CN103110602B - Disodium adenosine triphosphate troche medical composition - Google Patents
Disodium adenosine triphosphate troche medical composition Download PDFInfo
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- CN103110602B CN103110602B CN201310076725.4A CN201310076725A CN103110602B CN 103110602 B CN103110602 B CN 103110602B CN 201310076725 A CN201310076725 A CN 201310076725A CN 103110602 B CN103110602 B CN 103110602B
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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 if relate more specifically to the solid composite medicament that contains adenosine triphosphate or its pharmaceutical salts of the excellent storage stability that after preserving for a long time, active constituent content also can highly maintain.
Background technology
Adenosine triphosphate, is 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 phosphoric acid donor.Clinical conventional adenosine triphosphate 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, for example becomes known for for the stabilisation of the regulative mechanism of injury of head sequela, arrhythmia, accommodative asthenopia, is counted as the curative of chronic gastritis of digestive tract underactivity etc.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 the pharmaceutical salts preparation that particularly for example adenosine triphosphate disodium salt is active component of for example 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, in the haulage stage, use the desiccant such as silica gel, or carry out stored refrigerated, but exist due to adopt this additional store method increased follow desiccant use manufacturing cost, 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.Stabilization method as the derivant of ADP etc. discloses to regulate moisture as the stabilization method as feature below 4.0% in JP49-87684, but the method is the moisture containing 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 object.
For this reason, those skilled in the art expect there is new method, and clinical a kind of particularly solid composite medicament 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 of 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 particularly inorganic calcium salt and adenosine triphosphate or its pharmaceutical salts combines the pharmaceutical composition of making and 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: such as hydrate of calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium sulfate and solvate thereof.
As everyone knows, its molecular formula of calcium hydrogen phosphate is CaHPO
4, molecular weight approximately 136, every mole of calcium is equivalent to 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 100g calcium carbonate.These calcium salts can use 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 172g dicalcium phosphate dihydrate).But during in the present invention to these calcium salt meterings, be all converted to its anhydride meter (for example, for dicalcium phosphate dihydrate CaHPO
42H
2o, every mole of calcium is equivalent to 136g calcium hydrogen phosphate, recipe quantity is counted 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 " represent, for the adenosine triphosphate or its pharmaceutical salts of every 1 molar part, the calcium salt amount comprising in said composition is counted 10～40 molar part with calcium.For example comprise 1 mole of adenosine triphosphate disodium salt in a compositions, its weight is 551 grams, calcium salt amount is counted 10～40 moles with calcium, if use calcium hydrogen phosphate, be (10～40) × 136 gram=1360g～5440g, if use calcium phosphate, be (10～40) × 103 gram ÷ 3=1030g～4120g, if use calcium carbonate is (10～40) × 100 gram=1000g～4000g.While having 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 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.
According to the solid composite medicament of 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.
According to the solid composite medicament of 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.
In the time that pharmaceutical composition of the present invention is prepared into tablet, prepared by its mode that can prepare tablet by many routines, for example it can be prepared 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.In the time preparing the pharmaceutical composition of tablet form of the present invention with direct powder compression or dry granulation tablet forming technique, binding agent wherein adds with dry powder form.And in the time preparing the pharmaceutical composition of tablet form of the present invention with wet granule compression tablet technique, binding agent is wherein for example aqueous solution of solution or the alcoholic solution being mixed with, then join in powder to prepare wet granular, wet granule compression tablet technique is prepared tablet routinely; Or, in wet granule compression tablet technique, also can make these binding agents directly with powder type and other mixing of materials, then use for example water of wetting agent or aquiferous ethanol wet granular processed, wet granule compression tablet technique is prepared tablet routinely.In any case in wet granule compression tablet technique, the solvent of the wetting agent adding or preparation binder solution, is removed substantially at these solvents that obtain after dry finished granule wherein.
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 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 silicon dioxide for example silica sol, magnesium silicate, Pulvis Talci and combination thereof.Most preferred lubricant is magnesium stearate, Pulvis Talci, silicon dioxide and combination thereof.
