CN107753450A - A kind of composite electrolyte three-layer tablet - Google Patents
A kind of composite electrolyte three-layer tablet Download PDFInfo
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- CN107753450A CN107753450A CN201711203830.4A CN201711203830A CN107753450A CN 107753450 A CN107753450 A CN 107753450A CN 201711203830 A CN201711203830 A CN 201711203830A CN 107753450 A CN107753450 A CN 107753450A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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Abstract
The present invention relates to a kind of composite electrolyte three-layer tablet, belong to technical field of medical instruments.The composite electrolyte three-layer tablet, to be circular, oval or square, the three-layer tablet is the three-decker being made up of upper balance layer, core layer, lower balance layer.Composite electrolyte three-layer tablet of the present invention can direct-on-line application, alleviate the working strength of medical worker, it also avoid risk caused by operating error.In addition, said preparation, in fabrication stage, memory phase, pH stable, the term of validity of product is more more stable than all types of commodity used in existing market, can reach more than 2 years.With the requirement that blood purification technology develops, the application of composite electrolyte preparation three-layer tablet of the present invention will make haemodialysis control unit automatically prepare dialyzate from passive be transformed into using dialyzate, and this will be the much progress dialysed in product applications.
Description
Technical field
The present invention relates to a kind of composite electrolyte preparation and preparation method and application, more particularly to a kind of direct-on-line to use
Composite electrolyte preparation and preparation method and application, belong to technical field of medical instruments.
Background technology
Blood purification treatment is to work as metabolic poison in blood of human body to gather, and can not exclude and influence by itself organ dysfunction
During life, using by outside blood samples of patients lead body, blood is removed by blood cleaning equipments such as haemodialysis, hemodiafiltrations
In excessive metabolic waste or poisonous substance, reach the remedy measures that purification blood sustains life.
It is well known that metabolism is the basic guarantee of life, still, under given conditions, some things into body
Abnormal metabolism in matter or body, a series of pathological changes in body, or even threat to life can be caused, such as drug poisoning and chronic renal
Decline, these materials are so-called toxicant.Hemodialysis apparatus refers to the instrument that hyperfiltration treatment is carried out to blood, by super
Filter is handled, and the poisonous substance or other relevant materials in blood can be eliminated to external.In blood dialysis, in order to reach purification
Blood and the purpose of electrolyte balance, it is necessary to rely on safe and effective electrolyte dialyzate, it may be said that the life of haemodialysis purification
Reason function is completed by electrolyte dialyzate.
The dialyzate containing composite electrolyte clinically applied at present is also known as dialyzate A agent, mainly by sodium chloride, chlorination
Potassium, calcium chloride, magnesium chloride and pH adjusting agent composition.The A agent supplied currently on the market has two kinds of patterns：
1st, liquid-type.The usually liquid of 5-12 liters or so, loaded in polyethylene can, Clinical practice is more convenient.But
Due to being that aqueous stability is poor, in addition because being barreled form, its volume and weight is larger, and transport and storage cost are all very
It is high.
2nd, powdery type.Usually 1-2kg or so plastic bags pulvis, because moisture-free, weight and volume is smaller,
It is easy to store and transports.But because powder specific surface area is very big, contained acetic acid composition can penetrate packaging material in A agent
Volatilization, the long-term pH that stores can change, and the shelf-life of product is generally 1 year, and because powder dose-type can not be applied directly,
It could be used after water for dialysis dissolving need to being added by medical worker, so both add the unnecessary workload of medical worker,
Add the probability for occurring error in process for preparation.
CN1448145A、CN101678110A、CN102512361A、CN1917888A、CN1744884A、TW516961B
Deng several haemodialysis preparations of patent application publication and preparation method thereof, but prepared according to method disclosed in these patents
Product dissolves in pure water in diffused, it is impossible to keeps constant release of the electrolyte ingredient in certain period of time, therefore nothing
Method reaches the requirement of controlled release preparation Zero order release.
Therefore, long a kind of steady quality, the term of validity, manufacture, the blood that storage and transport cost is low, easy-to-use are researched and developed
Dialysis product turns into technical problem urgently to be resolved hurrily.
The content of the invention
The technical problems to be solved by the invention are that the defect for overcoming prior art provides a kind of composite electrolyte preparation, should
Preparation has the advantages that cost is low, storage and transport cost is low, steady quality, the term of validity are long, easy-to-use.
Technical problem of the present invention is realized by following technical scheme.
A kind of composite electrolyte preparation, the shape of the preparation include but are not limited to spherical, cylindricality but are not limited only to justify
Cylindricality, square column type, flat cylindricality or Polygonal column shape, piece shape include but are not limited to disc, ring piece shape, square shape sheet, multilayer tablet
Shape, clad sheet shape；Pharmaceutically acceptable adhesive, excipient, pH adjusting agent and following parts by weight can be contained in the preparation
Component：Calcium chloride 1~100, magnesium chloride 5~65, sodium acetate 50~200, sodium chloride 600~1700, potassium chloride 5~60；Institute
Stating preparation includes core and the balance layer being compressed on outside core；Exist in the core pH adjusting agent and calcium chloride, magnesium chloride,
The double salt that sodium acetate is formed, the double salt have X-ray diffraction specific at 2 θ=28.6 ° and 2 θ=40.7 ° and 2 θ=84.1 °
Peak.
