instruction dextrin).Therefore in one embodiment of the invention, described pharmaceutical composition is tablet, and, in adenosine triphosphate or its pharmaceutical salts of every 20 weight portions, wherein contains the dextrin of 5-80 weight portion (for example 10～60 weight portions, for example 10～50 weight portions).Tablet is clinical the most frequently used a kind of dosage form, and " Chinese pharmacopoeia all has detailed regulation to its performance to each edition, so that tablet meets the requirement of " safe, effective, controlled (being steady quality) ".Particularly, tablet is in the friability (mechanical performance of reflection tablet, the friability performance well tablet be beneficial to operations such as coating, transportation of processing) and tablet weight variation (reflect tablet tabletting performance and uniformity, the little uniformity that is conducive to administration of difference, the concordance of assurance therapeutic effect) should there is good performance.For example, version " " weight differential " (the formulation art technical staff also is referred to as " tablet weight variation " usually for tablet) inspection method and the general provision thereof of the tablet of two appendix page 5 regulations of Chinese pharmacopoeia in 2010, for example for tablet weight below 0.3g, " weight differential restriction " will be lower than 7.5%, otherwise product is defective.This " tablet weight variation " can be for controlling the deviation of weight between every, a collection of tablet, so that the dosage that the patient takes while using is accurate.Again for example, " two appendix of Chinese pharmacopoeia the 89th page (appendix XG) have been stipulated " the tablet friability inspection method " of tablet to version in 2010, and using " less loss weight " that the method measures as the whether qualified index of judge tablet quality.It generally is defined as: " less loss weight must not cross 1%; and the sheet that must not detect fracture, be full of cracks, pulverize ", herein, " less loss weight must not cross 1% " generally can be understood as, after every 100 gram tablets carry out this inspection technique processing, through tablet surface wearing and tearing etc., make tablet weight reduce, this reduction value can not surpass 1 gram, otherwise tablet is defective.Although " absolute value " of this less loss % by weight of 1% is lower, can reflect well the mechanical performance of inorganic agent.In the present invention, while relating to tablet weight variation (%), all with said method, measure, all measure with said method while relating to friability and/or less loss weight (%).
The present invention have been surprisingly found that, stability in compositions is useful for active component to use a certain amount of calcium salt of the present invention, particularly in compositions, calcium salt content is more than 2 times of active component mole with the calcium ion mole, preferably more than 5 times, while being more preferably more than 9 times, for the stability that improves active component, be quite obvious.
In addition, the present invention have been surprisingly found that, stability in compositions is useful for active component to use a certain amount of calcium salt of the present invention, yet when described calcium salt is increased to certain procedures, for example in the calcium ion mole be active component more than 60 times the time, be shaped and have adverse influence for tablet, to the plain sheet of coating not carry out the tablet friability while checking less loss weight can reach that thereby more than 2.1%, to cause tablet substantially to detect index defective, the deficiency of this mechanical performance also can cause adverse effect to the follow-up coating operation of tablet.Therefore in one embodiment of the invention, calcium salt content preferably is controlled at below 60 times of active component mole in the calcium ion mole, preferably, below 50 times, is more preferably below 40 times.
In the present invention, if be not specifically noted, refer to this material of general reference while mentioning " adenosine triphosphate ", and comprise particularly its disodium salt (being adenosine triphosphate disodium salt) for example of adenosine triphosphate and the acceptable salt of its pharmacy, and their solvate hydrate (for example adenosine triphosphate disodium salt trihydrate) for example.In a preferred embodiment of the invention, adenosine triphosphate used is that its adenosine triphosphate disodium salt trihydrate, particularly this active component meet the regulation under two ones the 28th page contained " adenosine triphosphate disodium salt " kind item of Chinese Pharmacopoeia version in 2010.While specifically testing hereinafter, if not otherwise indicated, active component used is the standard that meets above-mentioned pharmacopeia, and when the preparation compositions, while carrying out formula ratio calculating, all with its anhydride, calculate, for example indicate when inventory is 551 gram adenosine triphosphate disodium salt actual adenosine triphosphate disodium salt trihydrate 605 grams that add.
The inorganic calcium salt used in the present invention is some conventional pharmaceutic adjuvants, and they can easily be buied from the market, and meet relevant drug standard.In the present invention hereinafter tests, if not otherwise indicated, the calcium hydrogen phosphate used is commercial gained and meets the quality standard requirement (it is dihydrate) under two the 1164th page " calcium hydrogen phosphate " items of Chinese Pharmacopoeia version in 2010, the calcium phosphate dibasic anhydrous used is commercial gained and meets the quality standard requirement under 5.0 editions the 1160th page " calcium phosphate dibasic anhydrous " items of European Pharmacopoeia, the calcium phosphate used is commercial gained and meets the quality standard requirement under this kind item of American Pharmacopeia USP-NF1990 version, the calcium carbonate used is commercial gained and meets the quality standard requirement under two the 1096th page " calcium carbonate " items of Chinese Pharmacopoeia version in 2010, the calcium sulfate used is commercial gained and meets the quality standard requirement under two the 1236th page " calcium sulfate " items of Chinese Pharmacopoeia version in 2010.
In the present invention, when tablet coating that the present invention is prepared, coating material can be prepared voluntarily according to existing experience and knowledge; Perhaps directly buy from commercial channels, for example there is the happy Kanggong of card department in prominent domestic coating material supplier.In the present invention tablet is carried out when enteric coated, if not otherwise specified, coating fluid prescription used is: polyacrylic resin II 550g, tween 80 100ml, PEG-4000 80g, diethyl phthalate 80ml, Oleum Ricini 120ml, Tatrazine 5g, 95% ethanol add to 10000ml, coating to the tablet 2-8% that increases weight.