According to the solid composite medicament of first aspect present invention, the relative quantity of wherein said pharmaceutic adjuvant in compositions can be changing 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 can add in compositions with the amount of the 1-5% that accounts for composition total weight as the adjuvant of lubricant, for example can add in compositions with the amount of the 1-10% that accounts for composition total weight as the adjuvant of binding agent, for example can add in compositions with the amount of the 1-20% that accounts for composition total weight as the adjuvant of disintegrating agent, 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 solid composite medicament of first aspect present invention, wherein comprise:
According to the solid composite medicament of first aspect present invention, wherein comprise:
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 active dose in minimum package unit or the minimum medication unit of compositions is 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, in its every, comprising adenosine triphosphate disodium salt 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, 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 the friability of for example plain sheet 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 of the stable adenosine triphosphate of preparation or its pharmaceutical salts.
According to the purposes described in 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, or can be referred to as 20 ° of C), lucifuge, sealing place place after 2 years, in compositions, more than 80%, (preferably remaining rate is 85～100% to the remaining rate of active component adenosine triphosphate or its pharmaceutical salts, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
According to the purposes described in second aspect present invention, wherein said solid composite medicament is at 45 ± 2 ° of C (this temperature high temperature in the present invention, or can be referred to as 45 ° of C), lucifuge, sealing place place after 5 months, in compositions, more than 80%, (preferably remaining rate is 85～100% to the remaining rate of active component adenosine triphosphate or its pharmaceutical salts, preferably remaining rate is 90～100%), wherein said remaining rate (%) calculating formula is as follows:
According to the purposes described in 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, or can be referred to as 20 ° of C), lucifuge, sealing place place after 2 years, in compositions, more than 80%, (preferably remaining rate is 85～100% to the remaining rate of active component adenosine triphosphate or its pharmaceutical salts, 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, or can be referred to as 45 ° of C), lucifuge, sealing place place after 5 months, in compositions, more than 80%, (preferably remaining rate is 85～100% to the remaining rate of active component adenosine triphosphate or its pharmaceutical salts, 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 purposes described in second aspect present invention, in wherein said solid composite medicament, comprise adenosine triphosphate or its pharmaceutical salts, calcium salt and optional pharmaceutic adjuvant as active component.
According to the purposes described in second aspect present invention, the pharmaceutical salts of wherein said adenosine triphosphate is adenosine triphosphate disodium salt.
According to the purposes described in second aspect present invention, wherein said calcium salt is inorganic calcium salt.
According to the purposes described in second aspect present invention, wherein said inorganic calcium salt is selected from: such as hydrate of calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium sulfate and solvate thereof.
According to the purposes described in 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 purposes described in 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 purposes described in 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 purposes described in 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 purposes described in 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 purposes described in 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 disintegrating agent function.
According to the purposes described in second aspect present invention, wherein said solid composite medicament is the pharmaceutical preparation of tablet, granule or Capsule form.
According to the purposes described in 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 purposes described in 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 purposes described in 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 purposes described in 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 purposes described in 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.
In the time that pharmaceutical composition of the present invention is prepared into tablet, prepared by its mode that can prepare tablet by many routines, for example it can be prepared 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.In the time preparing the pharmaceutical composition of tablet form of the present invention with direct powder compression or dry granulation tablet forming technique, binding agent wherein adds with dry powder form.And in the time preparing the pharmaceutical composition of tablet form of the present invention with wet granule compression tablet technique, binding agent is wherein for example aqueous solution of solution or the alcoholic solution being mixed with, then join in powder to prepare wet granular, wet granule compression tablet technique is prepared tablet routinely; Or, in wet granule compression tablet technique, also can make these binding agents directly with powder type and other mixing of materials, then use for example water of wetting agent or aquiferous ethanol wet granular processed, wet granule compression tablet technique is prepared tablet routinely.In any case in wet granule compression tablet technique, the solvent of the wetting agent adding or preparation binder solution, is removed substantially at these solvents that obtain after dry finished granule wherein.
According to the purposes described in 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 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 silicon dioxide for example silica sol, magnesium silicate, Pulvis Talci and combination thereof.Most preferred lubricant is magnesium stearate, Pulvis Talci, silicon dioxide and combination thereof.