Above-mentioned composite electrolyte preparation, the core contain the component of following parts by weight：Calcium chloride 10~80, magnesium chloride 5
~50, sodium acetate 50~200, adhesive 0-50, excipient 0-300, pH adjusting agent 1-80；The balance layer contains following weight
The component of part：Calcium chloride 0~30, magnesium chloride 0~20, sodium chloride 600~1600, potassium chloride 5~50, adhesive 0-100, figuration
Agent 0-300, pH adjusting agent 1-50.
Preferably, above-mentioned composite electrolyte preparation, the preparation are the flat cylindricality of multi-core, and its diameter is in 2~20mm, height
Spend 3~20mm, 10~100Kg of hardness；Wherein, core contains the component of following parts by weight：Calcium chloride 10~65, magnesium chloride 5~
40th, sodium acetate 50~200, excipient 0-300, adhesive 0-50 and pH adjusting agent 1-80；Balance layer contains following parts by weight
Component：Calcium chloride 0-20, magnesium chloride 0-15, sodium chloride 600-1200, potassium chloride 10-50, adhesive 0-100, excipient 0-100
With pH adjusting agent 1-50.
Preferably, above-mentioned composite electrolyte preparation, the preparation are three-layer tablet, a diameter of 5~20mm, hardness is 10~
100Kg；Wherein, upper and lower two layers is balance layer, and its height is respectively 2~8mm, and intermediate layer is core, and its height is 2~8mm；
The upper and lower balance layer contains the component of following parts by weight：Calcium chloride 0-20, magnesium chloride 0-10, sodium chloride 500~1200, chlorine
Change potassium 5~50, excipient 0-100, adhesive 0-100 and pH adjusting agent 1-50, and foregoing solid materials gross weight 1-5%
Pure water；The core contains the component of following parts by weight：Calcium chloride 10~65, magnesium chloride 5~50, sodium acetate 50~200, tax
Shape agent 1-200, adhesive 0-50 and pH adjusting agent 1-80, and foregoing solid materials gross weight 1-5% pure water.
Preferably, above-mentioned composite electrolyte preparation, the preparation are clad sheet shape, and overall diameter is 5~20mm；Wherein, wrap
The upper and lower thickness of balance layer for wrapping up in core is 1~10mm；Peripheral thickness is 0-6mm, and hardness is 10~100Kg, and core thickness is 2
~8mm, a diameter of 2~18mm, hardness are 5~100Kg；The balance layer contains the component of following parts by weight：Calcium chloride 0-20,
Magnesium chloride 0-10, sodium chloride 600~1200, potassium chloride 5~50, excipient 0-100, adhesive 0-100 and pH adjusting agent 1-50
And foregoing solid materials gross weight 1-5% pure water；The core contains the component of following parts by weight：Calcium chloride 10~
65th, magnesium chloride 5~50, sodium acetate 50~200 and excipient 1-100, adhesive 0-50, pH adjusting agent 1-80 and foregoing solid
Body material gross weight 1-5% pure water.
Above-mentioned composite electrolyte preparation, pharmaceutically acceptable adhesive, excipient, pH adjusting agent and the calcium chloride,
The supplementary materials such as magnesium chloride, sodium acetate, sodium chloride, potassium chloride are containing the crystallization water or without the crystallization water.
Above-mentioned composite electrolyte preparation, described adhesive are the one or more in lactose, glucose, sucrose, chitosan；
The pH adjusting agent is acetic acid or its salt, lactic acid or its salt, citric acid or its salt, malic acid or its salt, sorbic acid or its salt, ammonia
One or more in base acid or its salt；The excipient is glucose, mannitol, sodium chloride, dextran, sorbierite or chlorine
Change the one or more in potassium.
A kind of preparation method of above-mentioned composite electrolyte preparation, the preparation method comprise at least pH adjusting agent and calcium chloride,
The step of magnesium chloride, sodium acetate form double salt.
The preparation method of above-mentioned composite electrolyte preparation, the pH adjusting agent form multiple with calcium chloride, magnesium chloride, sodium acetate
The step of salt, it is specially：Calcium chloride, magnesium chloride, sodium acetate are ground into fine powder and be well mixed, puts and adds in the range of 80~200 DEG C
Heat, material can be in plocoid mixture, continue insulation to constant weight, are added slowly with stirring pH adjusting agent and reacted, pH is adjusted
Section agent and sodium acetate, calcium chloride, the fusions of magnesium chloride react to form double salt.
Further, when composite electrolyte preparation of the present invention is flat cylindricality, its preparation method comprises the following steps：
(1) preparation of core part
Calcium chloride, magnesium chloride, sodium acetate, excipient, adhesive and the pH adjusting agent of coring core recipe quantity；By calcium chloride,
Magnesium chloride, sodium acetate are pulverized and mixed uniformly, are put and are heated in the range of 80~200 DEG C, and material can be in that thawing shape mixes in heating process
Thing, continue insulation to material constant weight；PH adjusting agent is added slowly with stirring to be reacted, now pH adjusting agent and sodium acetate,
Calcium chloride, the fusions of magnesium chloride react to form double salt, add excipient, are well mixed, and are pressed through dry granulating machine in 20-60KN
Contracting power is compacted, and uniform plocoid core particle is obtained through whole grain；
(2) preparation of layer segment is balanced
Take calcium chloride, magnesium chloride, sodium chloride, potassium chloride, adhesive, excipient and the pH adjusting agent of balance layer recipe quantity with
And 1~5% pure water of total solid substance weight, mixing granulation is carried out, particle removal moisture drying, whole grain, which obtains, uniformly puts down
Weigh layer particle；
(3) preparations shaping
Core particle and balance layer particle are put in V-Mixer and are well mixed, obtained particle is in 10KN-100KN
Pressure under, with punching type press be pressed into diameter 2~20mm, height 3~20mm, 10~100Kg of hardness flat post
Shape.