In the present invention, when pharmaceutical composition of the present invention is carried out to assay, can carry out according to the method for [assay] under two ones the 28th page contained " adenosine triphosphate disodium salt " kind item of Chinese Pharmacopoeia version in 2010, and show with the scale of adenosine triphosphate disodium salt contained in compositions.Especially, in the present invention, if not otherwise indicated, coated tablet carries out [assay] according to following methods, and the compositions of other dosage form can be measured content similarly:
(1) total nucleotide is got 20 of this product, accurately weighed, after removing coating, porphyrize, precision takes in right amount (approximately being equivalent to adenosine triphosphate disodium salt 0.1g), put in the 200ml measuring bottle, add the 0.1mol/L phosphate buffer and (get sodium hydrogen phosphate 35.8g, add water to 1000ml, anhydrous potassium dihydrogenphosphate 13.6g, add water to 1000ml, regulate pH value to 7.0) to scale, jolting makes to dissolve, filter, get subsequent filtrate appropriate, make the solution that contains 20 μ g in every 1ml with above-mentioned phosphate buffer, according to ultraviolet-spectrophotography (Chinese Pharmacopoeia version appendix IV A in 2010), measure, take above-mentioned buffer as blank solution, wavelength place at 259nm measures trap, press C
10h
14n
5na
2o
13p
3absorptance (E1%1cm) be 279 calculating.
(2) weight ratio of adenosine triphosphate disodium salt is measured according to high performance liquid chromatography (Chinese Pharmacopoeia version appendix V D in 2010).
Chromatographic condition and system suitability octadecyl silane are filler; With the 0.2mol/L phosphate buffer, (get sodium hydrogen phosphate 35.8g, potassium dihydrogen phosphate 13.6g, add water 900ml and dissolve, regulate pH value to 7.0 with the 1mol/L sodium hydroxide solution, add tetrabutyl ammonium bromide 1.61g, add water to 1000ml, shake up)-methanol (95:5) is mobile phase; Column temperature is 35 ℃; The detection wavelength is 259nm.Number of theoretical plate calculates and should be greater than 1500 by the adenosine triphosphate disodium salt peak; The separating degree of each chromatographic peak should be up to specification.Go out the peak order and be followed successively by adenosine monophosphate sodium (in the present invention can referred to as AMP), adenosine diphosphate (ADP) disodium (in the present invention can referred to as ADP) and adenosine triphosphate disodium salt (in the present invention can referred to as AMP).
It is appropriate that algoscopy is got above-mentioned subsequent filtrate, adds mobile phase and make the solution that contains 0.4mg in every 1ml; Get 10 μ l and inject high performance liquid chromatograph, record chromatogram, be calculated as follows adenosine triphosphate disodium salt (T
3) weight ratio in total nucleotide:
In formula: T
1---the peak area of adenosine monophosphate sodium;
T
2---the peak area of adenosine diphosphate (ADP) disodium;
T
3---the peak area of adenosine triphosphate disodium salt;
The peak area sum at Tx---other material peaks (except solvent peak and adjuvant peak);
0.671---the ratio of adenosine monophosphate sodium and adenosine triphosphate disodium salt molecular weight;
0.855---the ratio of adenosine diphosphate (ADP) disodium and adenosine triphosphate disodium salt molecular weight;
(3) be calculated as follows adenosine triphosphate disodium salt content:
The weight ratio of adenosine triphosphate disodium salt content (%)=total nucleotide * adenosine triphosphate disodium salt * 100%
In addition, can also measure the impurity (usually characterizing with " related substance ") in the present composition.In the present invention, when pharmaceutical composition of the present invention is carried out to determination of related substances, can carry out according to the method for " related substance " and [assay] under two ones the 28th page contained " adenosine triphosphate disodium salt " kind item of Chinese Pharmacopoeia version in 2010, and the relative quantity of the impurity containedly in compositions desolventizing, beyond adjuvant means.Especially, in the present invention, if not otherwise indicated, coated tablet carries out " related substance " according to following methods to be measured, and the compositions of other dosage form can be measured " related substance " similarly:
Method according to the weight ratio of adenosine triphosphate disodium salt in above-mentioned assay is measured, and is calculated as follows related substance:
When the inventor finds that preparation comprises the tablet of adenosine triphosphate or its salt, there is the tablet of specific formula as described herein and there is good pharmaceutics performance.
The specific embodiment
Further illustrate the present invention below by specific embodiment/experimental example, still, should be understood to, these embodiment and experimental example are only used for the use specifically described more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although, for to realize that many materials and operational approach that the object of the invention is used are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art.
Below during various tablet, if not otherwise indicated, tablet is all suppressed with the tablet machine of same model.And the tabletting punching-Mo that selects suitable size compares in the 1.65-1.75 scope so that different big or small tablet has suitable axial/radial stress the diameter/thickness of gained tablet; Various tablets, when compacting, all are controlled at the hardness of tablet the scope interior (using the tablet hardness tester of same model to measure tablet hardness) of 5-6kgf (i.e. 49～59N).In the example of following each sample preparation, if not otherwise indicated, preparation is 10000 slices/batch in batches.
test example 1: the study on the stability of adenosine triphosphate disodium salt and calcium salt (calcium carbonate) combination
By mole proportioning of listing in adenosine triphosphate disodium salt (being tested with 100 gram amounts for its every batch) and calcium salt calcium carbonate according to the form below, with the abundant mix homogeneously of lapping mode, then use the aluminum-plastic composite membrane bag hermetic package in mortar, every bag of powder loading amount is 5g.Each sample is white powder.Then these samples are placed 5 months in 45 ° of C, lucifuge, sealing place, are measured before and after so disposing the content of adenosine triphosphate disodium salt in sample, and after be calculated as follows the remaining rate (%) of active component adenosine triphosphate disodium salt in sample:
(the ratio of calcium salt (in calcium ion) molal quantity and ATP molal quantity of the proportioning of calcium salt and ATP in each sample, can " calcium/ATP ratio " mean) and the gained sample with high-temperature treatment the remaining rate (%) after May, and the outward appearance (color and luster) of after above-mentioned 45 ° of C dispose May, observing sample, the results are shown in Table 1.
Table 1
The sample that in table, " calcium/ATP ratio " is 0 means not add calcium salt, only with ATP, is tested.