According to the purposes described in second aspect present invention, the relative quantity of pharmaceutic adjuvant described in wherein said solid composite medicament in compositions can be changing 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 can add in compositions with the amount of the 1-5% that accounts for composition total weight as the adjuvant of lubricant, for example can add in compositions with the amount of the 1-10% that accounts for composition total weight as the adjuvant of binding agent, for example can add in compositions with the amount of the 1-20% that accounts for composition total weight as the adjuvant of disintegrating agent, 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 purposes described in second aspect present invention, in wherein said solid composite medicament, comprise:
According to the purposes described in 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 purposes described in 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 active dose in minimum package unit or the minimum medication unit of compositions is 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, in its every, comprising adenosine triphosphate disodium salt 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, 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 purposes described in 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 the friability of for example plain sheet 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 purposes described in solid composite medicament described in preparation first aspect present invention arbitrary embodiment or second aspect present invention any one, and it comprises the following steps:
(i) each crushing material is become can pass through 60 object 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, be prepared into tablet, capsule or granule by the preparation technology of tablet, capsule or granule;
(iv) optionally step (iii) gained tablet is carried out to coating for example enteric coated.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, 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.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein 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 be explained, 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, in the time that pharmaceutical composition of the present invention is pressed into tablet, in adenosine triphosphate or its pharmaceutical salts of every 20 weight portions, add wherein 5-80 weight portion (for example 10～60 weight portions, for example 10～50 weight portions) dextrin during as diluent, are very favourable (although relevant with friability aspect of performance with tablet weight difference without any technology instruction dextrin) for improving the tablet weight variation of tablet and the performance of friability two aspects.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 each edition " Chinese Pharmacopoeia " all has detailed regulation to its performance, so that tablet meets the requirement of " safe, effective, controlled (being steady quality) ".Particularly, tablet is in the friability (mechanical performance of reflection tablet, friability performance well tablet be beneficial to process the such as operation such as coating, transport) and tablet weight variation (reflection tablet tabletting performance and uniformity, the little uniformity that is conducive to administration of difference, the concordance of guarantee therapeutic effect) should there is good performance.For example, " weight differential " (formulation art technical staff is also referred to as " tablet weight variation " conventionally for tablet) inspection method and the general provision thereof of the tablet that two annex page 5 of version " Chinese Pharmacopoeia " in 2010 specify, 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 in a collection of tablet, so that the dosage that patient takes while using is accurate.Again for example, two annex of version " Chinese Pharmacopoeia " in 2010 the 89th page (annex XG) have specified " the tablet friability inspection method " of tablet, and " the less loss weight " measured using the method is as the whether qualified index of judge tablet quality.It is generally 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, every 100 grams of tablets carry out after this inspection technique processing, make tablet weight reduce through tablet surface wearing and tearing etc., this reduction value can not exceed 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 measure with said method, while relating to friability and/or less loss weight (%), all measure with said method.
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 when calcium salt content in compositions is the more than 2 times of active component mole with calcium ion mole, preferably more than 5 times, while being more preferably more than 9 times, be quite obvious for the stability that improves active component.
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, but in the time that described calcium salt is increased to certain procedures, for example in calcium ion mole be active component more than 60 times time, be shaped and have adverse influence for tablet, to the plain sheet of coating not carry out 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 is preferably controlled at below 60 times of active component mole in calcium ion mole, preferably, below 50 times, is more preferably below 40 times.
In the present invention, if be not specifically noted, while mentioning " adenosine triphosphate ", refer to this material of general reference, and comprise particularly for example its disodium salt (being adenosine triphosphate disodium salt) of adenosine triphosphate and the acceptable salt of its pharmacy, and for example hydrate of their solvate (for example adenosine triphosphate disodium salt trihydrate).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 the 28th page contained " adenosine triphosphate disodium salt " kind item of Chinese Pharmacopoeia version in 2010.In the time below carrying out specific experiment, if not otherwise indicated, active component used is the standard that meets above-mentioned pharmacopeia, and in the time of preparation compositions, while carrying out formula ratio calculating, all calculate with its anhydride, for example, indicate when inventory is 551 grams of adenosine triphosphate disodium salts actual 605 grams of the adenosine triphosphate disodium salt trihydrates that add.