When composite electrolyte preparation is three-layer tablet shape, its preparation method comprises the following steps：
(1) balance layer up and down is prepared
Take sodium chloride, the potassium chloride of upper and lower balance layer recipe quantity to be respectively crushed into fine powder, be placed in high-speed mixer granulator
In, add recipe quantity excipient, adhesive and pH adjusting agent and mixed；While mix, while in room temperature condition
Under be slowly added to foregoing solid materials gross weight 1-5% pure water, mix granulation, particle removal moisture drying, whole grain is standby,
Obtain balance layer particle；
(2) core part is prepared
Calcium chloride, magnesium chloride, sodium acetate, excipient, adhesive and the pH adjusting agent of intermediate layer core recipe quantity are taken, by chlorine
Change calcium, magnesium chloride, sodium acetate to be pulverized and mixed uniformly, put and heated in the range of 80-200 DEG C, material can be in thawing shape mixture, continue
Taken out when insulation is to material constant weight, put in mixer-granulator, be added slowly with stirring pH adjusting agent, be mixed into dry and comfortable
Grain, add adhesive, excipient is mixed；While mix, slow aforesaid solid thing at ambient temperature on one side
Matter gross weight 1-5% pure water, granulation is mixed, particle removal moisture drying, obtained particle whole grain is standby, obtains core
Grain；
(3) composite electrolyte preparation shapes
Take the balance layer particle of 50% amount to put slightly compression fixation in mould, add intermediate layer core particle, slightly compress
The balance layer particle of remaining 50% amount is added after fixation, with 80KN pressure compression moldings, obtains a diameter of 5~20mm, hardness is
10~100Kg three-layer tablet, wherein, upper and lower two layers is balance layer, and its height is respectively 2~8mm, and intermediate layer is core, and it is high
Spend for 2~8mm.
When composite electrolyte preparation is clad sheet, its preparation method comprises the following steps：
(1) balance layer is prepared
Sodium chloride, potassium chloride, calcium chloride, the magnesium chloride of balance layer recipe quantity are taken, is ground into fine powder, adds the viscous of recipe quantity
Mixture, excipient and pH adjusting agent, foregoing total solid substance weight 1-5% pure water is added, in high-speed mixing granulating machine
In, mixing granulation is carried out, particle removal moisture drying, whole grain is standby, obtains balance layer particle；
(2) core layer is prepared
Calcium chloride, magnesium chloride, sodium acetate, adhesive, excipient and the pH adjusting agent of coring core recipe quantity, by calcium chloride,
Magnesium chloride, sodium acetate are pulverized and mixed uniformly, are put and are heated in the range of 80-200 DEG C, and material can be in thawing shape mixture, continue to be incubated
Put to being taken out during material constant weight in mixer-granulator, be added slowly with stirring pH adjusting agent, be mixed into dry and comfortable particle, institute
Obtain particle and add excipient, be well mixed with V-Mixer, be compacted through dry granulating machine in 20-60KN compression stresses, obtain one
Core；
(3) composite electrolyte preparation shapes
Take the balance layer particle of 50% amount to put in mould, add a core, slightly compression adds residue after fixing
The balance layer particle of 50% amount, clad sheet is obtained with 80KN pressure compression moldings, its overall diameter is 5~20mm, wraps up the flat of core
The upper and lower thickness of layer that weighs is 1~10mm；Peripheral thickness is 0-6mm, and hardness is 10~100Kg, and core thickness is 2~8mm, diameter
For 2~18mm, hardness is 5~100Kg.
Further, the present invention provides the application of above-mentioned composite electrolyte preparation, i.e. the composite electrolyte preparation is direct
Application on site is applied to one proportioning pump of configuration not in the hemodialysis apparatus with conductivity feedback function, or direct-on-line
Possesses the hemodialysis apparatus of conductivity feedback function.
Further explanation to the present invention, A agent part is used in dialysis, usually by sodium chloride, potassium chloride, magnesium chloride, chlorination
Magnesium, acetic acid etc. form, and are a kind of mixtures of more components, this pulverulent mixture because each component dissolution velocity the problems such as, respectively
The release of the impossible balanced constant speed of kind composition, therefore do not possess the online possibility used.In order to solve above-mentioned problem, the present inventor
Have made intensive studies.As a result find：To said mixture by change its chemical constitution or physical aspect can realize it is above-mentioned
Purpose, and the stability of product can be improved, such as slow down the rise of pH value.