Complementary testing 1: take active component as 1 weight portion, be respectively in 3,9,15,30,60 sample and supplement and add the microcrystalline Cellulose of 1 weight portion, the starch of 1 weight portion, the sucrose of 0.5 weight portion, the magnesium stearate of 0.1 weight portion, the silicon dioxide of 0.2 weight portion at above-mentioned " calcium/ATP ratio ", in mortar with the abundant mix homogeneously of lapping mode, powder is packed in hard capsule case, every contains adenosine triphosphate disodium salt 20mg, then with the aluminum-plastic composite membrane bag, capsule is packed.The same method of these capsules is carried out to the test that 45 ° of C place 5 months, after May, outward appearance is identical with the sample of the formula of corresponding in table 1 " calcium/ATP ratio ", and the sample of the formula of corresponding in remaining rate and table 1 " calcium/ATP ratio " is basic identical, all differ less than 1.8%, for example calcium/ATP is 94.5% than the remaining rate that is 30 capsule, with respective samples result in table 1, differs 0.7%.
Complementary testing 2: above-mentioned complementary testing 1 each capsule powders is pressed into to tablet, with method, carries out the test that 45 ° of C place 5 months, after May, the sample of the formula of corresponding in remaining rate and table 1 " calcium/ATP ratio " is basic identical, all differs less than 1.6%.
test example 2: the study on the stability of adenosine triphosphate disodium salt and calcium salt (dicalcium phosphate dihydrate) combination
According to the method preparation sample of test example 1, and tested with method, the cosmetic variation of investigation sample sample after 45 ° of C, lucifuge, sealing place are placed 5 months, and measure the remaining rate (%) of so disposing adenosine triphosphate disodium salt in the sample of front and back.The result demonstration is basically identical with the result in table one, and the formula of same calcium/ATP ratio is identical with test example table 1 aspect appearance luster, and for example calcium/ATP is than for the sample of 4-6, being micro-yellow powder after 5 months; The formula of same calcium/ATP ratio aspect remaining rate (%) with test example 1 table 1 result basic identical (differ and all be less than 2.5 percentage points), for example calcium/ATP is 71.3% (with in table 1,73.1% differing 1.8%) than the remaining rates of sample (%) that are this test example of 5, for example calcium/ATP is 95.8% (with in table 1,94.5% differing 1.3%) than the remaining rates of sample (%) that are this test example of 15 again, and for example calcium/ATP is 94.4% (with in table 1,95.7% differing 1.3%) than the sample remnants rates (%) that are this test example of 25 again.
test example 3: the study on the stability of adenosine triphosphate disodium salt and calcium salt (calcium phosphate dibasic anhydrous) combination
According to the method preparation sample of test example 1, and tested with method, the cosmetic variation of investigation sample sample after 45 ° of C, lucifuge, sealing place are placed 5 months, and measure the remaining rate (%) of so disposing adenosine triphosphate disodium salt in the sample of front and back.The result demonstration is basically identical with the result in table 1, and the formula of same calcium/ATP ratio is identical with test example table 1 aspect appearance luster; The formula of same calcium/ATP ratio aspect remaining rate (%) with test example 1 table 1 result basic identical (differ and all be less than 2 percentage points), for example calcium/ATP is 72.5% (with in table 1,73.1% differing 0.6%) than the remaining rates of sample (%) that are this test example of 5, and for example calcium/ATP is 94.8% (with in table 1,94.1% differing 0.7%) than the sample remnants rates (%) that are this test example of 20 again.
Complementary testing 1 and complementary testing 2 in reference test example 1 prepare capsule and tablet, and result shows that the sample of the formula of corresponding " calcium/ATP ratio " in the remaining rate of each sample and table 1 is basic identical, all differs less than 2.7%.
test example 4: the study on the stability of adenosine triphosphate disodium salt and calcium salt (calcium phosphate) combination
According to the method preparation sample of test example 1, and tested with method, the cosmetic variation of investigation sample sample after 45 ° of C, lucifuge, sealing place are placed 5 months, and measure the remaining rate (%) of so disposing adenosine triphosphate disodium salt in the sample of front and back.The result demonstration is basically identical with the result in table 1, and the formula of same calcium/ATP ratio is identical with test example table 1 aspect appearance luster; The formula of same calcium/ATP ratio aspect remaining rate (%) with test example 1 table 1 result basic identical (differ and all be less than 3 percentage points), for example calcium/ATP is 70.6% (with in table 1,73.1% differing 2.5%) than the remaining rates of sample (%) that are this test example of 5, and for example calcium/ATP is 91.7% (with in table 1,94.1% differing 2.4%) than the sample remnants rates (%) that are this test example of 20 again.
test example 5: the study on the stability of adenosine triphosphate disodium salt and calcium salt (calcium sulfate) combination
According to the method preparation sample of test example 1, and tested with method, the cosmetic variation of investigation sample sample after 45 ° of C, lucifuge, sealing place are placed 5 months, and measure the remaining rate (%) of so disposing adenosine triphosphate disodium salt in the sample of front and back.Result shows all flavescence after 5 months of each sample, become yellow to pale yellow powder, and remaining rates of each sample (%) are all lower than 72%, and particularly the lower remaining rate of calcium salt consumption is lower, for example calcium/ATP is only 57.3% than the sample remnants rates (%) that are this test example of 50.Typically this remaining rate has been significantly less than the scope of the 90-110% in labelled amount of usually stipulating in drug standard, thereby can not fulfilling medicinal requirements.
Complementary testing 1: the formula according to the ATP tablet of 250mg in US6723737B1 description the 6th hurdle embodiment 1 prepares the ATP sheet, the same method is with the aluminum-plastic composite membrane bag hermetic package and measure 45 ° of C, lucifuge, sealing place and place after 5 months the remaining rate (%) of ATP in sample, and result is 81.2%.This sample remaining rate of ATP after 20 ± 2 ° of C, lucifuge, sealing place are placed 2 years is 83.7%.
Complementary testing 2: the method according to the record of US20030069203A1 description [0045] to [0051] section prepares the ATP capsule, the same method is with the aluminum-plastic composite membrane bag hermetic package and measure 45 ° of C, lucifuge, sealing place and place after 5 months the remaining rate (%) of ATP in sample, and result is 83.5%.This sample remaining rate of ATP after 20 ± 2 ° of C, lucifuge, sealing place are placed 2 years is 79.8%.