The inorganic calcium salt using is in the present invention some conventional pharmaceutic adjuvants, and they can easily be buied from the market, and meet relevant drug standard.In the present invention below tests, if not otherwise indicated, the calcium hydrogen phosphate using 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 using 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 using is commercial gained and meets the quality standard requirement under this kind item of American Pharmacopeia USP-NF1990 version, the calcium carbonate using 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 using 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 by prepared the present invention tablet coating, coating material can be prepared voluntarily according to existing experience and knowledge; Or 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 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, remove after coating, porphyrize, precision takes in right amount (being approximately equivalent to adenosine triphosphate disodium salt 0.1g), put in 200ml measuring bottle, add 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, measure according to ultraviolet-spectrophotography (Chinese Pharmacopoeia version annex IV A in 2010), taking 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 annex V D in 2010).
Chromatographic condition and system suitability octadecyl silane are filler; (get sodium hydrogen phosphate 35.8g with 0.2mol/L phosphate buffer, potassium dihydrogen phosphate 13.6g, the 900ml that adds water dissolves, with 1mol/L sodium hydroxide solution adjusting pH value to 7.0, add tetrabutyl ammonium bromide 1.61g, adding water to 1000ml, shake up)-methanol (95:5) is for mobile phase; Column temperature is 35 DEG C; Detection wavelength is 259nm.Number of theoretical plate calculates and should be greater than 1500 by adenosine triphosphate disodium salt peak; The separating degree of each chromatographic peak should conform with the regulations.Go out 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 containing 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:
Weight ratio × 100% of adenosine triphosphate disodium salt content (%)=total nucleotide × adenosine triphosphate disodium salt
In addition, can also measure the impurity (conventionally 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 the 28th page contained " adenosine triphosphate disodium salt " kind item of Chinese Pharmacopoeia version in 2010, and the relative quantity of impurity containedly in compositions desolventizing, beyond adjuvant represents.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.
Detailed description of the invention
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 describing 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 be well known in the art for realizing many materials and the operational approach that the object of the invention uses, 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.
When various tablet, if not otherwise indicated, tablet is all suppressed with the tablet machine of same model below.And the tabletting punching-Mo that selects suitable size compares within the scope of 1.65-1.75 so that different big or small tablet has suitable axial/radial stress the diameter/thickness of gained tablet; Various tablets, in the time of compacting, are all 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 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 (testing with 100 grams of amounts for its every batch) and calcium salt calcium carbonate according to the form below, in mortar with the abundant mix homogeneously of lapping mode, then use aluminum-plastic composite membrane bag hermetic package, 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 " represent) and gained sample with the remaining rate (%) after high-temperature treatment May, and the outward appearance (color and luster) of observing sample after above-mentioned 45 ° of C dispose May, the results are shown in Table 1.
Table 1
In table, " calcium/ATP ratio " is that 0 sample represents not add calcium salt, only tests with ATP.
Complementary testing 1: taking 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 aluminum-plastic composite membrane bag, capsule is packed.The same these capsules method is carried out to the test that 45 ° of C place 5 months, after May, the sample of the formula of outward appearance corresponding with table 1 " calcium/ATP ratio " is identical, 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, differs 0.7% with respective samples result in table 1.
Complementary testing 2: the each capsule powders of above-mentioned complementary testing 1 is pressed into tablet, carries out with method 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 test 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 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 was micro-yellow powder than the sample for 4-6 after 5 months; The formula of same calcium/ATP ratio aspect remaining rate (%) with test example 1 table 1 result basic identical (differ and be all less than 2.5 percentage points), for example calcium/ATP is 71.3% (with 73.1% differing 1.8% in table 1) than the remaining rates of sample (%) that are this test example of 5, for example calcium/ATP is 95.8% (with 94.5% differing 1.3% in table 1) than the remaining rates of sample (%) that are this test example of 15 again, and for example calcium/ATP is 94.4% (with 95.7% differing 1.3% in table 1) 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 test 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 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 be all less than 2 percentage points), for example calcium/ATP is 72.5% (with 73.1% differing 0.6% in table 1) than the remaining rates of sample (%) that are this test example of 5, and for example calcium/ATP is 94.8% (with 94.1% differing 0.7% in table 1) than the sample remnants rates (%) that are this test example of 20 again.