It is well known that being mostly sodium chloride in composite electrolyte formulation ingredients, sodium chloride molecular structure is a kind of special
Fixed space development model, the distribution of its particle is wide, and crystal grain contact point is more, and this causes sodium chloride easily to occur in the presence of external force
Attracting each other between crystal grain and produce plocoid consolidation phenomenon.Therefore, sodium chloride is both the master in composite electrolyte preparation
Chemical composition is wanted, and makes the framework ingredient of composite electrolyte preparation of the present invention.Composite electrolyte preparation of the present invention with
Sodium chloride is skeleton structure, and in pure water, balance layer makes the electrolyte concentration in solution be rapidly saturated reaching balance, continue and
Current ablate the lower stable various chemical compositions discharged in core of effect.In composite electrolyte preparation of the present invention, core
It is by electrolyte ingredient；The compositions such as calcium chloride, magnesium chloride, sodium acetate and pH adjusting agent form.Because of the solubility of this several composition
It is very big, the dissolution ratio and dissolution rate of each composition of control that under normal circumstances can not be balanced, the core prepared with the inventive method
Core realizes this purpose under the protection of balance layer.
In addition, the dialysis A agent of clinical practice is usually to be used as pH adjusting agent by the use of acetic acid.Acetic acid is a kind of irritant acid
Taste, volatilizable unitary organic acid.In commercially available dialysis A agent commodity, acetic acid be uniformly adhered to electrolyte crystallization or
Grain surface, thus there is very big surface area, it is easier the volatilization of acetic acid.Electrolyte ingredient is pressed into surface by the present invention
The solid of very little, and the pH adjusting agents such as acetic acid are fixed in core layer, it is therefore prevented that the volatilization of the pH adjusting agent such as acetic acid, it ensure that
The pH value of Storage period can be stablized more than 2 years.
In a word, the core and balance layer prepared with the inventive method, through formed under high compression pressure plocoid block/piece or other
The solids of shape, such as the flat cylindricality, three-layer tablet shape, clad sheet shape of particular configuration, its dissolution mechanism is also changed, by
The mode of diffusion dissolution is changed into the mode of corrosion, by adjusting chemical composition or ratio in preparation, it is possible to be prepared into
Meet blood cleaning equipment requirement can application on site product.
Composite electrolyte preparation provided by the invention, in clinical practice, medical worker can need not directly exist in capable preparation again
Line application.So-called " online " refers to the pure water that the pure water system purchased by blood cleaning equipment itself provides, with continuous
Mode flows through composite electrolyte preparation of the present invention, and obtained liquid is directly connected with the pipeline of haemodialysis control unit.From
And the working strength of medical worker is alleviated, it also avoid risk caused by operating error.With blood purification technology development
It is required that the application of composite electrolyte preparation of the present invention will be such that haemodialysis control unit is transformed into automatically using dialyzate from passive
Preparation dialyzate, this by be dialyse product applications on a much progress.
Brief description of the drawings
The digital micrograph photo of the core particle of Fig. 1 embodiments 1
The structural representation of the flat cylindricality piece of composite electrolyte preparation of Fig. 2 embodiments 1
The structural representation of the composite electrolyte preparation three-layer tablet of Fig. 3 embodiments 2
The structural representation of the composite electrolyte preparation cored shape piece of Fig. 4 embodiments 3
The composite electrolyte formulation X x ray diffraction collection of illustrative plates of Fig. 5 embodiments 1
The composite electrolyte formulation X x ray diffraction collection of illustrative plates of Fig. 6 embodiments 2
The composite electrolyte formulation X x ray diffraction collection of illustrative plates of Fig. 7 embodiments 3
The composite electrolyte formulation X x ray diffraction collection of illustrative plates of Fig. 8 comparative examples 1
The composite electrolyte formulation X x ray diffraction collection of illustrative plates of Fig. 9 comparative examples 2
The chromatography of ions figure of the electrolyte ingredient measure of Figure 10 embodiments 1
Figure 10 continues the chromatography of ions figure of the electrolyte ingredient measure of embodiment 1
The chromatography of ions figure of the electrolyte ingredient measure of Figure 11 embodiments 2
Figure 11 continues the chromatography of ions figure of the electrolyte ingredient measure of embodiment 2
The chromatography of ions figure of the electrolyte ingredient measure of Figure 12 embodiments 3
Figure 12 continues the chromatography of ions figure of the electrolyte ingredient measure of embodiment 3
The release curve of Figure 13 embodiments, comparative example and market product
Embodiment
The present invention is described in further detail below by embodiment, following examples can be used for explaining this
Invent but not as the restriction of the scope of the present invention, also have a lot of other embodiments in the protection domain that the present invention is limited
To be all within the scope of the present invention.