Complementary testing 3: prepare the ATP enteric coated capsule according to following methods: at a lower temperature under humidity, get ATP powder 20g and fully be mixed with into microcapsule with sodium carboxymethyl cellulose 15g, low-substituted hydroxypropyl cellulose 15g, cross-linked pvp 10g, gelatin 5g, then microcapsule and microcrystalline Cellulose 5g, starch 25g, Pulvis Talci 5g are fully mixed, dress and No. 3 enteric coated capsulees, be prepared into 1000 enteric coated capsulees, the ATP that each capsule contains 20mg.By the same method of this enteric coated capsule, with the aluminum-plastic composite membrane bag hermetic package and measure 45 ° of C, lucifuge, sealing place and place after 5 months the remaining rate (%) of ATP in sample, result is 76.3%.This sample remaining rate of ATP after 20 ± 2 ° of C, lucifuge, sealing place are placed 2 years is 79.7%.But, in above-mentioned enteric coated capsule preparation process, when by sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, the two is replaced with calcium hydrogen phosphate or calcium carbonate, the gained sample is with after the aluminum-plastic composite membrane bag hermetic package, measure 45 ° of C places 5 months and 20 ° of remaining rates that C places ATP after 2 years simultaneously, when result is used calcium hydrogen phosphate, 45 ° of C and 20 ° of remaining rates of the rear ATP of C placement are respectively 93.3% and 95.2%, and while using calcium carbonate, 45 ° of C and 20 ° of C place rear ATP remnants rate and are respectively 96.1% and 93.4%.
test example 6: the compositions investigation that keeps sample for a long time
Get respectively each calcium/ATP in test example 1,2,3,4 than being totally 24,9,15,25,35,40,50 sample, under aluminum-plastic composite membrane bag hermetic package condition, in 20 ± 2 ° of C, lucifuge, sealing place, place 2 years, measure before and after so disposing the content of adenosine triphosphate disodium salt in sample, and after be calculated as follows the remaining rate (%) of active component adenosine triphosphate disodium salt in sample:
The result demonstration, after 24 samples measuring are placed 2 years at ambient temperature, in sample, the remaining rate (%) of active component adenosine triphosphate disodium salt is all between 92.6%～97.3%.For example, it is 94.3% that test example 1 calcium/ATP places the remaining rate of adenosine triphosphate disodium salt after 2 years at ambient temperature than the sample that is 9, it is 97.3% that test example 2 calcium/ATP places the remaining rate of adenosine triphosphate disodium salt after 2 years at ambient temperature than the sample that is 15, it is 96.1% that test example 3 calcium/ATP places the remaining rate of adenosine triphosphate disodium salt after 2 years at ambient temperature than the sample that is 25, and it is 93.6% that test example 4 calcium/ATP places the remaining rate of adenosine triphosphate disodium salt after 2 years at ambient temperature than the sample that is 50.
Complementary testing 1: get respectively in test example 1,2,3,4 each calcium/ATP than the sample that is 1,3,6, and in test example 5 calcium/ATP than the sample that is 5,10,30, make these samples under aluminum-plastic composite membrane bag hermetic package condition, in 20 ± 2 ° of C, lucifuge, sealing place, place 2 years, measure the content of so disposing adenosine triphosphate disodium salt in the sample of front and back, and the remaining rate (%) of active component adenosine triphosphate disodium salt in calculation sample, the remaining rate (%) of these samples is all lower than 80%, in 33%～78% scope as a result.
test example 7: tablet tabletting test
Formula (every amount, preparation is 10000/batches in batches):
| Adenosine triphosphate disodium salt | 20mg |
| Cross-linking sodium carboxymethyl cellulose | 5mg |
| Calcium hydrogen phosphate (anhydride) | 100mg |
| Dextrin | 30mg |
| Starch (the punching slurry is used) | 1.5mg |
| Silicon dioxide | 2mg |
| Magnesium stearate | 1.5mg |
Method for making: (1) is by starch punching slurry, standby as binding agent; (2) adenosine triphosphate disodium salt, sodium carboxymethyl cellulose, calcium hydrogen phosphate, dextrin are fully mixed, with binding agent soft material processed, cross 18 orders and granulate, 60 ° of C dryings; (3) dry granule is mixed homogeneously with silicon dioxide and magnesium stearate, tabletting.The gained tablet after measured, tablet weight variation 2.3%, friability less loss weight 0.21%.
Complementary testing 1: calcium hydrogen phosphate (anhydride) in above test example 7 is changed to dicalcium phosphate dihydrate, calcium carbonate or calcium phosphate, with the method film-making, three kinds of tablet weight differences of gained are in 1.5%～3.4% scope, in friability less loss weight 0.13%～0.32% scope, show and use other calcium salt also to there is similar results.The tablet of three kinds of tablets and test example 7 seals in 20 ± 2 ° of C, lucifuge, vial to be placed 2 years, after 2 years in tablet the remaining rate (%) of adenosine triphosphate disodium salt all in 93.3%～98.7% scope.
Complementary testing 2: the calcium salt in above test example 7 is used respectively to four kinds, calcium hydrogen phosphate (anhydride), dicalcium phosphate dihydrate, calcium carbonate or calcium phosphate; starch adds with powder and does not rush slurry; adopt conventional dry granulation tablet forming technique; after fully being mixed, each material is squeezed into large tablet with dry granulating machine; again with being broken into 16-24 purpose granule; then be pressed into tablet; four kinds of tablet weight differences of gained are in 1.2%～3.1% scope, in friability less loss weight 0.09%～0.31% scope.
Complementary testing 3: change the calcium salt consumption in above test example 7 into 50mg (be ATP approximately 10 moles doubly), 200mg (be ATP approximately 40 moles doubly), 300mg (be ATP approximately 60 moles doubly) or 400mg (be ATP approximately 80 moles doubly), according to test example 7 methods, prepare tablet.The tablet weight difference of calcium salt consumption 50mg and 200mg is in 1.4%～3.3% scope as a result, and friability less loss weight is in 0.1%～0.33% scope; And the tablet weight difference of calcium salt consumption 300mg and 400mg is in 1.0%～3.2% scope, but friability less loss weight is respectively 2.1% and 2.6%, and has the crack performance that distinct program is all arranged to occur.