Capsule and tablet are prepared in complementary testing 1 and complementary testing 2 in reference test example 1, 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 test 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 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 be all less than 3 percentage points), for example calcium/ATP is 70.6% (with 73.1% differing 2.5% in table 1) than the remaining rates of sample (%) that are this test example of 5, and for example calcium/ATP is 91.7% (with 94.1% differing 2.4% in table 1) 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 test 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 the remaining rate of each sample (%) is all lower than 72%, particularly the lower remaining rate of calcium salt consumption is lower, and for example calcium/ATP is only 57.3% than the remaining rates of sample (%) that are this test example of 50.Typically this remaining rate be significantly less than in drug standard conventionally regulation in the 90-110% of labelled amount scope, 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 is prepared ATP sheet, the same method is with aluminum-plastic composite membrane bag hermetic package and measure 45 ° of C, lucifuge, sealing place and place after 5 months the remaining rates 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 for recording according to US20030069203A1 description [0045] to [0051] section is prepared ATP capsule, the same method is with aluminum-plastic composite membrane bag hermetic package and measure 45 ° of C, lucifuge, sealing place and place after 5 months the remaining rates 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 ATP enteric coated capsule according to following methods: at a lower temperature under humidity, get ATP powder 20g and be fully 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 this enteric coated capsule method, with aluminum-plastic composite membrane bag hermetic package and measure 45 ° of C, lucifuge, sealing place and place after 5 months the remaining rates 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, gained sample is with after 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, after 45 ° of C and 20 ° of C placements, the remaining rate of ATP is respectively 93.3% and 95.2%, and while using calcium carbonate, 45 ° of C and 20 ° of C place the remaining rate of rear ATP 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, place 2 years in 20 ± 2 ° of C, lucifuge, sealing place, 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:
Result demonstration, 24 samples measuring are placed after 2 years at ambient temperature, and 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, place 2 years in 20 ± 2 ° of C, lucifuge, sealing place, 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 of result is all lower than 80%, in 33%～78% scope.
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 (punching slurry is used) | 1.5mg |
| Silicon dioxide | 2mg |
| Magnesium stearate | 1.5mg |
Method for making: (1) is by starch punching slurry, for subsequent use 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 are dry; (3) dry granule is mixed homogeneously with silicon dioxide and magnesium stearate, tabletting.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 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 object 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 approximately 40 moles of ATP doubly), 300mg (be approximately 60 moles of ATP doubly) or 400mg (be approximately 80 moles of ATP doubly), prepare tablet according to test example 7 methods.The tablet weight difference of result calcium salt consumption 50mg and 200mg is in 1.4%～3.3% scope, 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 and all have the crack performance of distinct program 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 approximately 20 moles of ATP doubly), 110mg (be approximately 30 moles of ATP doubly), 145mg (be approximately 40 moles of ATP doubly), 181mg (be approximately 50 moles of ATP doubly), 218mg (be approximately 60 moles of ATP doubly) or 272mg (be approximately 75 moles of ATP doubly) into, prepares tablet according to the dry granulation tablet forming technique of above complementary testing 2.7 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 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 have and all have the crack performance of distinct program to occur.
Complementary testing 5: dextrin consumption in above test example 7 is changed to 0mg (with conventional microcrystalline cellulose excipients replacement), 0mg (replacing with commonly using adjuvant lactose), 5mg (replacing with commonly using microcrystalline cellulose excipients 25mg), 10mg (using conventional microcrystalline cellulose excipients 20mg to replace), 25mg (using conventional microcrystalline cellulose excipients 10mg replacement), 50mg or 75mg, obtains 7 kinds of tablets according to test example 7 method for makings.The tablet weight difference that result dextrin consumption is changed to 0mg, 0mg and 5mg 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, dextrin consumption is greater than/equals 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, for subsequent use 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 are dry; (3) dry granule is mixed homogeneously with silicon dioxide and magnesium stearate, tabletting.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 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 object 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 approximately 40 moles of ATP doubly), 375mg (be approximately 60 moles of ATP doubly) or 500mg (be approximately 80 moles of ATP doubly), prepare tablet according to test example 8 methods.The tablet weight difference of result calcium salt consumption 62mg and 250mg is in 1.2%～3.1% scope, 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 and all have the crack performance of distinct program to occur.