The composite electrolyte preparation of the present invention of embodiment 1 (flat cylindricality) and its preparation
【Prescription】
Core part
Electrolyte ingredient：
Calcium chloride 42.5g
Magnesium chloride 20g
Sodium acetate 120g
Adjunct ingredient：
Acetic acid 33g
Sodium chloride 200g
Balance layer segment
Electrolyte ingredient：
Sodium chloride 950g
Potassium chloride 28g
Adjunct ingredient：
Glucose 20g
Citric acid 20g
【Preparation method】
It is prepared by core part：Calcium chloride, magnesium chloride, sodium acetate are ground into fine powder, through 120 DEG C of heat dryings, material is in
Plocoid mixture, continue insulation to constant weight, put in mixer-granulator, mixed, is slowly added at ambient temperature
Acetic acid, dry and comfortable particle is mixed into, gained particle adds other auxiliary materials, is well mixed with V-Mixer, through dry granulating machine
It is compacted in 20-60KN compression stresses, obtains core particle；
Layer segment is balanced to prepare：Take sodium chloride, potassium chloride to be ground into fine powder, add auxiliary material and total solid substance weight
1-5% pure water, in high-speed mixing granulating machine, mixing granulation is carried out, particle removal moisture drying, whole grain, which obtains, uniformly puts down
Weigh layer particle；
By core particle and balance layer particle, put in V-Mixer and be well mixed, pressure of the obtained particle in 80KN
Under, flat cylindricality is pressed into punching type press, its a diameter of 8-10mm, length 5-7mm, hardness 25-100Kg.Implement
The composite electrolyte preparation of the present invention of example 2 (three-layer tablet shape) and its preparation
【Prescription】
Core part
Electrolyte ingredient：
Calcium chloride 37.5g
Magnesium chloride 18g
Sodium acetate 120g
Adjunct ingredient：
Acetic acid 28g
Sodium chloride 150g
Balance layer segment
Electrolyte ingredient：
Adjunct ingredient：
Citric acid 25g
【Preparation method】
It is prepared by core part：It is prepared by core part：Calcium chloride, magnesium chloride, sodium acetate are ground into fine powder, added through 120 DEG C
Heated drying, material are in plocoid mixture, continue insulation to constant weight, put in mixer-granulator, mixed, in room temperature bar
Acetic acid is slowly added under part, is mixed into dry and comfortable particle, gained particle adds other auxiliary materials and total solid substance weight 1-
5% pure water, granulation is mixed evenly, particle removal moisture drying, obtains core particle；
Layer segment is balanced to prepare：Take sodium chloride, potassium chloride, citric acid to be ground into fine powder, add total solid substance weight 1-
5% pure water, in high-speed mixing granulating machine, mixing granulation is carried out, particle removal moisture drying, obtains balance layer particle；
The balance layer particle of 50% amount is taken, puts after slightly compressing fixation in mould, adds core particle, slightly compression is solid
The balance layer particle of remaining 50% amount is added after fixed, with 80KN pressure compression moldings, obtains three-layer tablet, a diameter of 8-10mm；Its
In, upper and lower balance layer thickness is respectively 2-3mm；Wherein interbed core thickness be 2-3mm, hardness 25-100Kg.
The composite electrolyte preparation of the present invention of embodiment 3 (clad sheet shape) and its preparation
【Prescription】
Core part
Electrolyte ingredient：
Calcium chloride 32.5g
Magnesium chloride 15g
Sodium acetate 120g
Adjunct ingredient：
Acetic acid 30g
Sodium chloride 150g
Balance layer segment
Electrolyte ingredient：
Adjunct ingredient：
Citric acid 25g
【Preparation method】
It is prepared by core part：Calcium chloride, magnesium chloride, sodium acetate are ground into fine powder, through 120 DEG C of heat dryings, material is in
Plocoid mixture, continue insulation to constant weight, put in mixer-granulator, mixed, is slowly added at ambient temperature
Acetic acid, dry and comfortable particle being mixed into, gained particle adds other auxiliary materials and total solid substance weight 1-5% pure water,
Granulation is mixed evenly, particle removal moisture drying, obtains core particle, core is pressed into 60KN pressure；
Layer segment is balanced to prepare：Take sodium chloride, potassium chloride, citric acid to be ground into fine powder, add total solid substance weight 1-
5% pure water, in high-speed mixing granulating machine, mixing granulation is carried out, particle removal moisture drying, obtains balance layer particle；
The balance layer particle of 50% amount is taken, random site in a mold adds a core, after slightly compression is fixed
The balance layer particle of remaining 50% amount is added, with 80KN pressure compression moldings, obtains clad sheet, its a diameter of 8-10mm, balance
Thickness degree is 2-4mm；Its chip layer thickness is 2-6mm, diameter 2-88mm, hardness 25-100Kg.
Comparative example 1
TW516961B discloses two kinds of solid dialysis agent, wherein, a kind of solid dialysis agent, containing by sodium chloride, chlorine
Change the electrolyte composition and pH adjusting agent of potassium, calcium chloride, magnesium chloride and sodium acetate composition as essential component, glucose conduct
Any condition, it has：A, one contain by sodium chloride and potassium chloride institute into group in select at least one to be used as principal component
Stratum nucleare, and b, one contain double salt, other electrolyte compositions and the pH regulation that generations is reacted by sodium acetate and calcium chloride
Agent and two layers of double salt layer construction of glucose as any condition.
Another solid dialysis agent, contains the electricity being made up of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate
Matter composition is solved with pH adjusting agent and glucose as essential component, it has：A, one contains by sodium chloride and potassium chloride
Institute into group in select it is at least one using the stratum nucleare (center) as principal component；B, one contains by sodium acetate and calcium chloride reaction production
(intermediate layer) of the double salt layer of the double salt of life, other electrolyte compositions and pH adjusting agent and c, one containing glucose it
The three-layer structure of outer layer.
In the inventive technique scheme, sodium acetate and calcium chloride reaction generation double salt are disclosed, the double salt has X-ray diffraction
Characteristic peak, double salt are uniformly covered on stratum nucleare.
The present invention has reproduced the technology of patent TW516961B embodiments 1, is added in ware is stirred and passes through 50 eye mesh screens
Sodium chloride 250g, potassium chloride 6.15g, magnesium chloride 4.27g, sodium acetate 20.34g and pure water 4.7g, after being uniformly mixed,
Stir while be heated to 70 DEG C, add calcium chloride 9.07g, continue to stir, pelletize, whole grain after drying, be slowly stirred lower slow
It is slow to add 4.9g acetic acid, continue to be slowly stirred and be mixed to get preparation.