Complementary testing 4: change the calcium salt in above test example 7 into calcium carbonate, consumption changes 37mg (be ATP approximately 10 moles doubly), 73mg (be ATP approximately 20 moles doubly), 110mg (be ATP approximately 30 moles doubly), 145mg (be ATP approximately 40 moles doubly), 181mg (be ATP approximately 50 moles doubly), 218mg (be ATP approximately 60 moles doubly) or 272mg (be ATP approximately 75 moles doubly) into, according to the dry granulation tablet forming technique of above complementary testing 2, prepares tablet.7 kinds of tablet weight differences of gained are all in 0.8%～3.4% scope.But friability less loss weight demonstrates the variation relevant with the calcium salt consumption, four kinds of tablet friability less loss weight of 37mg, 73mg, 110mg and 145mg calcium salt consumption are in 0.11%～0.34% scope; But three kinds of tablet friability less loss weight of 181mg, 218mg and 272mg calcium salt consumption are in 2.2%～2.75% scope, and there is the crack performance that distinct program is all arranged to occur.
Complementary testing 5: dextrin consumption in above test example 7 is changed to 0mg (replacing with microcrystalline cellulose excipients commonly used), 0mg (replacing with adjuvant lactose commonly used), 5mg (replacing with microcrystalline cellulose excipients 25mg commonly used), 10mg (replacing with microcrystalline cellulose excipients 20mg commonly used), 25mg (replacing with microcrystalline cellulose excipients 10mg commonly used), 50mg or 75mg, according to test example 7 method for makings, obtains 7 kinds of tablets.The tablet weight difference that the dextrin consumption is changed to 0mg, 0mg and 5mg as a result is respectively 6.8%, 7.3% and 7.1%, and friability less loss weight is respectively 0.91%, 0.94% and 0.88%.And the tablet weight difference that in prescription, the dextrin consumption was greater than/equaled 10mg is in 1.3%～3.6% scope, in friability less loss weight 0.12%～0.33% scope.
test example 8: tablet tabletting test
Formula (every amount, preparation is 10000/batches in batches):
| Adenosine triphosphate disodium salt | 20mg |
| Polyvinylpolypyrrolidone | 8mg |
| Calcium hydrogen phosphate (two water things) | 120mg |
| Dextrin | 25mg |
| Polyvinylpyrrolidone | 4mg |
| Silicon dioxide | 2mg |
| Magnesium stearate | 1mg |
Method for making: (1) is mixed with polyvinylpyrrolidone with 80% ethanol 5% solution, standby as binding agent; (2) adenosine triphosphate disodium salt, polyvinylpolypyrrolidone, calcium hydrogen phosphate, dextrin are fully mixed, with binding agent soft material processed, cross 18 orders and granulate, 60 ° of C dryings; (3) dry granule is mixed homogeneously with silicon dioxide and magnesium stearate, tabletting.The gained tablet after measured, tablet weight variation 1.7%, friability less loss weight 0.14%.
Complementary testing 1: calcium hydrogen phosphate in above test example 8 (two water things) is changed to calcium hydrogen phosphate anhydride, calcium carbonate or calcium phosphate, with the method film-making, three kinds of tablet weight differences of gained are in 1.2%～3.5% scope, in friability less loss weight 0.08%～0.33% scope, show and use other calcium salt also to there is similar results.The tablet of three kinds of tablets and test example 8 seals in 20 ± 2 ° of C, lucifuge, vial to be placed 2 years, after 2 years in tablet the remaining rate (%) of adenosine triphosphate disodium salt all in 92.4%～97.7% scope.
Complementary testing 2: the calcium salt in above test example 8 is used respectively to four kinds, calcium hydrogen phosphate (anhydride), dicalcium phosphate dihydrate, calcium carbonate or calcium phosphate; polyvinylpyrrolidone adds with powder and does not rush slurry; adopt conventional dry granulation tablet forming technique; after fully being mixed, each material is squeezed into large tablet with dry granulating machine; again with being broken into 16-24 purpose granule; then be pressed into tablet; four kinds of tablet weight differences of gained are in 0.8%～2.7% scope, in friability less loss weight 0.11%～0.30% scope.
Complementary testing 3: change the calcium salt consumption in above test example 8 into 62mg (be ATP approximately 10 moles doubly), 250mg (be ATP approximately 40 moles doubly), 375mg (be ATP approximately 60 moles doubly) or 500mg (be ATP approximately 80 moles doubly), according to test example 8 methods, prepare tablet.The tablet weight difference of calcium salt consumption 62mg and 250mg is in 1.2%～3.1% scope as a result, and friability less loss weight is in 0.12%～0.32% scope; And the tablet weight difference of calcium salt consumption 375mg and 500mg is in 1.2%～3.5% scope, but friability less loss weight is respectively 2.4% and 2.3%, and has the crack performance that distinct program is all arranged to occur.
Complementary testing 4: dextrin consumption in above test example 8 is changed to 0mg (replacing with microcrystalline cellulose excipients commonly used), 0mg (replacing with adjuvant lactose commonly used), 5mg (replacing with supplementary product starch 25mg commonly used), 10mg (replacing with supplementary product starch 20mg commonly used), 25mg (replacing with supplementary product starch 10mg commonly used), 50mg or 75mg, according to test example 7 method for makings, obtains 7 kinds of tablets.The tablet weight difference that the dextrin consumption is changed to 0mg, 0mg and 5mg as a result is respectively 7.0%, 6.9% and 7.4%, and friability less loss weight is respectively 0.96%, 0.91% and 0.93%.And the tablet weight difference that in prescription, the dextrin consumption was greater than/equaled 10mg is in 1.4%～3.2% scope, in friability less loss weight 0.14%～0.35% scope.
embodiment 1: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Carboxymethyl starch sodium | 5mg |
| L-Methionine | 1mg |
| Calcium hydrogen phosphate (two water things) | 150mg |
| Dextrin | 25mg |
| PEG4000 | 7 |
| Silicon dioxide | 3mg |
| Magnesium stearate | 1mg |
Method for making: PEG4000 is mixed with to 5% solution as binding agent with 70% ethanol, each material except silicon dioxide and magnesium stearate is fully mixed to the rear binding agent wet granulation of using, granule is mixed homogeneously with silicon dioxide and magnesium stearate after drying, then be pressed into tablet, every containing adenosine triphosphate disodium salt 20mg.