Complementary testing 4: dextrin consumption in above test example 8 is changed to 0mg (with conventional microcrystalline cellulose excipients replacement), 0mg (replacing with commonly using adjuvant lactose), 5mg (replacing with commonly using supplementary product starch 25mg), 10mg (using conventional supplementary product starch 20mg to replace), 25mg (using conventional supplementary product starch 10mg replacement), 50mg or 75mg, obtains 7 kinds of tablets according to test example 7 method for makings.The tablet weight difference that result dextrin consumption is changed to 0mg, 0mg and 5mg 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, dextrin consumption is greater than/equals 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 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 (weightening finish 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 by encapsulated 1/5 final temperature granule, 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, is then 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 room temperature sealing.
This element sheet is carried out to coating (weightening finish 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 by encapsulated 1/10 final temperature granule, 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 replacement hydroxyl element the third cellulose | 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 object granule; silicon dioxide and magnesium stearate are mixed with 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 room temperature sealing.
This element sheet is carried out to coating (weightening finish 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 by encapsulated 1/10 final temperature granule, 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 replacement hydroxyl element the third cellulose | 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 object granule; magnesium stearate is mixed with 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 room temperature sealing.
This element sheet is carried out to coating (weightening finish 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 by encapsulated 1/10 final temperature granule, 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 replacement hydroxyl element the third cellulose | 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 replacement hydroxyl element the third cellulose | 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 replacement hydroxyl element the third cellulose | 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 (25)
1. the purposes of calcium salt in the solid composite medicament of the stable adenosine triphosphate of preparation or its pharmaceutical salts; Wherein:
In described solid composite medicament, comprise adenosine triphosphate or its pharmaceutical salts, calcium salt and the optional pharmaceutic adjuvant except described calcium salt as active component,
Described calcium salt is selected from: calcium hydrogen phosphate, calcium phosphate, calcium carbonate and hydrate thereof,
The adenosine triphosphate that comprises 1 molar part in described solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 9 ~ 40 molar part.
2. according to the purposes of claim 1, wherein said solid composite medicament is placed after 2 years in 20 ± 2 ° of C, lucifuge, sealing place, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 85 ~ 100%, and wherein said remaining rate (%) calculating formula is as follows:
。
3. according to the purposes of claim 2, wherein said solid composite medicament is placed after 2 years in 20 ± 2 ° of C, lucifuge, sealing place, and in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 90 ~ 100%.
4. according to the purposes of claim 1, wherein said solid composite medicament is placed after 5 months in 45 ± 2 ° of C, lucifuge, sealing place, in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 85 ~ 100%, and wherein said remaining rate (%) calculating formula is as follows:
。
5. according to the purposes of claim 4, wherein said solid composite medicament is placed after 5 months in 45 ± 2 ° of C, lucifuge, sealing place, and in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 90 ~ 100%.
6. according to the purposes of claim 1, it is characterized in that following (i) and (ii):
(i) described solid composite medicament is placed after 2 years in 20 ± 2 ° of C, lucifuge, sealing place, and in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 85 ~ 100%, and wherein said remaining rate (%) calculating formula is as follows:
；
(ii) described solid composite medicament is placed after 5 months in 45 ± 2 ° of C, lucifuge, sealing place, and in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 85 ~ 100%, and wherein said remaining rate (%) calculating formula is as follows:
。
7. according to the purposes of claim 6, it is characterized in that following (i) and (ii):
(i) described solid composite medicament is placed after 2 years in 20 ± 2 ° of C, lucifuge, sealing place, and in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 90 ~ 100%, and wherein said remaining rate (%) calculating formula is as follows:
；
(ii) described solid composite medicament is placed after 5 months in 45 ± 2 ° of C, lucifuge, sealing place, and in compositions, the remaining rate of active component adenosine triphosphate or its pharmaceutical salts is 90 ~ 100%, and wherein said remaining rate (%) calculating formula is as follows:
。
8. according to the purposes of claim 1, it is characterized in that: the pharmaceutical salts of described adenosine triphosphate is adenosine triphosphate disodium salt.
9. according to the purposes of claim 1, 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.
10. according to the purposes of claim 1, wherein said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, lubricant.
11. according to the purposes of claim 1, and described solid composite medicament is the pharmaceutical preparation that is tablet, granule or Capsule form.
12. according to the purposes of claim 1, the pharmaceutical preparation that wherein said solid composite medicament is tablet form, and this tablet is the tablet of coating.