Comparative example 2
CN1744884A discloses a kind of solid formulation for dialysis, and it includes electrolyte composition, pH adjusting agent and grape
Sugar, electrolyte composition include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, and coatingparticles are coated by coating, quilt
Coating contains in film X-ray diffraction --- CuK α；λ=1.54058,1 ° of incidence angle θ=--- in 2 θ=21.3-21.5 °
And there is the salt at specific peak at 2 θ=27.6-27.8 °, the salt is glucose and calcium chloride and the reaction product of sodium acetate.
The present invention has reproduced patent CN1744884A technology contents, added in stirring mixer ware sodium chloride 200g,
Potassium chloride 4.8g, calcium chloride 7.1g, sodium acetate 26.6g, glucose 30.4g are uniformly mixed, addition glucose containing 2.2g,
The solution of 3.3g magnesium chlorides and 2.5g water, agitated granulation, add 3.9g acetic acid after drying and be well mixed, obtain preparation.
Test case 1
Core obtained by the embodiment of the present invention, its digital micrograph photo is as shown in figure 1, thus to scheme the visible present invention compound
The core of electrolyte preparations has by compression plocoid outward appearance.Fig. 2, Fig. 3, Fig. 4 are embodiment 1-3 composite electrolyte systems of the present invention
Agent structural representation.Wherein, Fig. 1：In figure A be core, B be balance layer；Fig. 2：1 it is upper balance layer in figure, 2 be core layer, 3 is
Lower balance layer；Fig. 3：In figure A be core, B be balance layer.
Test case 2
The X-ray diffraction result of preparation is as shown in Fig. 5,6,7 obtained by the embodiment of the present invention 1,2.In order to definitely
Preparation technology is understood to the influence in preparation in material composition, using Bruker D8advance X-ray diffractometers, according to
JY/T009-1996X ray diffraction methods measure.By Fig. 5,6,7 Suo Shi 2 θ=28.6 ° and 2 θ=40.7 ° with
And 2 θ=84.1 ° nearby detect specific peak.Show acetic acid and sodium acetate, calcium chloride and magnesium chloride generation double salt.
Test case 3
By comparative example 1 and the preparation of the gained of comparative example 2, measured with the identical method of test case 2, its X ray spreads out
Penetrate result and nearby do not detect appearance in 2 θ=28.6 ° and 2 θ=40.7 ° and 2 θ=84.1 ° as shown in Figure 8,9.
Test case 4
5 parts of samples are randomly selected from the preparation of embodiment 1, every part of sample precision weighs about 18.5 grams, is dissolved in 500 millis
Pure water is risen, then dilutes 5 times, with reference to YY0598-2015 standards, Na is measured with ICS-600 models ion-chromatographic analyzer+、K+、
Mg++、Ca++、Cl-Each electrolyte concentration, measurement result are shown in Table 1 and Figure 10, Tu10Xu.
1 each electrolyte ingredient of table is dense (mmol/L)
5 parts of samples are randomly selected from the preparation of embodiment 2, every part of sample precision weighs about 18.5 grams, is dissolved in 500 millis
Pure water is risen, then dilutes 5 times, with reference to YY0598-2015 standards, Na is measured with ICS-600 models ion-chromatographic analyzer+、K+、
Mg++、Ca++、Cl-Each electrolyte concentration, measurement result are shown in Table 2 and Figure 11, Tu11Xu.
2 each electrolyte ingredient of table is dense (mmol/L)
| Na+ | K+ | Mg++ | Ca++ | Cl- | |
| N=1 | 109.2 | 2.01 | 0.49 | 1.56 | 110.3 |
| N=2 | 108.1 | 2.04 | 0.50 | 1.58 | 109.5 |
| N=3 | 107.6 | 1.98 | 0.48 | 1.52 | 109.9 |
| N=4 | 109.3 | 2.03 | 0.49 | 1.57 | 110.7 |
| N=5 | 108.1 | 1.99 | 0.48 | 1.56 | 109.8 |
| Average value | 108.5 | 2.01 | 0.49 | 1.56 | 110.0 |
| Standard deviation | 0.75 | 0.03 | 0.01 | 0.02 | 0.47 |
| The coefficient of variation | 0.69 | 1.24 | 1.43 | 1.48 | 0.43 |
5 parts of samples are randomly selected from the preparation of embodiment 3, every part of sample precision weighs about 18.5 grams, is dissolved in 500 millis
Pure water is risen, then dilutes 5 times, with reference to YY0598-2015 standards, Na is measured with ICS-600 models ion-chromatographic analyzer+、K+、
Mg++、Ca++、Cl-Each electrolyte concentration, measurement result are shown in Table 3 and Figure 12, Tu12Xu.
3 each electrolyte ingredient of table is dense (mmol/L)
| Na+ | K+ | Mg++ | Ca++ | Cl- | |
| N=1 | 110.0 | 1.99 | 0.48 | 1.53 | 110.3 |
| N=2 | 108.2 | 1.99 | 0.49 | 1.52 | 111.6 |
| N=3 | 108.6 | 2.00 | 0.48 | 1.56 | 109.5 |
| N=4 | 109.3 | 2.03 | 0.49 | 1.49 | 110.8 |
| N=5 | 109.2 | 2.01 | 0.48 | 1.55 | 109.5 |
| Average value | 109.0 | 2.00 | 0.48 | 1.53 | 110.3 |
| Standard deviation | 0.69 | 0.02 | 0.01 | 0.03 | 0.90 |
| The coefficient of variation | 0.63 | 0.87 | 1.46 | 1.76 | 0.82 |
As shown in table 1 to 3：In all samples, the content and uniformity of each electrolyte ingredient are preferable.