After measured, this tablet (plain sheet) tablet weight variation is 1.4%, and friability less loss weight 0.26% seals (being that the room temperature sealing is placed 2 years) the remaining rate 94.2% of adenosine triphosphate disodium salt after 2 years of placing in 20 ± 2 ° of C, lucifuge, vial.
This element sheet is carried out to coating (increasing weight 2%) with enteric coating material, and the remaining rate 93.4% of adenosine triphosphate disodium salt after 2 years is placed in the sealing of gained tablet room temperature.
Above before tabletting, that 1/5 final temperature granule is encapsulated, obtain every capsule containing adenosine triphosphate disodium salt 20mg, the remaining rate 93.8% of adenosine triphosphate disodium salt after 2 years is placed in its room temperature sealing.
embodiment 2: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Cross-linking sodium carboxymethyl cellulose | 5mg |
| Calcium carbonate | 120mg |
| Dextrin | 45mg |
| Polyvinylpyrrolidone | 7 |
| Magnesium stearate | 3mg |
Method for making: polyvinylpyrrolidone is mixed with to 5% solution as binding agent with 70% ethanol, each material except magnesium stearate is fully mixed to the rear binding agent wet granulation of using, granule is mixed homogeneously with magnesium stearate after drying, then is pressed into tablet, and every containing adenosine triphosphate disodium salt 20mg.
After measured, this tablet (plain sheet) tablet weight variation is 2.0%, friability less loss weight 0.29%, and the remaining rate 95.5% of adenosine triphosphate disodium salt after 2 years is placed in the room temperature sealing.
This element sheet is carried out to coating (increasing weight 8%) with enteric coating material, and the remaining rate 94.8% of adenosine triphosphate disodium salt after 2 years is placed in the sealing of gained tablet room temperature.
Above before tabletting, that 1/10 final temperature granule is encapsulated, obtain every capsule containing adenosine triphosphate disodium salt 20mg, the remaining rate 94.6% of adenosine triphosphate disodium salt after 2 years is placed in its room temperature sealing.
embodiment 3: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Low hydroxyl element the third cellulose that replaces | 3.8mg |
| L-Methionine | 1.2mg |
| Calcium hydrogen phosphate (anhydrous) | 100mg |
| Dextrin | 35mg |
| Starch | 1mg |
| Silicon dioxide | 3mg |
| Magnesium stearate | 1mg |
Method for making: adopt conventional dry granulation tablet forming technique; after fully being mixed, each material except silicon dioxide and magnesium stearate is squeezed into large tablet with dry granulating machine; be broken into again 16-24 purpose granule; silicon dioxide and magnesium stearate are mixed with the gained uniform particles; then be pressed into tablet, every containing adenosine triphosphate disodium salt 20mg.
After measured, this tablet (plain sheet) tablet weight variation is 1.8%, friability less loss weight 0.17%, and the remaining rate 95.4% of adenosine triphosphate disodium salt after 2 years is placed in the room temperature sealing.
This element sheet is carried out to coating (increasing weight 5%) with enteric coating material, and the remaining rate 95.8% of adenosine triphosphate disodium salt after 2 years is placed in the sealing of gained tablet room temperature.
Above before tabletting, that 1/10 final temperature granule is encapsulated, obtain every capsule containing adenosine triphosphate disodium salt 20mg, the remaining rate 94.7% of adenosine triphosphate disodium salt after 2 years is placed in its room temperature sealing.
embodiment 4: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Low hydroxyl element the third cellulose that replaces | 8mg |
| Calcium phosphate | 120mg |
| Dextrin | 35mg |
| Polyvinylpyrrolidone | 5mg |
| Magnesium stearate | 2mg |
Method for making: adopt conventional dry granulation tablet forming technique; after fully being mixed, each material except magnesium stearate is squeezed into large tablet with dry granulating machine; be broken into again 16-24 purpose granule; magnesium stearate is mixed with the gained uniform particles; then be pressed into tablet, every containing adenosine triphosphate disodium salt 20mg.
After measured, this tablet (plain sheet) tablet weight variation is 1.4%, friability less loss weight 0.23%, and the remaining rate 92.6% of adenosine triphosphate disodium salt after 2 years is placed in the room temperature sealing.
This element sheet is carried out to coating (increasing weight 6%) with enteric coating material, and the remaining rate 93.1% of adenosine triphosphate disodium salt after 2 years is placed in the sealing of gained tablet room temperature.
Above before tabletting, that 1/10 final temperature granule is encapsulated, obtain every capsule containing adenosine triphosphate disodium salt 20mg, the remaining rate 93.3% of adenosine triphosphate disodium salt after 2 years is placed in its room temperature sealing.
embodiment 5: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Low hydroxyl element the third cellulose that replaces | 5mg |
| Calcium hydrogen phosphate (anhydrous) | 40 moles of ATP doubly |
| Dextrin | 10mg |
| Polyvinylpyrrolidone | 4mg |
| Magnesium stearate | 1mg |
Method for making: according to embodiment 4 method preparations enteric coated.
Element sheet tablet weight variation is 1.3%, friability less loss weight 0.21%; The sealing of element sheet and casing sheet room temperature is placed after 2 years the remaining rate of adenosine triphosphate disodium salt in 92.2%～93.1% scope.
embodiment 6: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Low hydroxyl element the third cellulose that replaces | 8mg |
| Calcium carbonate | 25 moles of ATP doubly |
| Dextrin | 30mg |
| Polyvinylpyrrolidone | 5mg |
| Silicon dioxide | 2mg |
Method for making: according to embodiment 4 method preparations enteric coated.