13. according to the purposes of claim 1, the pharmaceutical preparation that wherein said solid composite medicament is tablet form, and this tablet is the tablet of parcel enteric coating.
14. according to the purposes of claim 10, and described diluent is selected from: one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, sucrose, mannitol, sorbitol, starch, dextrin, magnesium trisilicate.
15. according to the purposes of claim 10, and wherein said disintegrating agent is selected from: one or more in polyvinylpolypyrrolidone, hydroxypropyl cellulose, copolyvidone, methylcellulose, carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone.
16. according to the purposes of claim 10, and wherein said 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.
17. according to the purposes of claim 10, and wherein said 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 or its glyceride, sodium stearyl fumarate, silicon dioxide, magnesium silicate.
18. according to the purposes of claim 1, in wherein said solid composite medicament, comprises:
Adenosine triphosphate or its pharmaceutical salts: 20 weight portions,
Calcium salt: be adenosine triphosphate or its pharmaceutical salts mole 9 ~ 40 times in compositions in its mole of calcium ion, and
Pharmaceutic adjuvant: 10-100 weight portion.
19. according to the purposes of claim 1, in wherein said solid composite medicament, comprises:
Adenosine triphosphate or its pharmaceutical salts: 20 weight portions,
Calcium salt: be adenosine triphosphate or its pharmaceutical salts mole 10 ~ 40 times in compositions in its mole of calcium ion, and
Pharmaceutic adjuvant: 20 ~ 80 weight portions.
20. according to the purposes of claim 10, in wherein said solid composite medicament, comprises:
Adenosine triphosphate or its pharmaceutical salts: 20 weight portions,
Calcium salt: be adenosine triphosphate or its pharmaceutical salts mole 9 ~ 40 times in compositions in its mole of calcium ion,
Diluent: 5-80 weight portion,
Disintegrating agent: 0.5 ~ 15 weight portion,
Binding agent: 0.5 ~ 10 weight portion, and
Lubricant: 0.5 ~ 15 weight portion.
21. according to the purposes of claim 10, in wherein said solid composite medicament, comprises:
Adenosine triphosphate or its pharmaceutical salts: 20 weight portions,
Calcium salt: be adenosine triphosphate or its pharmaceutical salts mole 10 ~ 40 times in compositions in its mole of calcium ion,
Diluent: 10 ~ 60 weight portions,
Disintegrating agent: 1 ~ 10 weight portion,
Binding agent: 0.5 ~ 5 weight portion, and
Lubricant: 1 ~ 10 weight portion.
22. according to the purposes of claim 1-21 any one, and wherein said solid composite medicament is the pharmaceutical preparation that is tablet form, in adenosine triphosphate or its pharmaceutical salts of every 20 weight portions, comprises the dextrin as 10 ~ 50 weight portions of diluent in this tablet.
23. 1 kinds of solid composite medicaments, wherein comprise adenosine triphosphate or its pharmaceutical salts, calcium salt and the optional pharmaceutic adjuvant except described calcium salt as active component, wherein:
Described calcium salt is selected from: calcium hydrogen phosphate, calcium phosphate, calcium carbonate and hydrate thereof,
The adenosine triphosphate that comprises 1 molar part in described solid composite medicament or its pharmaceutical salts, and in the calcium salt of calcium ion 9 ~ 40 molar part.
The method of the solid composite medicament described in 24. preparation claim 1-22 any one in purposes, it comprises the following steps:
(i) each crushing material is become can pass through 60 object 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, be prepared into tablet, capsule or granule by the preparation technology of tablet, capsule or granule;
(iv) optionally step (iii) gained tablet is carried out to coating.
25. prepare the method for solid composite medicament described in claim 23, and it comprises the following steps:
(i) each crushing material is become can pass through 60 object 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, be prepared into tablet, capsule or granule by the preparation technology of tablet, capsule or granule;
(iv) optionally step (iii) gained tablet is carried out to coating.
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1666748A (en) * | 2004-03-10 | 2005-09-14 | 孙明杰 | Oral formulation of adetphos |
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| CN1666748A (en) * | 2004-03-10 | 2005-09-14 | 孙明杰 | Oral formulation of adetphos |
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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. |
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