Test case 5
With reference to Pharmacopoeia of People's Republic of China two annex of version in 2015 to the drug release determination method of controlled release preparation to implementing
Example 1-3 and comparative example 1,2 and market product (MT-F) carry out drug release determination, and specific detection method is according to state food medicine prison
The YY0598-2015 standards of management board's promulgation are superintended and directed, 4 and Figure 13 institutes are as a result shown in Table (using the average of K-Mg-Ca content as test value)
Show.
The embodiment of table 4 and comparative example composite electrolyte drug release determination result
| Time (min) | 50min | 100min | 150min | 200min | 250min |
| Embodiment 1 | 22% | 43% | 63% | 81% | 95% |
| Embodiment 2 | 22% | 44% | 66% | 86% | 95% |
| Embodiment 3 | 24% | 50% | 68% | 86% | 93% |
| Comparative example 1 | 63% | 78% | 89% | 92% | 98% |
| Comparative example 2 | 70% | 86% | 93% | 95% | 97% |
| MT-F | 65% | 79% | 90% | 91% | 97% |
From above-mentioned experiment, each embodiment products obtained therefrom has the effect of constant release, can be gentle in 5 hours or so
Each electrolyte ingredient is discharged, meets the zero-order rule release of controlled release preparation；Comparative example 1,2 and release market product early stage compared with
There is obvious phenomenon of burst release soon, later stage release is more slowly without sustained release and controlled-release effect, it is impossible to constant release electrolyte ingredient.
Test case 6
It is directly online to be tested using electrolyte dissolution when clinical blood is dialysed；Example 1-3 composite electrolyte preparations
1200 grams, it is placed in plastic barrel or bag with filter, simulation dialysis machine prepares the operation principle of dialyzing agent A liquid, device
It is suitable for reading couple with pure water, lower mouth couples with proportioning pump, and the ratio that the pump is set should meet the requirement of dialysis machine, receive on time
Collect preparation solution, the assay method in the YY0598-2015 standards promulgated according to Chinese food Drug Administration, with K+、Ca++、Mg++To represent dissolution situation of the measure electrolyte ingredient within 5 hours, 5-7 the results are shown in Table.
Dissolution result during the simulation clinical blood dialysis of the composite electrolyte preparation of 5 embodiment of table 1
| K+ | Ca++ | Mg++ | |
| 50(min) | 1.71 | 1.43 | 0.60 |
| 100(min) | 1.53 | 1.42 | 0.64 |
| 150(min) | 1.7 | 1.37 | 0.58 |
| 200(min) | 1.63 | 1.34 | 0.54 |
| 250(min) | 1.51 | 1.34 | 0.56 |
| Average value | 1.62 | 1.38 | 0.58 |
Dissolution result during the simulation clinical blood dialysis of the composite electrolyte preparation of 6 embodiment of table 2
| K+ | Ca++ | Mg++ | |
| 50(min) | 1.66 | 1.79 | 0.64 |
| 100(min) | 1.83 | 1.63 | 0.62 |
| 150(min) | 1.79 | 1.71 | 0.60 |
| 200(min) | 1.69 | 1.60 | 0.57 |
| 250(min) | 1.65 | 1.57 | 0.54 |
| Average value | 1.72 | 1.66 | 0.59 |
Dissolution result during the simulation clinical blood dialysis of the composite electrolyte preparation of 7 embodiment of table 3
| K+ | Ca++ | Mg++ | |
| 50(min) | 2.11 | 1.42 | 0.54 |
| 100(min) | 2.06 | 1.49 | 0.6 |
| 150(min) | 1.93 | 1.48 | 0.56 |
| 200(min) | 2.01 | 1.61 | 0.64 |
| 250(min) | 1.91 | 1.55 | 0.63 |
| Average value | 2.0 | 1.51 | 0.59 |
As seen from the above table, composite electrolyte preparation of the present invention can equably dissolution electrolyte, meet the requirement of clinic.
Test case 7
Market MT-F products, comparative example 1, the product of comparative example 2 are taken, experimental method such as test case 6, the results are shown in Table 8-10.
Dissolution result during 8 market MT-F product simulations clinical blood dialysis of table
| K+ | Ca++ | Mg++ | |
| 50(min) | 5.34 | 4.94 | 1.34 |
| 100(min) | 2.83 | 1.18 | 0.52 |
| 150(min) | 0.78 | 0.65 | 0.19 |
| 200(min) | 0.3 | 0.3 | 0.07 |
| 250(min) | 0.09 | 0.1 | 0.03 |
| Average value | 1.87 | 1.43 | 0.43 |
Dissolution result when the product simulation clinical blood of 9 comparative example of table 1 is dialysed
Dissolution result when the product simulation clinical blood of 10 comparative example of table 2 is dialysed
| K+ | Ca++ | Mg++ | |
| 50(min) | 6.21 | 4.27 | 1.22 |
| 100(min) | 1.01 | 1.11 | 0.30 |
| 150(min) | 0.7 | 0.41 | 0.11 |
| 200(min) | 0.04 | 0.01 | 0.08 |
| 250(min) | 0.02 | 0 | 0.01 |
| Average value | 1.59 | 1.16 | 0.34 |
The result of test case 7 shows that market product, comparative example 1, the product of comparative example 2 are because electrolyte dissolution is unbalanced therefore faces
Bed does not have the online possibility used.