Element sheet tablet weight variation is 1.2%, friability less loss weight 0.30%; The sealing of element sheet and casing sheet room temperature is placed after 2 years the remaining rate of adenosine triphosphate disodium salt in 93.1%～94.4% scope.
embodiment 7: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Low hydroxyl element the third cellulose that replaces | 10mg |
| Calcium phosphate | 10 moles of ATP doubly |
| Dextrin | 50mg |
| Microcrystalline Cellulose | 13 |
| Polyvinylpyrrolidone | 5mg |
| Pulvis Talci | 2mg |
Method for making: according to embodiment 2 method preparations enteric coated.
Element sheet tablet weight variation is 1.4%, friability less loss weight 0.33%; The sealing of element sheet and casing sheet room temperature is placed after 2 years the remaining rate of adenosine triphosphate disodium salt in 93.3%～94.2% scope.
embodiment 8: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Calcium hydrogen phosphate (anhydrous) | 10 moles of ATP doubly |
| Dextrin (diluent) | 50mg |
| Carboxymethyl starch sodium (disintegrating agent) | 1mg |
| Polyvinylpyrrolidone (binding agent) | 0.5mg |
| Magnesium stearate (lubricant) | 10mg |
Method for making: according to embodiment 4 method preparations enteric coated.
Element sheet tablet weight variation is 1.8%, friability less loss weight 0.31%; The sealing of element sheet and casing sheet room temperature is placed after 2 years the remaining rate of adenosine triphosphate disodium salt in 91.5%～93.0% scope.
embodiment 9: the pharmaceutical composition (tablet) that preparation contains adenosine triphosphate disodium salt
Formula (every amount):
| Adenosine triphosphate disodium salt | 20mg |
| Calcium hydrogen phosphate (dihydrate) | 40 moles of ATP doubly |
| Dextrin (diluent) | 10mg |
| Carboxymethyl starch sodium (disintegrating agent) | 10mg |
| Polyvinylpyrrolidone (binding agent) | 5mg |
| Magnesium stearate (lubricant) | 1mg |
Method for making: according to embodiment 4 method preparations enteric coated.
Element sheet tablet weight variation is 1.7%, friability less loss weight 0.23%; The sealing of element sheet and casing sheet room temperature is placed after 2 years the remaining rate of adenosine triphosphate disodium salt in 95.3%～96.0% scope.
Sample prepared by above-mentioned each test example or embodiment, each sample remaining rate of adenosine triphosphate disodium salt after room temperature (i.e. 20 ± 2 ° of C) sealing is placed 2 years all equates (all differ and be no more than 2 percentage points) substantially with this sample remaining rate of adenosine triphosphate disodium salt after high temperature (i.e. 45 ± 2 ° of C) sealing is placed 5 months.
Claims (15)
1. the purposes of calcium salt in the solid composite medicament of the stable adenosine triphosphate of preparation or its pharmaceutical salts.
2. according to the purposes of claim 1, at 20 ± 2 ° of C, (this temperature also can be described as room temperature or room temperature to wherein said solid composite medicament in the present invention, perhaps can be referred to as 20 ° of C), lucifuge, sealing place place after 2 years, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
3. according to the purposes of claim 1, wherein said solid composite medicament is at 45 ± 2 ° of C (this temperature high temperature in the present invention, perhaps can be referred to as 45 ° of C), lucifuge, sealing place place after 5 months, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
4. according to the purposes of claim 1, it is characterized in that following (i) and/or (ii):
(i) at 20 ± 2 ° of C, (this temperature also can be described as room temperature or room temperature to described solid composite medicament in the present invention, perhaps can be referred to as 20 ° of C), lucifuge, sealing place place after 2 years, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
(ii) described solid composite medicament is at 45 ± 2 ° of C (this temperature high temperature in the present invention, perhaps can be referred to as 45 ° of C), lucifuge, sealing place place after 5 months, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is more than 80%, (preferably remaining rate is 85～100%, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
5. according to the purposes of claim 1-4 any one, comprise adenosine triphosphate or its pharmaceutical salts, calcium salt and optional pharmaceutic adjuvant as active component in wherein said solid composite medicament.
6. according to the purposes of claim 1-5 any one, it is characterized in that:
The pharmaceutical salts of described adenosine triphosphate is adenosine triphosphate disodium salt;
Described calcium salt is inorganic calcium salt; And/or
Described inorganic calcium salt is selected from: calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium sulfate and solvate thereof be hydrate for example.
7. according to the purposes of claim 1-6 any one, the adenosine triphosphate that comprises 1 molar part in wherein said solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 2～60 molar part, 5～50 molar part, 9～40 molar part or 10～40 molar part.
8. according to the purposes of claim 1-7 any one, pharmaceutic adjuvant described in wherein said solid composite medicament is the acceptable adjuvant of pharmacy except described calcium salt; Described pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, lubricant etc.
9. according to the purposes of claim 1-8 any one, it is characterized in that:
Described solid composite medicament is the pharmaceutical preparation of tablet, granule or Capsule form;
The pharmaceutical preparation that described solid composite medicament is tablet form, this tablet is the tablet of coating; And/or
The pharmaceutical preparation that described solid composite medicament is tablet form, this tablet is the tablet of parcel enteric coating.
10. according to the purposes of claim 1-9 any one, it is characterized in that:
Described diluent is selected from: one or more of sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, differential silica gel, Pulvis Talci, magnesium stearate etc.;
Described disintegrating agent is selected from: polyvinylpolypyrrolidone, microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, differential silica gel, Pulvis Talci, one or more of magnesium stearate etc.,
Described binding agent is selected from: microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, calcium hydrogen phosphate, calcium carbonate, calcium sulfate, magnesium trisilicate, hypromellose, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, differential silica gel, Pulvis Talci, one or more of magnesium stearate etc., and/or
Described lubricant is to be selected from following one or more: magnesium stearate, aluminium stearate, calcium stearate, PEG4000 to 8000, Pulvis Talci, castor oil hydrogenated, stearic acid and salt thereof or glyceride, sodium stearyl fumarate etc. and combination thereof, and for example silica sol, magnesium silicate, Pulvis Talci and combination thereof of silicon dioxide.