Test case 8
For the stability of Study of Product, with reference to Pharmacopoeia of People's Republic of China two annex stability tests of version in 2015
Guideline hot test method and annex pH value determination method, test the dialyzate after being diluted with sodium acid carbonate, as a result see
Table 11.
The stability test data of table 11
| Sample | 0 day | 5 days | 10 days |
| Embodiment 1 | 7.38 | 7.4 | 7.41 |
| Embodiment 2 | 7.35 | 7.38 | 7.42 |
| Embodiment 3 | 7.37 | 7.38 | 7.4 |
| Comparative example 1 | 7.32 | 8.01 | 8.41 |
| Comparative example 2 | 7.31 | 8.03 | 8.38 |
| MT-F | 7.27 | 7.78 | 8.33 |
When the dialyzate pH value of clinical practice is more than 7.6, being normally carried out for treatment can be influenceed, embodiment 1-3 pH value is equal
In the requirement that 7.4 or so meet clinic.
The explanation of above example is only intended to help and understands the present invention, is not intended to limit the invention, all in the present invention
Spirit and principle within, any modification, equivalent substitution and improvements made etc., should be included in protection scope of the present invention it
It is interior.
Claims (8)
1. a kind of composite electrolyte three-layer tablet, it is circular, oval or square, it is characterised in that the three-layer tablet is by upper flat
Weigh the three-decker that layer (1), core layer (2), lower balance layer (3) are formed.
2. composite electrolyte three-layer tablet according to claim 1, it is characterised in that a diameter of 5~20mm of the three-layer tablet,
Hardness is 10~100Kg；Wherein, upper balance layer (1), lower balance layer (3) height are respectively 2~8mm, and core layer (2) is highly 2
~8mm.
3. composite electrolyte three-layer tablet according to claim 1 or 2, it is characterised in that the core layer (2) is by double salt
And/or excipient, adhesive are formed, the double salt is formed by pH adjusting agent and calcium chloride, magnesium chloride, sodium acetate, in 2 θ=28.6 °
And have the specific peak of X-ray diffraction at 2 θ=40.7 ° and 2 θ=84.1 °.
4. composite electrolyte three-layer tablet according to claim 3, it is characterised in that the upper balance layer (1), lower balance layer
(3) it is made up of sodium chloride, potassium chloride, excipient, pH adjusting agent and/or calcium chloride, magnesium chloride, adhesive.
5. composite electrolyte three-layer tablet according to claim 1, it is characterised in that the core layer (2) is containing following heavy
Measure the component of part：Calcium chloride 10~65, magnesium chloride 5~50, sodium acetate 50~200, excipient 1-200, adhesive 0-50 and pH
Conditioning agent 1-80, and foregoing solid materials gross weight 1-5% pure water；The upper balance layer (1), lower balance layer (3) contain
There is the component of following parts by weight：Calcium chloride 0-20, magnesium chloride 0-10, sodium chloride 500~1200, potassium chloride 5~50, excipient 0-
100th, adhesive 0-100 and pH adjusting agent 1-50, and foregoing solid materials gross weight 1-5% pure water.
6. composite electrolyte three-layer tablet according to claim 4, it is characterised in that described adhesive be lactose, glucose,
One or more in sucrose, chitosan；The pH adjusting agent is acetic acid or its salt, lactic acid or its salt, citric acid or its salt, apple
One or more in tartaric acid or its salt, sorbic acid or its salt, amino acid or its salt；The excipient be glucose, mannitol,
One or more in sodium chloride, dextran, sorbierite or potassium chloride.
7. prepare the method for composite electrolyte three-layer tablet as claimed in claim 3, it is characterised in that the preparation method comprises at least
The step of acetic acid forms double salt with calcium chloride, magnesium chloride, sodium acetate.
8. the application of the composite electrolyte three-layer tablet described in claim 1 or 2, it is characterised in that the composite electrolyte three-layer tablet
Direct-on-line is applied to the haemodialysis with conductivity feedback function, or direct-on-line is applied to one proportioning pump of configuration not
Possessing has the hemodialysis apparatus of conductivity feedback function.
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| Application Number | Priority Date | Filing Date | Title |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW516961B (en) * | 1995-08-02 | 2003-01-11 | Tomita Pharma | Preparation for dialysis and method of preparing solid preparation for dialysis |
| CN1744884A (en) * | 2003-01-31 | 2006-03-08 | 玛奈克股份有限公司 | Solid preparation for dialysis and process for producing the same |
-
2017
- 2017-11-27 CN CN201711203830.4A patent/CN107753450A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW516961B (en) * | 1995-08-02 | 2003-01-11 | Tomita Pharma | Preparation for dialysis and method of preparing solid preparation for dialysis |
| CN1744884A (en) * | 2003-01-31 | 2006-03-08 | 玛奈克股份有限公司 | Solid preparation for dialysis and process for producing the same |
Non-Patent Citations (1)
| Title |
|---|
| 秦浩正: "《中学生学习辞典 化学卷》", 30 September 2012, 世界图书上海出版公司 * |
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