11., according to the purposes of claim 1-10 any one, comprise in wherein said solid composite medicament:
12., according to the purposes of claim 1-11 any one, comprise in wherein said solid composite medicament:
13., according to the purposes of claim 1-12 any one, wherein said solid composite medicament is the pharmaceutical preparation that is tablet, granule or Capsule form; Further, its pharmaceutical preparation that is tablet form, this tablet is the tablet of coating; Further, its pharmaceutical preparation that is tablet form, this tablet is the tablet of parcel enteric coating.
14. a solid composite medicament, wherein comprise adenosine triphosphate or its pharmaceutical salts, calcium salt and optional pharmaceutic adjuvant as active component; Further, it has the described feature of embodiment as arbitrary as the description first aspect.
15. the method for the solid composite medicament described in preparation claim 1-14 any one, it comprises the following steps:
(i) each crushing material is become can pass through 60 purpose fine powders;
(ii) adenosine triphosphate or its salt are fully mixed homogeneously with calcium salt;
(iii) step (ii) the gained mixture pharmaceutic adjuvant optional with other mixed homogeneously, by the preparation technology of tablet, capsule or granule, be prepared into tablet, capsule or granule;
(iv) optionally step (iii) gained tablet is carried out to coating for example enteric coated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310076725.4A CN103110602B (en) | 2013-03-12 | 2013-03-12 | Disodium adenosine triphosphate troche medical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310076725.4A CN103110602B (en) | 2013-03-12 | 2013-03-12 | Disodium adenosine triphosphate troche medical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103110602A true CN103110602A (en) | 2013-05-22 |
| CN103110602B CN103110602B (en) | 2014-09-24 |
Family
ID=48409002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310076725.4A Active CN103110602B (en) | 2013-03-12 | 2013-03-12 | Disodium adenosine triphosphate troche medical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103110602B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016046734A3 (en) * | 2014-09-22 | 2016-06-30 | University Of The Western Cape | Compounds and compositions for treatment of tuberculosis |
| CN106619554A (en) * | 2016-10-12 | 2017-05-10 | 南京康凯生物科技有限公司 | Adenosine triphosphate disodium tablet and preparation method thereof |
| CN107233322A (en) * | 2017-05-04 | 2017-10-10 | 广西大海阳光药业有限公司 | It is a kind of to treat progressive myatrophy, cerebral hemorrhage sequelae, the pharmaceutical preparation of cardiac insufficiency |
| CN111346062A (en) * | 2020-03-11 | 2020-06-30 | 左人杰 | Orally disintegrating tablet with composite calcium salt for improving stability of main drug and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1666748A (en) * | 2004-03-10 | 2005-09-14 | 孙明杰 | Oral formulation of adetphos |
-
2013
- 2013-03-12 CN CN201310076725.4A patent/CN103110602B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1666748A (en) * | 2004-03-10 | 2005-09-14 | 孙明杰 | Oral formulation of adetphos |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016046734A3 (en) * | 2014-09-22 | 2016-06-30 | University Of The Western Cape | Compounds and compositions for treatment of tuberculosis |
| CN106619554A (en) * | 2016-10-12 | 2017-05-10 | 南京康凯生物科技有限公司 | Adenosine triphosphate disodium tablet and preparation method thereof |
| CN107233322A (en) * | 2017-05-04 | 2017-10-10 | 广西大海阳光药业有限公司 | It is a kind of to treat progressive myatrophy, cerebral hemorrhage sequelae, the pharmaceutical preparation of cardiac insufficiency |
| CN111346062A (en) * | 2020-03-11 | 2020-06-30 | 左人杰 | Orally disintegrating tablet with composite calcium salt for improving stability of main drug and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103110602B (en) | 2014-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103127024B (en) | Stable disodium adenosine triphosphate tablet | |
| US10064826B2 (en) | Direct compression and dry granulation processes for preparing carglumic acid tablets having less impurities than those produced by wet granulation process | |
| EP2448561B1 (en) | Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and their therapeutic application | |
| MX2009002336A (en) | Imatinib compositions. | |
| CN103110602B (en) | Disodium adenosine triphosphate troche medical composition | |
| KR102184254B1 (en) | Solid pharmaceutical preparation containing levothyroxine | |
| EP1976522B1 (en) | Pharmaceutical composition containing montelukast | |
| JP2023175743A (en) | Pharmaceutical composition containing poorly soluble basic drug | |
| US7198802B2 (en) | Tablet obtained by direct compression comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid as active ingredient | |
| CN102813656A (en) | Stable medicine composition of 5-methyltetrahydrofolic acid or salt thereof | |
| EP2538924B1 (en) | Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation | |
| AU2013365715A1 (en) | A pharmaceutical composition containing candesartan cilexetil and amlodipine | |
| KR20160002177A (en) | Pharmaceutical composition comprising oseltamivir free base | |
| JP2016037463A (en) | Pharmaceutical composition containing voriconazole | |
| US20180250233A1 (en) | Tablets having media independent active substance delivery | |
| WO2017093890A1 (en) | Clobazam tablet formulation and process for its preparation | |
| JP6114573B2 (en) | Solid formulation containing loxoprofen sodium and antacid | |
| JP2022130003A (en) | Solid preparation containing chinese medicine extract or vegetable herbal medicine extract, and method for producing the same, and method for improving the ease of disintegration of solid preparation | |
| BRPI0621739A2 (en) | stable formulation consisting of wetting sensitive drugs and their manufacturing procedure | |
| KR102102462B1 (en) | Pharmaceutical composition comprising oseltamivir free base | |
| US20230055674A1 (en) | Cellulose composition and tablet | |
| KR20220024543A (en) | Composition comprising metformin HCl, vitamin B12 and one or more flow additives | |
| KR20220123271A (en) | 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2- Stable immediate release tablet and capsule formulation of en-1-one | |
| CN117695285A (en) | JAK kinase inhibitor pharmaceutical composition | |
| JP2018016609A (en) | Solid formulation containing bazedoxifene acetate and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |