JP2008023146A - Solid formulation for dialysis and method for producing the same - Google Patents
Solid formulation for dialysis and method for producing the same Download PDFInfo
- Publication number
- JP2008023146A JP2008023146A JP2006200391A JP2006200391A JP2008023146A JP 2008023146 A JP2008023146 A JP 2008023146A JP 2006200391 A JP2006200391 A JP 2006200391A JP 2006200391 A JP2006200391 A JP 2006200391A JP 2008023146 A JP2008023146 A JP 2008023146A
- Authority
- JP
- Japan
- Prior art keywords
- dialysis
- chloride
- solid preparation
- glucose
- solid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- External Artificial Organs (AREA)
Abstract
Description
本発明は、腎不全患者の透析療法に使用される重炭酸透析液調製用の透析用固形剤に関し、詳しくは、造粒の際に母核となる粒子である母粒子の表面が、特定の塩を含む被覆層で覆われた、防湿性、含量均一性、流動性、耐固結性、ブドウ糖の安定性に優れた透析用固形剤及びその製造方法に関する。 The present invention relates to a solid preparation for dialysis for preparing a bicarbonate dialysate used for dialysis therapy of patients with renal failure. Specifically, the surface of the mother particle, which is a particle serving as a mother nucleus during granulation, has a specific surface. The present invention relates to a solid preparation for dialysis that is covered with a coating layer containing salt and is excellent in moisture resistance, content uniformity, fluidity, anti-caking property, and glucose stability, and a method for producing the same.
透析療法は、腎不全患者の治療法として確立されており、老廃物の除去、電解質の調節等を目的に定期的な永続的治療として行われている。透析療法に用いられる透析液は、正常な血清電解質濃度に類似した組成を持つように作成されており、近年では生体に負担の少ない重炭酸透析剤が用いられている。重炭酸透析液は、重炭酸ナトリウムが塩化カルシウムや塩化マグネシウムと反応して炭酸塩の沈殿を生じるため、一般的に塩化カルシウムや塩化マグネシウムを含み重炭酸ナトリウムを含まない製剤(A剤)と重炭酸ナトリウムを含み塩化カルシウムや塩化マグネシウムを含まない製剤(B剤)との2剤に分けられており、使用直前にそれぞれが溶解、希釈混合されて重炭酸透析液が調製される。 Dialysis therapy has been established as a treatment method for patients with renal failure, and is performed as a regular permanent treatment for the purpose of removing wastes, adjusting electrolytes, and the like. The dialysate used for dialysis therapy is prepared so as to have a composition similar to a normal serum electrolyte concentration, and in recent years, a bicarbonate dialysis agent having a small burden on a living body is used. Since bicarbonate bicarbonate reacts with calcium chloride and magnesium chloride to cause precipitation of carbonate, bicarbonate dialysate generally contains a preparation (agent A) that contains calcium chloride or magnesium chloride and does not contain sodium bicarbonate. The preparation is divided into two preparations (form B) containing sodium carbonate and not containing calcium chloride or magnesium chloride, and each is dissolved, diluted and mixed immediately before use to prepare a bicarbonate dialysate.
現在、血液透析で使用されている主な製剤の形式は、A濃厚原液+B濃厚原液の「液液タイプ」、A濃厚原液+B粉末剤(重炭酸ナトリウム)の「液粉タイプ」、A粉末剤+B粉末剤の「粉粉タイプ」の3種類がある。「液液タイプ」、「液粉タイプ」のうち濃厚原液の製剤は、通常ポリエチレン製の容器に10kg前後の濃厚液が充填されているため容器の嵩が大きく質量があり、輸送、搬入、保管スペース、取り扱い方法、使用済み容器の廃棄等について、種々の課題を抱えている。 Currently, the main formulation types used in hemodialysis are A liquid concentrate + B liquid concentrate “liquid type”, A liquid concentrate + B powder (sodium bicarbonate) “liquid powder type”, A powder There are three types of "powder type" of + B powder. Of the “liquid-liquid type” and “liquid-powder type”, concentrated concentrates are usually filled with about 10 kg of concentrated liquid in a polyethylene container, so the container is bulky and has a large mass. There are various issues regarding space, handling methods, disposal of used containers, etc.
これらの問題を解決するために、近年、A剤を粉末化した「粉粉タイプ」の固形剤が開発されて使用されつつある。この固形剤は、病院などの医療現場で専用の溶解装置を使用して「液液タイプ」の濃厚原液と同程度の濃度の原液に一旦溶解され、その後、希釈され透析液濃度に調整される。 In order to solve these problems, in recent years, a “powder type” solid preparation obtained by pulverizing the agent A has been developed and used. This solid preparation is once dissolved in a stock solution of the same concentration as the “liquid-liquid type” concentrated stock solution using a dedicated dissolution apparatus in a medical field such as a hospital, and then diluted to adjust the dialysate concentration. .
このような固形剤の製剤化方法としては、従来よりスプレードライ法、湿式造粒法、乾式造粒法などが良く知られている。いずれの方法も一長一短があり、製造方法や品質の面で満足すべきものとは言えない。スプレードライ法による製剤は、嵩高く、水分や粒度にばらつきがあり、酸成分が揮発するため一定のpHを与えることが難しい。例えば、転動撹拌流動層造粒装置内で転動流動中の塩化ナトリウム粒子に電解質成分を含有する混合物の水溶液を噴霧して塩化ナトリウム粒子の表面が電解質成分を含有する混合物の微粒子で均一に覆われた透析用固形剤を得ようとする場合に、塩化ナトリウム粒子を覆う被覆層は、流動している造粒物同士の衝突により剥離しやすいという欠点がある。更に、電解質成分を溶解した上に、噴霧乾燥をしなければならないために、エネルギー原単位を著しく悪化させる。 Conventionally, spray drying, wet granulation, dry granulation, and the like are well known as methods for formulating such solid agents. Both methods have advantages and disadvantages, and are not satisfactory in terms of manufacturing method and quality. The preparation by the spray drying method is bulky, varies in moisture and particle size, and the acid component volatilizes, so it is difficult to give a constant pH. For example, the aqueous solution of the mixture containing the electrolyte component is sprayed onto the sodium chloride particles that are rolling and flowing in the tumbling stirring fluidized bed granulator, so that the surface of the sodium chloride particles is uniformly made of fine particles of the mixture containing the electrolyte components. When it is going to obtain the covered solid agent for dialysis, the coating layer which covers sodium chloride particles has a fault that it is easy to peel off due to collision of the fluidized granulated materials. Furthermore, since the electrolyte component must be dissolved and spray-dried, the energy intensity is greatly deteriorated.
また、流動層造粒装置では、もっぱら造粒に関与しなかった粒子は、バグフィルターまで粒子が浮遊して、最後まで造粒に関与しない粒子が存在するので微粒子が多くなり、粒度分布がブロードとなる欠点がある。更に、湿式造粒法として、潮解性の塩化カルシウム及び/又は塩化マグネシウムをバインダーとすることで、添加する水量を少なくすることによって造粒時間を大幅に短縮できることが提案されている。この方法は、高速攪拌型造粒装置を用いて造粒する方法であるが、造粒物が造粒装置機器へ付着し、収率が低下する上、核となる成分が多いため乾燥工程や混合工程等で偏析するという欠点がある。また、乾式造粒法は、均一性を保持するために、粉砕、混合等の煩雑な工程が避けられず、使用設備や外部からの異物混入により汚染されやすいという欠点がある。 In the fluidized bed granulator, particles that are not involved in granulation float up to the bag filter, and there are particles that do not participate in granulation until the end. There is a drawback. Furthermore, as a wet granulation method, it has been proposed that deliquescent calcium chloride and / or magnesium chloride can be used as a binder so that the granulation time can be significantly shortened by reducing the amount of water to be added. This method is a method of granulating using a high-speed agitation granulator, but the granulated material adheres to the granulator equipment, the yield decreases, and since there are many core components, the drying step and There is a disadvantage that segregation occurs in the mixing process. In addition, the dry granulation method has a drawback that complicated processes such as pulverization and mixing are unavoidable in order to maintain uniformity, and it is easily contaminated by foreign substances mixed from the equipment used or from the outside.
そこで、このような点に着目した、粉砕等の煩雑な工程が不要な製造方法で、嵩比重、安息角及び溶解速度が良好でコンパクトな固形製剤の提案がなされている(例えば特許文献1及び特許文献2を参照)。しかし、塩化ナトリウム、塩化カリウム、塩化マグネシウム、塩化カルシウムと純水とを混合し、攪拌し、加熱し(68℃)、酢酸ナトリウムを添加して加熱混合を続けた場合に、内容物に特異な粘りが生じ、粘度が著しく増大し攪拌が困難になる。また、塩化ナトリウム、塩化カリウム、塩化マグネシウム、酢酸ナトリウムと純水とを混合し、攪拌し、加熱(60℃)し、塩化カルシウムを添加して加熱混合を続けた場合に、内容物に特異な粘りが生じ、粘度が著しく増大して攪拌が困難になる。そのため、通常の攪拌装置では製造が困難であり、攪拌能力の極めて大きな設備が必要となり、設備が特殊化、大型化するために製造費用が著しく増加するという問題があった。これより、安価に、容易に製造できる製剤が求められている。 Therefore, a solid preparation with a good bulk specific gravity, angle of repose, and dissolution rate has been proposed with a manufacturing method that pays attention to such points and does not require complicated steps such as grinding (for example, Patent Document 1 and (See Patent Document 2). However, when sodium chloride, potassium chloride, magnesium chloride, calcium chloride and pure water are mixed, stirred and heated (68 ° C), and sodium acetate is added and heating and mixing is continued, it is peculiar to the contents. Stickiness occurs, the viscosity increases significantly and stirring becomes difficult. Also, when sodium chloride, potassium chloride, magnesium chloride, sodium acetate and pure water are mixed, stirred, heated (60 ° C.), calcium chloride is added and heating and mixing is continued, it is peculiar to the contents. Stickiness occurs, the viscosity increases significantly, and stirring becomes difficult. For this reason, it is difficult to manufacture with a normal stirring apparatus, and equipment with extremely large stirring capacity is required, and the manufacturing cost is significantly increased because the equipment is specialized and enlarged. Accordingly, there is a demand for a preparation that can be easily produced at low cost.
また、核粒子に電解質を含有する水溶液を噴霧し、乾燥させて第一組成物を得、糖成分を含む核粒子に同種又は異種の糖成分の水溶液を噴霧し、乾燥させて第二組成物を得、第一組成物に酸を混合した後に、第二組成物を混合して固形透析用製剤を得ることが開示されている(例えば特許文献3を参照)。特許文献1、特許文献2及び特許文献3のいずれにおいても60℃以上で長時間加熱する必要があり、造粒中にブドウ糖が分解、着色するおそれが強く、特許文献1、特許文献2及び特許文献3に記載される透析用製剤は、含量均一性に劣る恐れがある。更に、これらの透析用製剤の被覆層は、微細な粒子が結合剤を介して付着、積層されたもので、外部要因の影響を受けやすくなるため、ブドウ糖の分解、着色が経時的により一層進みやすいという欠点を有し、保存安定性に欠けるという大きな問題を抱えている。 Also, an aqueous solution containing an electrolyte is sprayed onto the core particles and dried to obtain a first composition, and an aqueous solution of the same or different sugar component is sprayed onto the core particles containing the sugar component and dried to form the second composition. It is disclosed that after mixing the acid with the first composition, the second composition is mixed to obtain a solid dialysis preparation (see, for example, Patent Document 3). In any of Patent Document 1, Patent Document 2 and Patent Document 3, it is necessary to heat at 60 ° C. or higher for a long time, and there is a strong possibility that glucose is decomposed and colored during granulation. Patent Document 1, Patent Document 2 and Patent The dialysis preparation described in Document 3 may be inferior in content uniformity. Furthermore, the coating layers of these dialysis preparations are made by attaching and laminating fine particles via a binder, and are easily affected by external factors, so that the decomposition and coloring of glucose further progresses over time. It has the disadvantage that it is easy to handle and lacks storage stability.
更に、これらの透析用製剤は、被覆層の構造上の特性より、輸送時に被覆層が剥離しやすく微粉が生じやすい製剤となっており、静電気の発生と相まって種々の問題が発生している。例えば、製造工程では製品充填時に発塵と同時に静電気が発生し、包装袋のシール部に微粉が付着してシール強度が低下するという不都合が見られ、最悪の場合に破袋することも考えられる。一方、透析現場の取り扱い時においては、透析液調製時に酢酸を含んだ粉塵が飛散し、作業環境が悪くなるとともに、静電気により固形剤が袋の中に残りやすいという問題点が生じている。更に、包材外側にも静電気の発生により異物が付着し、溶解時の異物混入の原因にもなっており、改善が強く求められていた。 Furthermore, these dialysis preparations are preparations in which the coating layer is easily peeled off during transportation due to the structural characteristics of the coating layer, and fine powders are easily generated, and various problems occur in combination with the generation of static electricity. For example, in the manufacturing process, static electricity is generated at the same time as dust generation during product filling, and there is a disadvantage that the fine powder adheres to the sealing part of the packaging bag and the sealing strength is lowered. In the worst case, the bag may be broken. . On the other hand, when handling the dialysis site, dust containing acetic acid is scattered during preparation of the dialysis solution, and the working environment is deteriorated, and the solid agent tends to remain in the bag due to static electricity. Furthermore, foreign matter adheres to the outer side of the packaging material due to the generation of static electricity, which also causes foreign matter to be mixed during melting, and there has been a strong demand for improvement.
上述した課題を解決しようとして、本出願人は、製造段階においても、保存時においてもブドウ糖が安定に存在し、分解や着色の恐れがなく、保存安定性、含量均一性、更には対摩損性にも優れ、医療現場での作業性が極めて良好な透析用固形剤として、薄膜X線回折で2θ=21.3〜21.5°及び2θ=27.6〜27.8°(CuKα;λ=1.54058Å、入射角θ=1°)に特定のピークを有する塩を含む被覆層で、母粒子が覆われている透析用固形剤を提案した(例えば特許文献4を参照)。更に、本出願人は、防湿性、含量均一性、流動性、耐固結性が極めて良好な固形透析用製剤として、薄膜X線回折で2θ=6.4〜6.6°(CuKα;λ=1.54058Å、入射角θ=1°)に特定のピークを有する塩を含む被覆層で、母粒子が覆われている透析用固形剤及びその簡便で生産性に優れた新たな製造方法を提案した(例えば特許文献5を参照)。
本発明の目的は、本出願人が先に提案した課題を解決するための手段の他に、重炭酸透析液を調製するために必要な電解質、pH調整剤及び/又はブドウ糖からなる透析用固形剤において、防湿性、含量均一性、流動性、耐固結性、ブドウ糖の安定性に優れ、静電気の発生を防止した作業性の極めて良好な透析用固形剤及び、簡便な方法で機器への粉体付着の低減を含む生産性に優れた製造方法を提供することにある。 The object of the present invention is to provide a solid for dialysis comprising an electrolyte, a pH adjusting agent and / or glucose necessary for preparing a bicarbonate dialysis solution, in addition to means for solving the problems previously proposed by the present applicant. In the preparation, dialysis solid agent with excellent moisture resistance, uniformity of content, fluidity, anti-caking property, glucose stability, excellent workability that prevents the generation of static electricity, and simple method An object of the present invention is to provide a production method excellent in productivity including reduction of powder adhesion.
本発明者等は、上述した課題を解決するために、少なくとも塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム及び酢酸ナトリウムが存在する系において、微粉末懸濁液を用いて攪拌混合温度と剪断力を所定範囲に設定し、所定時間以上攪拌混合すると、複雑な造粒操作や特殊な設備を用いることなく、母粒子に被覆層が形成され、防湿性、含量均一性、流動性、耐固結性、ブドウ糖の安定性に優れ、静電気の発生を防止した作業性の極めて良好な透析用固形剤が得られることを見出した。また、所定範囲濃度の微粉末懸濁液を用いると、一般的な攪拌造粒装置で経済的かつ容易に造粒物が調製でき、更に、造粒時における機器への粉体付着が低減することができる生産性の優れた製造方法を見出した。 In order to solve the above-described problems, the present inventors have used a fine powder suspension in a system in which at least sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium acetate are present, and the stirring and mixing temperature and shear force. Is set to a predetermined range and mixed for a predetermined time or longer, a coating layer is formed on the mother particles without complicated granulation operation or special equipment, and moisture resistance, content uniformity, fluidity, anti-caking property It was found that a dialysis solid preparation with excellent workability and glucose stability and extremely good workability that prevents generation of static electricity can be obtained. In addition, when a fine powder suspension having a predetermined range of concentration is used, a granulated product can be prepared economically and easily with a general agitation granulator, and further, powder adhesion to equipment during granulation is reduced. We have found a production method with excellent productivity.
即ち、本発明(1)は、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウムを含む電解質組成物及びpH調整剤を含む透析用固形剤において、薄膜X線回折で2θ=10.1〜10.3°(CuKα;λ=1.54058Å、入射角θ=1°)に特定のピークを有する塩を含む被覆層で、母粒子が覆われていることを特徴とする透析用固形剤である。 That is, the present invention (1) is based on thin film X-ray diffraction with 2θ = 10.1 in an dialysis solid agent containing an electrolyte composition containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and a pH adjuster. A solid agent for dialysis characterized in that a base particle is covered with a coating layer containing a salt having a specific peak at ˜10.3 ° (CuKα; λ = 1.54058 mm, incident angle θ = 1 °) It is.
また、本発明(2)は、顆粒状及び/又は細粒状である、前記発明(1)の透析用固形剤である。 Moreover, this invention (2) is a solid preparation for dialysis of the said invention (1) which is a granular form and / or a fine granule.
更に、本発明(3)は、前記塩が塩化カルシウムと酢酸ナトリウムとの高次化合物である、前記発明(1)又は(2)の透析用固形剤である。 Further, the present invention (3) is the solid preparation for dialysis according to the invention (1) or (2), wherein the salt is a higher order compound of calcium chloride and sodium acetate.
また、本発明(4)は、前記発明(1)〜(3)のいずれか一つの透析用固形剤と、ブドウ糖及び重炭酸ナトリウムを含む固形剤とからなる3剤型重炭酸透析用固形剤である。 In addition, the present invention (4) is a three-agent type solid preparation for bicarbonate dialysis comprising the solid preparation for dialysis according to any one of the inventions (1) to (3) and a solid preparation containing glucose and sodium bicarbonate. It is.
更に、本発明(5)は、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウムを含む電解質組成物及びpH調整剤を原料として含む透析用固形剤の製造方法であって、下記〔1〕〜〔8〕の工程を含む方法:
〔1〕原料成分である粉体及び/又は粒体の塩化ナトリウム、塩化カリウム、塩化カルシウム、酢酸ナトリウムを混合し;
〔2〕電解質組成物全体の質量に対して0.3〜3.2質量%の水に、電解質組成物中の塩化カリウム全体の質量に対して4〜84質量%の塩化カリウムを溶解して水溶液にし;
〔3〕工程〔2〕の水溶液に、電解質組成物中の酢酸ナトリウム全体の質量に対して5〜50質量%の酢酸ナトリウムを攪拌下で添加し、懸濁液を調製し;
〔4〕工程〔3〕の懸濁液に、電解質組成物中の塩化マグネシウム全量を攪拌下で添加し、微粉末懸濁液を調製し;
〔5〕工程〔1〕の混合物に、工程〔4〕の微粉末懸濁液を添加し、50℃以下の温度で攪拌混合して混合物を得;
〔6〕工程〔5〕の混合物を、該混合物1kgあたり0.001kW/kg以上の剪断力下、50℃以下の温度で1分間以上攪拌造粒して顆粒状及び/又は細粒状の造粒物を得;
〔7〕工程〔6〕の造粒物を乾燥し;
〔8〕工程〔7〕の造粒物に、pH調整剤を混合する。
Furthermore, the present invention (5) is a method for producing a solid preparation for dialysis comprising an electrolyte composition containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, and a pH adjuster as raw materials. ]-The method including the process of [8]:
[1] Mixing powder and / or granule sodium chloride, potassium chloride, calcium chloride, sodium acetate as raw material components;
[2] Dissolving 4 to 84% by mass of potassium chloride with respect to the total mass of potassium chloride in the electrolyte composition in 0.3 to 3.2% by mass of water based on the total mass of the electrolyte composition. In aqueous solution;
[3] To the aqueous solution of step [2], 5 to 50% by mass of sodium acetate based on the total mass of sodium acetate in the electrolyte composition is added with stirring to prepare a suspension;
[4] To the suspension of step [3], the whole amount of magnesium chloride in the electrolyte composition is added with stirring to prepare a fine powder suspension;
[5] Add the fine powder suspension of step [4] to the mixture of step [1] and stir and mix at a temperature of 50 ° C. or lower to obtain a mixture;
[6] Granulate and / or fine granulated by stirring and granulating the mixture of step [5] for 1 minute or more at a temperature of 50 ° C. or less under a shearing force of 0.001 kW / kg or more per 1 kg of the mixture Get things;
[7] Dry the granulated product of step [6];
[8] A pH adjuster is mixed with the granulated product in the step [7].
尚、本明細書における「剪断力」とは、以下式で算出された値をいう:
剪断力[kW/kg]={(負荷時の電流値[A]−無負荷時の電流値[A])/定格電流値[A]}×モーター容量[kW]/内容物質量[kg]
負荷時の電流値:攪拌造粒時における攪拌型混合造粒装置の攪拌モーターの電流値[A]無負荷時の電流値:空運転時(攪拌造粒時と同回転数)における該装置の攪拌モーターの電流値[A]
定格電流値:該装置の攪拌モーターの定格電流値[A]
モーター容量:該装置の攪拌モーターのモーター容量[kW]
内容物質量:攪拌造粒時における該装置内の該混合物質量[kg]
In the present specification, “shearing force” refers to a value calculated by the following formula:
Shear force [kW / kg] = {(Current value [A] at load-Current value [A] at no load) / Rated current value [A]} × Motor capacity [kW] / Content amount [kg]
Current value during loading: current value of the stirring motor of the stirring type mixing granulator during stirring granulation [A] Current value during no load: the value of the apparatus during idle operation (same rotational speed as during stirring granulation) Stirring motor current [A]
Rated current value: Rated current value [A] of the stirring motor of the device
Motor capacity: Motor capacity [kW] of the stirring motor of the apparatus
Content of substance: Amount of mixed substance in the apparatus during stirring granulation [kg]
更に、本発明(6)は、前記発明(1)〜(3)のいずれか一つの透析用固形剤に、酢酸を添加する前に又は添加すると同時に又は添加した後にブドウ糖を添加し、酢酸湿潤下で該透析用固形剤とブドウ糖とを混合して、ブドウ糖の表面に該透析用固形剤の被覆層の一部を被覆形成し、該透析用固形剤の被覆層と該ブドウ糖の被覆層とに酢酸が吸着してサラサラすることを特徴とする、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウムを含む電解質組成物及び酢酸並びにブドウ糖からなる透析用固形剤の製造方法である。 Furthermore, in the present invention (6), glucose is added to the dialysis solid preparation according to any one of the inventions (1) to (3) before or simultaneously with the addition of acetic acid, or after the addition. The dialysis solid agent and glucose are mixed to form a part of the coating layer of the dialysis solid agent on the surface of the glucose, and the dialysis solid agent coating layer and the glucose coating layer An electrolytic composition containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, and a method for producing a solid preparation for dialysis consisting of acetic acid and glucose, characterized in that acetic acid is adsorbed on the surface.
また、本発明(7)は、前記発明(6)の製造方法により得られる透析用固形剤である。 Moreover, this invention (7) is the solid agent for dialysis obtained by the manufacturing method of the said invention (6).
更に、本発明(8)は、前記発明(7)の透析用固形剤と、重炭酸ナトリウムを含む固形剤とからなる2剤型重炭酸透析用固形剤である。 Further, the present invention (8) is a two-agent type solid preparation for bicarbonate dialysis comprising the solid preparation for dialysis of the invention (7) and a solid preparation containing sodium bicarbonate.
また、本発明(9)は、透湿度(40℃、90%RH)2.0g/m2・24hr以下であり、背面電極効果を有する積層構造の防湿包材に収納されている、前記発明(1)〜(4)及び前記発明(7)〜(8)のいずれか一つの透析用固形剤である。 Further, the present invention (9) has a moisture permeability (40 ° C., 90% RH) of 2.0 g / m 2 · 24 hr or less and is housed in a moisture-proof packaging material having a laminated structure having a back electrode effect. The solid preparation for dialysis according to any one of (1) to (4) and the inventions (7) to (8).
また、本発明(10)は、透析用固形剤が、前記発明(1)〜(4)及び前記発明(9)のいずれか一つの透析用固形剤である前記発明(5)の製造方法である。 Moreover, this invention (10) is a manufacturing method of the said invention (5) whose solid agent for dialysis is a solid agent for dialysis any one of the said invention (1)-(4) and the said invention (9). is there.
本発明の透析用固形剤は、特定の塩を含む被覆層で母粒子を被覆した造粒物であり、防湿性、含量均一性、流動性、耐固結性、ブドウ糖の安定性が極めて良好である。 The solid agent for dialysis of the present invention is a granulated product in which mother particles are coated with a coating layer containing a specific salt, and has extremely good moisture resistance, content uniformity, fluidity, anti-caking property, and glucose stability. It is.
更には、本発明の透析用固形剤の製造方法によれば、従来の透析用固形剤の製造方法と比べて、粉砕、篩などの煩雑な操作を必要とすることなく、湿潤な粒子であった混合物が、サラサラとした見かけ上乾燥した顆粒状及び/又は細粒状の造粒物となり、容易に造粒が完成する。したがって、次工程である移送、乾燥、混合等のハンドリングが極めて容易となる。また、塩化カリウム/酢酸ナトリウム/塩化マグネシウム/水で調製した微粉末懸濁液を用いて得られる造粒物は、被覆層中に微粉末懸濁液成分(塩化物、酢酸塩)を含有するので、塩化カリウムと酢酸ナトリウムとを母粒子として用いても、塩化カリウムと酢酸ナトリウムとの含有が均一にでき、微量成分の塩化マグネシウムの含量も均一にできる。更に、微粉末懸濁液中の酢酸塩と塩化カルシウムとが反応した反応生成物も被覆層中に含有することによって、微量成分である塩化カルシウムの含量が均一にできる(例えば、試験例4において、8.5206gを6箇所サンプリングし、通常使用される約1質量%濃度の透析液にして測定し、ほぼ均一な値を示した)。更には、微粉末懸濁液に使用する水の量が少ないため、一般的な攪拌造粒機で適度な粘性状態で造粒物が容易に調製できると共に、微粉末懸濁液を用いて調製した際には、造粒時における機器への粉体付着の低減を含む生産性に優れた効果を奏する。 Furthermore, according to the method for producing a dialysis solid preparation of the present invention, compared to the conventional method for producing a dialysis solid preparation, the particles are wet without requiring complicated operations such as grinding and sieving. The resulting mixture is a smooth and apparently dried granular and / or fine granulated product, which is easily completed. Therefore, handling such as transfer, drying, and mixing, which are the next steps, becomes extremely easy. Moreover, the granulated material obtained by using the fine powder suspension prepared with potassium chloride / sodium acetate / magnesium chloride / water contains the fine powder suspension component (chloride, acetate) in the coating layer. Therefore, even if potassium chloride and sodium acetate are used as mother particles, the content of potassium chloride and sodium acetate can be made uniform, and the content of the minor component magnesium chloride can be made uniform. Furthermore, the reaction product obtained by reacting acetate and calcium chloride in the fine powder suspension is also contained in the coating layer, so that the content of calcium chloride as a trace component can be made uniform (for example, in Test Example 4). 8.5206 g was sampled at 6 points and measured with a dialysate having a concentration of about 1% by mass which is usually used, and showed a substantially uniform value). Furthermore, since the amount of water used in the fine powder suspension is small, a granulated product can be easily prepared in a moderate viscosity state with a general stirring granulator and prepared using the fine powder suspension. When it does, the effect which was excellent in productivity including reduction of the powder adhesion to the apparatus at the time of granulation is produced.
本発明の透析用固形剤は、成分組成としては、従来のものと本質的には変わりなく、各種電解質組成物(塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム及び酢酸ナトリウム)及びpH調整剤を含むものである。ここで、pH調整剤としては、薬理学的に許容されるものであれば特に制限されるものではなく、例えば、酢酸、塩酸等の液体状の酸、乳酸、クエン酸、りんご酸、二酢酸ナトリウム等の固体状の酸を挙げることができ、これらを単独で又は組み合わせて用いてもよい。好適には、酢酸及び二酢酸ナトリウムである。 The solid composition for dialysis of the present invention is essentially the same as the conventional composition, and includes various electrolyte compositions (sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate) and a pH adjuster. Is included. Here, the pH adjuster is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include liquid acids such as acetic acid and hydrochloric acid, lactic acid, citric acid, malic acid, and diacetic acid. A solid acid such as sodium can be mentioned, and these may be used alone or in combination. Preference is given to acetic acid and sodium diacetate.
本発明の透析用固形剤の特徴は、特定の塩を含む被覆層で母粒子が覆われている点にある。 The feature of the solid agent for dialysis of the present invention is that the base particles are covered with a coating layer containing a specific salt.
本発明に係る被覆層は、薄膜X線回折において、2θ=10.1〜10.3゜(CuKα;λ=1.54058Å、入射角θ=1°)に特定のピークを有する塩を含む。ここで、該塩の必須成分の特定を消去法により行った結果、該塩が塩化カルシウムと酢酸ナトリウムとに由来する高次化合物であることが判明した。ここで、高次化合物とは2次以上の化合物のことであり、具体的には、複塩、錯塩、有機分子化合物、水和物等の化合物である。 The coating layer according to the present invention contains a salt having a specific peak at 2θ = 10.1 to 10.3 ° (CuKα; λ = 1.54058 °, incident angle θ = 1 °) in thin film X-ray diffraction. Here, as a result of performing identification of the essential components of the salt by the elimination method, it was found that the salt is a higher order compound derived from calcium chloride and sodium acetate. Here, the higher order compound is a compound of a secondary or higher order, and specifically, is a compound such as a double salt, a complex salt, an organic molecular compound, and a hydrate.
通常、透析用固形剤の原料成分として、吸湿性の高い塩化カルシウムや塩化マグネシウムが使用されるが、本発明の透析用固形剤は、極めて防湿性に優れている。これは、攪拌造粒工程において塩化カルシウムや塩化マグネシウムが酢酸ナトリウムと特異的に反応して得られる塩等(塩化カルシウムと酢酸ナトリウムとに由来する高次化合物、酢酸カルシウム、酢酸マグネシウム等)が被覆層に含まれるためと推定される。また、該塩を含む透析用固形剤は、所定の水に溶解すれば所定の電解質イオン濃度になることが確認されている。 Usually, calcium chloride or magnesium chloride having high hygroscopicity is used as a raw material component of the dialysis solid agent, but the dialysis solid agent of the present invention is extremely excellent in moisture resistance. This is covered with salts (such as higher compounds derived from calcium chloride and sodium acetate, calcium acetate, magnesium acetate, etc.) obtained by specifically reacting calcium chloride or magnesium chloride with sodium acetate in the stirring granulation process. Presumed to be included in the layer. Further, it has been confirmed that the dialysis solid preparation containing the salt has a predetermined electrolyte ion concentration when dissolved in a predetermined water.
尚、本発明に係る被覆層は、該塩以外の成分を含んでいてもよく、例えば、透析用固形剤の原料である、塩化ナトリウム、塩化カリウム、酢酸ナトリウム及びpH調整剤等を挙げることができる。任意成分であるブドウ糖を使用する場合に、固体状の酸では、他の必須成分を含む造粒物が形成された後に、ブドウ糖がこの造粒物に添加混合される。この場合に、ブドウ糖は単独粒子として存在しているか、被覆層中に入り込むかして、透析用固形剤中に存在することとなる。他方、液体状の酸では、pH調整剤を添加する前にもしくは添加すると同時に又は添加した後にブドウ糖を添加し、湿潤下で透析用固形剤とブドウ糖とを混合すると、ブドウ糖の表面に透析用固形剤の被覆層の一部が被覆形成され透析用固形剤中に存在する。 The coating layer according to the present invention may contain components other than the salt, and examples thereof include sodium chloride, potassium chloride, sodium acetate and a pH adjuster which are raw materials for dialysis solid agents. it can. When glucose, which is an optional component, is used, in the case of a solid acid, after a granulated product containing other essential components is formed, glucose is added to the granulated product and mixed. In this case, glucose exists as a single particle or enters the coating layer and exists in the dialysis solid agent. On the other hand, in the case of a liquid acid, when glucose is added before, at the same time as or after addition of the pH adjuster, and the dialysis solid agent and glucose are mixed under humidity, the dialysis solids are added to the surface of the glucose. A portion of the coating layer of the agent is coated and present in the dialysis solid.
本発明の母粒子は、特に限定されず、透析用固形剤の原料成分を含む。例えば、塩化ナトリウムからなる母粒子、他の成分(例えば、塩化カリウム、酢酸ナトリウム)からなる母粒子を挙げることができる。但し、塩化カルシウムが母粒子となる場合は、他の成分を潮解しない程度に存在することが好ましい。 The mother particle of the present invention is not particularly limited and includes a raw material component of a dialysis solid agent. For example, mother particles made of sodium chloride and mother particles made of other components (for example, potassium chloride and sodium acetate) can be mentioned. However, when calcium chloride is the mother particle, it is preferably present to the extent that other components are not deliquescent.
以上述べたように、被覆層中に該塩が含まれている限り、例えば、塩化ナトリウムが被覆層に含まれていても、酢酸ナトリウムが母粒子に含まれていても、更には、透析用固形剤の原料成分や反応生成物が、母粒子・被覆層のいずれに含まれていても、或いは両方に含まれていても構わない。但し、塩化カルシウム及び塩化マグネシウムは被覆層に含まれることが好ましい。これは、塩化カルシウムや塩化マグネシウムは、潮解性があるため、母粒子として使用し難いためである。 As described above, as long as the salt is contained in the coating layer, for example, sodium chloride is contained in the coating layer, sodium acetate is contained in the mother particles, The raw material component and reaction product of the solid agent may be contained in either the mother particle or the coating layer, or may be contained in both. However, calcium chloride and magnesium chloride are preferably included in the coating layer. This is because calcium chloride and magnesium chloride are deliquescent and difficult to use as mother particles.
本発明に係る透析用固形剤は、典型的には、顆粒状及び/又は細粒状の造粒物である。そして、その平均粒径は、約200〜800μmであり、被覆層の厚さは5〜70μmであることが好適である。ここで、該造粒物は、母粒子の表面に被覆層が形成された単独の粒子であってもよいし、複数の被覆された母粒子が被覆層を介して結合したものであってもよい。造粒物のうち単独の粒子の形状は、やや丸みを帯びた立方体のものが中心である。他方、被覆層を介して結合したものは、数個の被覆された立方体状の粒子が結合した形状である。 The dialysis solid preparation according to the present invention is typically a granulated and / or fine granulated product. And the average particle diameter is about 200-800 micrometers, and it is suitable that the thickness of a coating layer is 5-70 micrometers. Here, the granulated product may be a single particle in which a coating layer is formed on the surface of the mother particle, or a plurality of coated mother particles may be bonded through the coating layer. Good. Of the granulated material, the shape of a single particle is centered on a slightly rounded cube. On the other hand, what is bonded via the coating layer is a shape in which several coated cubic particles are bonded.
次に、本発明の透析用固形剤の製造方法は、塩化カリウム/酢酸ナトリウム/塩化マグネシウム微粉末懸濁液を用いて調製する製造方法であり、使用する水の量が少ないため、一般的な攪拌造粒機で適度な粘性状態で造粒が容易に調製できる。 Next, the method for producing a dialysis solid preparation of the present invention is a production method prepared using a potassium chloride / sodium acetate / magnesium chloride fine powder suspension, and since the amount of water used is small, Granulation can be easily prepared with an agitation granulator in an appropriate viscosity state.
本発明の透析用固形剤の製造方法は、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウムを含む電解質組成物及びpH調整剤を原料として含む透析用固形剤の製造方法であって、下記〔1〕〜〔8〕の工程を含む方法:
〔1〕原料成分である粉体及び/又は粒体の塩化ナトリウム、塩化カリウム、塩化カルシウム、酢酸ナトリウムを混合し;
〔2〕電解質組成物全体の質量に対して0.3〜3.2質量%の水に、電解質組成物中の塩化カリウム全体の質量に対して4〜84質量%の塩化カリウムを溶解して水溶液にし;
〔3〕工程〔2〕の水溶液に、電解質組成物中の酢酸ナトリウム全体の質量に対して5〜50質量%の酢酸ナトリウムを攪拌下で添加し、懸濁液を調製し;
〔4〕工程〔3〕の懸濁液に、電解質組成物中の塩化マグネシウム全量を攪拌下で添加し、微粉末懸濁液を調製し;
〔5〕工程〔1〕の混合物に、工程〔4〕の微粉末懸濁液を添加し、50℃以下の温度で攪拌混合して混合物を得;
〔6〕工程〔5〕の混合物を、該混合物1kgあたり0.001kW/kg以上の剪断力下、50℃以下の温度で1分間以上攪拌造粒して顆粒状及び/又は細粒状の造粒物を得;
〔7〕工程〔6〕の造粒物を乾燥し;
〔8〕工程〔7〕の造粒物に、pH調整剤を混合する。
The method for producing a dialysis solid preparation of the present invention is a method for producing a dialysis solid preparation comprising, as a raw material, an electrolyte composition containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium acetate, and a pH adjuster. A method comprising the following steps [1] to [8]:
[1] Mixing powder and / or granule sodium chloride, potassium chloride, calcium chloride, sodium acetate as raw material components;
[2] Dissolving 4 to 84% by mass of potassium chloride with respect to the total mass of potassium chloride in the electrolyte composition in 0.3 to 3.2% by mass of water based on the total mass of the electrolyte composition. In aqueous solution;
[3] To the aqueous solution of step [2], 5 to 50% by mass of sodium acetate based on the total mass of sodium acetate in the electrolyte composition is added with stirring to prepare a suspension;
[4] To the suspension of step [3], the whole amount of magnesium chloride in the electrolyte composition is added with stirring to prepare a fine powder suspension;
[5] Add the fine powder suspension of step [4] to the mixture of step [1] and stir and mix at a temperature of 50 ° C. or lower to obtain a mixture;
[6] Granulate and / or fine granulated by stirring and granulating the mixture of step [5] for 1 minute or more at a temperature of 50 ° C. or less under a shearing force of 0.001 kW / kg or more per 1 kg of the mixture Get things;
[7] Dry the granulated product of step [6];
[8] A pH adjuster is mixed with the granulated product in the step [7].
まず、本発明に係る「粉体及び/又は粒体」について説明する。本発明に係る「粉体及び/又は粒体」は、該透析用固形剤の1種以上の原料成分(塩化ナトリウム、塩化カリウム、酢酸ナトリウム、塩化カルシウム、塩化マグネシウム及びpH調整剤からなる原料群から選択される1種以上)からなる。加えて、該粉体及び/又は粒体は、基本的には乾燥形態にある。 First, “powder and / or granules” according to the present invention will be described. The “powder and / or granule” according to the present invention includes one or more raw material components of the dialysis solid agent (raw material group consisting of sodium chloride, potassium chloride, sodium acetate, calcium chloride, magnesium chloride and a pH adjuster). 1 type or more selected from. In addition, the powder and / or granules are basically in a dry form.
ここで、「粉体及び/又は粒体」として、塩化ナトリウム、塩化カリウム、酢酸ナトリウムを用いる場合、各粒子の粒子径は特に限定されるものではないが、各粒子径の差ができるだけ小さくなるような組合せが、含量均一性の保持という面から好ましい。即ち、平均粒径は200〜600μm程度のものが好ましく、それぞれの粒子の平均粒径の差が、全粒子の平均粒径の30%以内になるような組合せが好ましい。また、塩化カルシウムの粒径は、300μm以下が望ましい。 Here, when sodium chloride, potassium chloride, or sodium acetate is used as the “powder and / or granule”, the particle diameter of each particle is not particularly limited, but the difference between the particle diameters is as small as possible. Such a combination is preferable from the viewpoint of maintaining content uniformity. That is, the average particle size is preferably about 200 to 600 μm, and a combination in which the difference in average particle size of each particle is within 30% of the average particle size of all particles is preferable. The particle size of calcium chloride is desirably 300 μm or less.
次に、本発明に係る工程〔2〕の、「水溶液」に関して説明する。以下、特記しない限り、この水溶液を「該水溶液」という。該水溶液の溶質は、特に限定されず、透析用固形剤の原料成分である、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウムからなる群より選択される1種以上である。 Next, the “aqueous solution” in the step [2] according to the present invention will be described. Hereinafter, this aqueous solution is referred to as “the aqueous solution” unless otherwise specified. The solute of the aqueous solution is not particularly limited, and is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, which are raw material components of the dialysis solid agent.
該水溶液の好ましい態様は、塩化カリウムを含むものである。この場合、塩化カリウムを溶解して水溶液にするのに用いる水の量は、電解質組成物全体の質量に対して0.3〜3.2質量%が好ましく、好適には0.6〜2.6質量%である。また、塩化カリウムを溶解して水溶液にするのに用いる塩化カリウムの量は、塩化カリウム全体の質量に対して4質量%以上が好ましく、好適には4〜84質量%であり、より好適には30〜50質量%である。但し、水溶液を調製する際の温度は0〜100℃であり、塩化カリウムの水への溶解度は温度によって大きく変わるので、塩化カリウムの添加量を4〜84質量%と極めて広い範囲で示したもので、要するに塩化カリウムを水溶液として使用することを意味するものである。水の量は、塩化カリウムの水溶液を調製するのに必要な最少量を用いるのが好ましい。 A preferred embodiment of the aqueous solution contains potassium chloride. In this case, the amount of water used for dissolving potassium chloride to form an aqueous solution is preferably 0.3 to 3.2% by mass, and preferably 0.6 to 2.% by mass with respect to the mass of the entire electrolyte composition. 6% by mass. Further, the amount of potassium chloride used for dissolving potassium chloride to form an aqueous solution is preferably 4% by mass or more, preferably 4 to 84% by mass, more preferably 4% by mass to the total mass of potassium chloride. 30-50% by mass. However, the temperature at which the aqueous solution is prepared is 0 to 100 ° C., and the solubility of potassium chloride in water varies greatly depending on the temperature. Therefore, the amount of potassium chloride added is 4 to 84% by mass and is shown in a very wide range. In short, this means that potassium chloride is used as an aqueous solution. It is preferable to use the minimum amount of water necessary to prepare an aqueous solution of potassium chloride.
ここで、塩化カリウム全体量を母粒子として用いると、造粒後の次工程(移送、乾燥、混合等)で偏析を起こし、含量均一性試験(例えば、試験例4のように造粒物中から8.5206gを6箇所サンプリングし、通常使用される約1質量%濃度の透析液にして測定)を行うと塩化カリウムの含量が均一にできないおそれがある。しかし、該水溶液中に塩化カリウムの一部を用いると、塩化カリウムの一部は、母粒子となる電解質組成物(例えば、塩化ナトリウム、塩化カリウム、酢酸ナトリウム)の被覆層中に塩化カリウムが含有されるので、造粒後及び次工程後の塩化カリウムの含量が均一にできる。具体的には、塩化カリウム全体の質量に対して30〜50質量%の塩化カリウムを被覆層中に含有した透析用固形剤の造粒後及び次工程後における塩化カリウムの含量の均一性は、100質量%の塩化カリウムを被覆層中に含有した透析用固形剤の造粒後及び次工程後における塩化カリウムの含量の均一性と同程度である。更に、塩化カリウムの一部だけを水溶液とするため、造粒時の水の量は少ない量で調製できる。 Here, when the total amount of potassium chloride is used as the mother particles, segregation occurs in the subsequent steps after granulation (transfer, drying, mixing, etc.), and the content uniformity test (for example, as in Test Example 4) If 8.5206 g is sampled at 6 points and measured with a dialysate having a concentration of about 1% by mass which is usually used, the potassium chloride content may not be uniform. However, when a part of potassium chloride is used in the aqueous solution, a part of the potassium chloride is contained in the coating layer of the electrolyte composition (for example, sodium chloride, potassium chloride, sodium acetate) serving as mother particles. Therefore, the content of potassium chloride after granulation and after the next step can be made uniform. Specifically, the uniformity of the content of potassium chloride after granulation and after the next step of the solid preparation for dialysis containing 30-50% by mass of potassium chloride in the coating layer with respect to the total mass of potassium chloride is: After the granulation of the solid agent for dialysis containing 100% by mass of potassium chloride in the coating layer and the uniformity of the potassium chloride content after the next step. Furthermore, since only a part of the potassium chloride is used as the aqueous solution, the amount of water during granulation can be prepared with a small amount.
次に、本発明に係る工程〔3〕の「懸濁液」に関して説明する。以下、特記しない限り、この懸濁液を「該懸濁液」という。該水溶液に添加する溶質は酢酸ナトリウムである。 Next, the “suspension” in the step [3] according to the present invention will be described. Hereinafter, unless otherwise specified, this suspension is referred to as “the suspension”. The solute added to the aqueous solution is sodium acetate.
該懸濁液の好ましい態様は、塩化カリウムを含む水溶液に、酢酸ナトリウムを添加することによって得られる懸濁液である。懸濁液の主成分は塩化カリウムと酢酸ナトリウムとであることが粉末X線回折から判明している。また、該懸濁液に用いる酢酸ナトリウム量は電解質組成物中の酢酸ナトリウム量全体の質量に対して、5〜50質量%が好ましく、好適には10〜30質量%である。該懸濁液を調製する際の温度は0〜100℃である。 A preferred embodiment of the suspension is a suspension obtained by adding sodium acetate to an aqueous solution containing potassium chloride. It has been found from powder X-ray diffraction that the main components of the suspension are potassium chloride and sodium acetate. Moreover, 5-50 mass% is preferable with respect to the mass of the whole amount of sodium acetate in electrolyte composition, and the amount of sodium acetate used for this suspension is 10-30 mass% suitably. The temperature at which the suspension is prepared is 0 to 100 ° C.
また、該懸濁液中の粒子の平均粒径の大半は10μm以下(該懸濁液に関与しなかった酢酸ナトリウムの粒径は添加時の粒径のままである)である。尚、該懸濁液の調製方法はジェットミルのような粉砕機を特に用いることなく、攪拌混合するだけの操作で極めて容易に調製できることが特徴である。 Further, most of the average particle size of the particles in the suspension is 10 μm or less (the particle size of sodium acetate that was not involved in the suspension remains the particle size at the time of addition). The method for preparing the suspension is characterized in that it can be prepared very easily by an operation of stirring and mixing without using a pulverizer such as a jet mill.
次に、本発明に係る工程〔4〕の「微粉末懸濁液」に関して説明する。以下、特記しない限り、この微粉末懸濁液を「該微粉末懸濁液」という。該微粉末懸濁液に添加する溶質は、塩化マグネシウムである。 Next, the “fine powder suspension” in the step [4] according to the present invention will be described. Hereinafter, unless otherwise specified, this fine powder suspension is referred to as “the fine powder suspension”. The solute added to the fine powder suspension is magnesium chloride.
該懸濁液の好ましい態様は、塩化カリウムと酢酸ナトリウムとを含む懸濁液に、塩化マグネシウムを添加することによって得られる微粉末懸濁液である。懸濁物の主成分は塩化カリウムと塩化ナトリウムと酢酸マグネシウムとであることが粉末X線回折から判明している。また、該微粉末懸濁液に用いる塩化マグネシウムの量は電解質組成物中の塩化マグネシウム全量の質量に対して、好適には100質量%である。 A preferred embodiment of the suspension is a fine powder suspension obtained by adding magnesium chloride to a suspension containing potassium chloride and sodium acetate. It has been found from powder X-ray diffraction that the main components of the suspension are potassium chloride, sodium chloride and magnesium acetate. The amount of magnesium chloride used in the fine powder suspension is preferably 100% by mass with respect to the total mass of magnesium chloride in the electrolyte composition.
また、該微粉末懸濁液中の平均粒子径は10μm以下(該懸濁液に関与しなかった酢酸ナトリウムは塩化マグネシウムと反応して微粉末塩化ナトリウムが析出する)である。尚、該微粉末懸濁液の調製方法はジェットミルのような粉砕機を特に用いることなく、攪拌混合するだけの操作で安価に調製できることが特徴である。 Further, the average particle size in the fine powder suspension is 10 μm or less (sodium acetate not involved in the suspension reacts with magnesium chloride to precipitate fine powder sodium chloride). The method for preparing the fine powder suspension is characterized in that it can be prepared at a low cost by simply stirring and mixing without using a pulverizer such as a jet mill.
更には、該微粉末懸濁液を用いることによって得られる造粒物中から一定量をサンプリング(例えば、試験例4において8.5206gを6箇所でサンプリングした)し通常使用される透析液濃度(約1質量%)にした際には、微量成分である塩化カルシウムと塩化マグネシウムとの含量均一性が向上し、塩化カリウムと酢酸ナトリウムとの大半を母粒子として用いてもカリウムイオンと酢酸イオンとの含量均一性が向上する。 Furthermore, a certain amount is sampled from the granulated product obtained by using the fine powder suspension (for example, 8.5206 g was sampled at 6 locations in Test Example 4), and the dialysate concentration normally used ( (About 1% by mass), the content uniformity of trace amounts of calcium chloride and magnesium chloride is improved. Even if most of potassium chloride and sodium acetate are used as mother particles, potassium ions and acetate ions The content uniformity of the is improved.
「粉体及び/又は粒体」と「微粉末懸濁液」の組合せの好適な例を挙げると、「粉体及び/又は粒体」が、塩化ナトリウム、塩化カリウム、塩化カルシウム、酢酸ナトリウムを含み、「微粉末懸濁液」が、塩化カリウムと酢酸ナトリウムと塩化マグネシウムとを含むものである。 As a suitable example of the combination of “powder and / or granules” and “fine powder suspension”, “powder and / or granules” may contain sodium chloride, potassium chloride, calcium chloride, sodium acetate. The “fine powder suspension” contains potassium chloride, sodium acetate and magnesium chloride.
尚、透析用固形剤の全原料を「粉体及び/又は粒体」+「微粉末懸濁液」に使用する必要は無く、原料の一部を以後の工程で添加してもよい。例えば、pH調整剤に関しては、乾燥後に添加することが好ましい。 Note that it is not necessary to use all raw materials for the dialysis solid agent in “powder and / or granules” + “fine powder suspension”, and a part of the raw materials may be added in the subsequent steps. For example, the pH adjuster is preferably added after drying.
次に、製造方法における各種条件につき説明する。該微粉末懸濁液添加から造粒完了までの時間は、塩化カルシウムと酢酸ナトリウムとに由来する高次化合物の塩を形成するのに要する時間、生成した造粒物の含量均一性及びサラサラ化(水分を約3質量%含有するにもかかわらず、流動性が良く、防湿性が高く、付着や凝集性の要因となる自由水が、被覆層の表面にほとんど無い造粒物になること)を考慮すると、1分以上が好適であり、より好適には3分以上であり、更に好適には10分以上である。一方、破砕防止の観点から40分以下が好適である。 Next, various conditions in the manufacturing method will be described. The time from the addition of the fine powder suspension to the completion of granulation is the time required to form a salt of a higher-order compound derived from calcium chloride and sodium acetate, the content uniformity of the produced granulated product and smoothness (Despite containing about 3% by mass of water, the fluidity is good, the moisture resistance is high, and free water that causes adhesion and cohesion becomes a granulated product with almost no surface on the surface of the coating layer.) Is preferably 1 minute or longer, more preferably 3 minutes or longer, and even more preferably 10 minutes or longer. On the other hand, 40 minutes or less is preferable from the viewpoint of preventing crushing.
次に、撹拌時に加える剪断力について説明する。まず、本発明に係る剪断力の定義につき説明する。撹拌型混合造粒装置を使用した場合、本発明に係る撹拌造粒時において、撹拌翼の回転によって撹拌翼と該装置内壁との間で該混合物に剪断力が加わる。この剪断力の大きさを、該装置の撹拌モーターの負荷量(モーターの電流値)を用いて前記式にて算出し、その値を該混合物1kgあたりに加えた剪断力とした。次に、サラサラ化のために必要な剪断力は、0.001kW/kg以上であり、好適には0.005kW/kg以上であり、更に好適には0.01kW/kg以上である。また、上限に関しては、内温上昇や破砕防止の観点から、0.05kW/kg以下であることが好適である。 Next, the shearing force applied at the time of stirring is demonstrated. First, the definition of the shearing force according to the present invention will be described. When a stirring type mixing granulator is used, during the stirring granulation according to the present invention, a shearing force is applied to the mixture between the stirring blade and the inner wall of the device by the rotation of the stirring blade. The magnitude of this shear force was calculated by the above formula using the load of the stirring motor (current value of the motor) of the apparatus, and the value was defined as the shear force applied per 1 kg of the mixture. Next, the shearing force required for smoothing is 0.001 kW / kg or more, preferably 0.005 kW / kg or more, and more preferably 0.01 kW / kg or more. The upper limit is preferably 0.05 kW / kg or less from the viewpoint of increasing the internal temperature and preventing crushing.
また、撹拌混合と撹拌造粒とは、常温で実施することができる。場合により、常温よりも高い又は低い温度で実施してよいが、温度が高い程、反応が速くなるので、速い反応を望む場合には、温度が高い方が好ましい。但し、高い温度で実施する場合には、攪拌熱と反応熱とで造粒時の温度が上昇するので、酢酸ナトリウムの一部が溶融状態となり、機器への粉体付着が多くなる恐れがある。そのため、温度は、常温よりもそれ程高くすることはできない。尚、本発明の造粒を実施する好ましい温度は、内温50℃以下である。下限値は、特に限定されないが、好適には0℃以上であり、より好適には10〜50℃である。 Moreover, stirring and mixing and stirring granulation can be performed at normal temperature. In some cases, the reaction may be carried out at a temperature higher or lower than room temperature, but the higher the temperature, the faster the reaction. Therefore, when a fast reaction is desired, a higher temperature is preferred. However, when it is carried out at a high temperature, the temperature at the time of granulation rises due to the heat of stirring and the heat of reaction, so that a part of sodium acetate may be in a molten state and the powder may adhere to the equipment. . Therefore, the temperature cannot be so much higher than the normal temperature. In addition, the preferable temperature which implements the granulation of this invention is 50 degrees C or less of internal temperature. Although a lower limit is not specifically limited, Preferably it is 0 degreeC or more, More preferably, it is 10-50 degreeC.
該粉体及び/又は粒体中に該微粉末懸濁液を添加する方法であるが、特に制限は無く、一括添加もしくは分割添加でもよく、噴霧する方式であってもよい。また、該微粉末懸濁液の温度(添加前)は、0〜100℃が好ましく、好適には40〜90℃である。但し、ハンドリング面を考慮すると、微粉末懸濁液を調製した際の温度で添加することが好ましい。 The fine powder suspension is added to the powder and / or the granule, but there is no particular limitation, and batch addition or divided addition may be used, or a spraying method may be used. Moreover, 0-100 degreeC is preferable and the temperature (before addition) of this fine powder suspension is 40-90 degreeC suitably. However, considering the handling surface, it is preferable to add at the temperature when the fine powder suspension is prepared.
尚、撹拌混合工程及び撹拌造粒工程で使用する撹拌型混合造粒装置としては、高速攪拌型造粒装置が好適である。操作条件は、通常混合、造粒する一般的条件の範囲内で目的は充分達成される。 In addition, as a stirring type mixing granulator used in a stirring mixing process and a stirring granulation process, a high-speed stirring type granulating apparatus is suitable. The purpose of the operation is sufficiently achieved within the range of general conditions for normal mixing and granulation.
次に、撹拌造粒工程で得られた造粒物を乾燥する。乾燥工程に使用する乾燥装置は、特に限定されないが、撹拌造粒工程で使用した装置内で造粒物を乾燥するのが望ましい。この方法によると生成した造粒物を引き続き撹拌しながら底部撹拌軸より熱風を送風し、内温を50℃〜55℃に保持することで、約5〜20分間という短時間に、造粒物の水分を1質量%以下まで乾燥させることができる。その他の装置では流動層乾燥装置、回転乾燥装置などが好適である。 Next, the granulated product obtained in the stirring granulation step is dried. Although the drying apparatus used for a drying process is not specifically limited, It is desirable to dry a granulated material within the apparatus used at the stirring granulation process. According to this method, while continuously stirring the produced granulated material, hot air is blown from the bottom stirring shaft, and the internal temperature is maintained at 50 ° C to 55 ° C. Can be dried to 1% by mass or less. In other apparatuses, a fluidized bed drying apparatus, a rotary drying apparatus, etc. are suitable.
必要に応じて、乾燥前、乾燥途中又は乾燥後にpH調整剤を添加混合し、整粒して顆粒状及び/又は細粒状の本透析用固形剤を得る。 If necessary, a pH adjuster is added and mixed before drying, during or after drying, and sized to obtain a granular and / or fine solid dialysis solid preparation.
本発明の透析用固形剤にブドウ糖を添加するときの製造方法につき説明する。本発明の透析用固形剤に、酢酸を添加する前又は添加すると同時に又は添加した後にブドウ糖を添加し、酢酸湿潤下で該透析用固形剤とブドウ糖とを混合して、ブドウ糖の表面に該透析用固形剤の被覆層の一部を被覆形成し、該透析用固形剤の被覆層と該ブドウ糖の被覆層とに酢酸が吸着してサラサラする。この時に、塩化ナトリウムを含む母粒子の被覆層中には、電解質組成物と酢酸と極微量のブドウ糖とを含有した全成分が含有する。他方、ブドウ糖の母粒子の被覆層中には、電解質組成物と酢酸と極微量の塩化ナトリウムとを含有する。また、ブドウ糖をコーティングするため、他の電解質組成物や酢酸との接触面積が小さくなり安定性が向上する。更には、ブドウ糖の表面に該透析用固形剤の被覆層の一部が被覆形成されるので、ブドウ糖を単に混合するよりは、含量均一性が保持できる。 The production method when glucose is added to the dialysis solid preparation of the present invention will be described. Glucose is added to the dialysis solid preparation of the present invention before, at the same time as or after addition of acetic acid, and the dialysis solid preparation and glucose are mixed under acetic acid wet condition, and the dialysis is applied to the surface of glucose. A part of the coating layer of the solid agent for coating is formed by coating, and acetic acid is adsorbed to the coating layer of the solid agent for dialysis and the coating layer of glucose to make it smooth. At this time, the coating layer of the mother particles containing sodium chloride contains all components containing the electrolyte composition, acetic acid, and a trace amount of glucose. On the other hand, the coating layer of glucose mother particles contains an electrolyte composition, acetic acid and a trace amount of sodium chloride. Moreover, since glucose is coated, the contact area with other electrolyte compositions and acetic acid is reduced, and stability is improved. Further, since a part of the coating layer of the dialysis solid agent is coated on the surface of glucose, the content uniformity can be maintained rather than simply mixing glucose.
通常、ブドウ糖の表面を電解質組成物でコーティングするには、流動層造粒装置によるコーティング又は透析用固形剤を調製中にブドウ糖を添加してコーティングを行うため、60℃以上で長時間加熱する必要があり、造粒中にブドウ糖が分解し、着色している恐れが強い。しかし、本発明の製造方法によれば、常温又はそれよりもやや高い温度で数分の混合時間でブドウ糖をコーティングすることができる。また、ブドウ糖表面のコーティング量は酢酸湿潤時間により異なる。具体的には、本発明の透析用固形剤全量とブドウ糖全量との混合物に酢酸を添加することが好ましい。本発明の透析用固形剤の一部とブドウ糖全量との混合物に酢酸を添加してもよい。この場合、透析用固形剤の一部が透析用固形剤全量に対して20質量%よりも少ない量になると、酢酸が吸着できずにサラサラしないおそれがある。 Usually, in order to coat the surface of glucose with an electrolyte composition, it is necessary to heat at 60 ° C. or higher for a long time because glucose is added during coating with a fluidized bed granulator or a solid preparation for dialysis. There is a strong possibility that glucose is decomposed and colored during granulation. However, according to the production method of the present invention, glucose can be coated at normal temperature or slightly higher than that at a mixing time of several minutes. Also, the coating amount on the glucose surface varies depending on the acetic acid wetting time. Specifically, it is preferable to add acetic acid to the mixture of the total amount of the solid agent for dialysis of the present invention and the total amount of glucose. Acetic acid may be added to a mixture of a part of the dialysis solid preparation of the present invention and the total amount of glucose. In this case, if a part of the dialysis solid agent is less than 20% by mass with respect to the total amount of dialysis solid agent, acetic acid cannot be adsorbed and it may not be smooth.
混合装置に関しては、特に限定されないが、回転式混合装置、撹拌式混合装置を用いることが好ましい。 Although it does not specifically limit regarding a mixer, It is preferable to use a rotary mixer and a stirring mixer.
本発明において、ブドウ糖を透析用固形剤に添加する場合には、ブドウ糖を別途添加しないで、重炭酸透析液を作製することができる。一方、ブドウ糖を透析用固形剤に添加しないで、ブドウ糖を、重炭酸透析液を作製する際に、別途添加してもよい。 In the present invention, when adding glucose to the dialysis solid preparation, a bicarbonate dialysate can be prepared without adding glucose separately. On the other hand, glucose may be added separately when preparing a bicarbonate dialysate without adding glucose to the dialysis solid preparation.
本発明の透析用固形剤を所定の水に溶解すれば重炭酸透析液を、例えば下記の濃度に調整することができる:
Na+ 125〜150 mEq/L
K+ 1.0〜3.0 mEq/L
Ca2+ 1.5〜3.5 mEq/L
Mg2+ 0.5〜1.5 mEq/L
Cl− 90.0〜135 mEq/L
CH3CO2 − 5.0〜10.0 mEq/L
HCO3 − 20.0〜35.0 mEq/L
ブドウ糖 0.5〜2.5 g/L
If the solid agent for dialysis of the present invention is dissolved in predetermined water, the bicarbonate dialysis solution can be adjusted to the following concentration, for example:
Na + 125 to 150 mEq / L
K + 1.0 to 3.0 mEq / L
Ca 2+ 1.5-3.5 mEq / L
Mg 2+ 0.5-1.5 mEq / L
Cl - 90.0-135 mEq / L
CH 3 CO 2 - 5.0~10.0 mEq / L
HCO 3 - 20.0~35.0 mEq / L
Glucose 0.5-2.5 g / L
このようにして得られる透析用固形剤の包装材料としては、防湿性能が良く、しかも背面電極効果を有するものが好ましい。従来より帯電防止剤を樹脂に練りこんでフィルムを作成し、帯電防止機能を有する包装材料に加工して使用された例はあったが、樹脂からのブリード現象により製品に異物が混入するなどの不都合が見られた。これに比べ、本発明において帯電防止剤はフィルムの接着に使用する接着剤中に含まれているためフィルムを浸透することはなく、ブリード現象は起こりえない。帯電防止剤は透析用固形剤と接するフィルム面の裏側にある接着剤中にあり、背面まで帯電防止機能を有するラミネートフィルムである。すなわち、透湿度(40℃、90%RH)2.0g/m2・24hr以下のフィルム、例えばシリカ蒸着フィルムを用い、静電防止性接着剤、例えばボンディップ(コニシ社製)を用いて接着したラミネートフィルムを用いて加工した背面電極効果を有する包装材料に透析用固形剤を充填、包装するのが好ましい。その様な積層構造を有するラミネートフィルムの構成例としては、
PET/SiOX/ボンディップ/PE、
PVA/SiOX/ボンディップ/PE、
ONY/SiOX/ボンディップ/PE、
PET/SiOX/ボンディップ/CPP、
OPP/SiOX/ボンディップ/CPP、
を挙げることができ、これらを包装材料に加工して用いることができる。ラミネートフィルムは公知の方法により容易に製造できる。製造方法の一例としては、静電防止性接着剤の必要量を計り取り、必要により溶剤で希釈するなどして液が均一になるように混合し、グラビアコーター、リバースコーター等のコーターを用いて上記のフィルムに塗布し、温風乾燥して完全に硬化させる方法を挙げることができる。得られたラミネートフィルムはヒートシールすることによって包装材料に加工することができる。
As a packaging material for the solid preparation for dialysis thus obtained, a material having good moisture-proof performance and having a back electrode effect is preferable. There has been an example where a film was made by kneading an antistatic agent into a resin and then processed into a packaging material having an antistatic function, but foreign substances are mixed into the product due to the bleeding phenomenon from the resin. Inconvenience was seen. In contrast, in the present invention, since the antistatic agent is contained in the adhesive used for bonding the film, it does not penetrate the film, and the bleeding phenomenon cannot occur. The antistatic agent is a laminate film that is in the adhesive on the back side of the film surface in contact with the dialysis solid agent and has an antistatic function up to the back surface. That is, a film having a water vapor transmission rate (40 ° C., 90% RH) of 2.0 g / m 2 · 24 hr or less, such as a silica vapor deposition film, is bonded using an antistatic adhesive such as Bondip (manufactured by Konishi). It is preferable to fill and package a dialysis solid agent in a packaging material having a back electrode effect processed using the laminated film. As a configuration example of a laminate film having such a laminated structure,
PET / SiO X / Bondip / PE,
PVA / SiO X / Bondip / PE,
ONY / SiO X / Bondip / PE
PET / SiO X / Bondip / CPP,
OPP / SiO X / Bondip / CPP,
These can be processed into packaging materials and used. The laminate film can be easily produced by a known method. As an example of the manufacturing method, measure the necessary amount of antistatic adhesive, mix with a solution such as diluting with a solvent if necessary, and use a coater such as a gravure coater or reverse coater. The method of apply | coating to said film, drying by warm air, and making it harden | cure can be mentioned. The obtained laminate film can be processed into a packaging material by heat sealing.
以下に本発明の実施例を示して、更に具体的に説明する。 Hereinafter, the present invention will be described more specifically with reference to examples.
[実施例1]
塩化ナトリウム7500g、塩化カリウム98.9g、塩化カルシウム221.8g、酢酸ナトリウム802gを攪拌型混合造粒装置(深江パウテック株式会社製 ハイスピードミキサーFS−GS−25J)に仕込み、攪拌混合して混合物を得た。回転数70rpm(剪断力0.01kW/kg)で混合攪拌しながら、内温40℃で、塩化カリウム80.9gを90℃精製水162gに溶解した後に、酢酸ナトリウム89.1gを添加して懸濁液を調製し、更に、塩化マグネシウム122.4gを添加して、微粉末懸濁液を調製して、混合物に添加した。添加直後に、湿潤な粒子状であった内容物が、30分間混合攪拌するとサラサラとした顆粒状となった。一旦造粒物を取り出して、水分が0.5質量%以下になるまで80℃の条件下で乾燥した。得られた造粒物に酢酸145.3gを添加し、5分間混合攪拌した後に、造粒物を取り出し、整粒して顆粒状及び細粒状の製剤を得た。
[Example 1]
7500 g of sodium chloride, 98.9 g of potassium chloride, 221.8 g of calcium chloride, and 802 g of sodium acetate were charged into a stirring type mixing granulator (High Speed Mixer FS-GS-25J, manufactured by Fukae Pautech Co., Ltd.), and mixed by stirring. Obtained. While mixing and stirring at a rotational speed of 70 rpm (shearing force 0.01 kW / kg), 80.9 g of potassium chloride was dissolved in 162 g of 90 ° C. purified water at an internal temperature of 40 ° C., and then 89.1 g of sodium acetate was added and suspended. A turbid solution was prepared, and further 122.4 g of magnesium chloride was added to prepare a fine powder suspension and added to the mixture. Immediately after the addition, the contents that were in the form of wet particles became smooth granules when mixed and stirred for 30 minutes. The granulated product was once taken out and dried under the condition of 80 ° C. until the water content became 0.5% by mass or less. After adding 145.3 g of acetic acid to the obtained granulated product and mixing and stirring for 5 minutes, the granulated product was taken out and sized to obtain granular and fine granular preparations.
[実施例2]
実施例1で得られた造粒物(酢酸添加前)4457.6g(実施例1で得られた造粒物の50質量%)とブドウ糖1204.7gとを混合し、酢酸145.3gを添加し、サラサラとした顆粒状となった。その後、残りの実施例1で得られた造粒物(酢酸添加前)4457.6g(実施例1で得られた造粒物の50質量%)を添加して、5分間攪拌混合した後に、造粒物を取り出し、整粒して顆粒状及び細粒状の製剤を得た。
[Example 2]
4457.6 g of granulated product obtained in Example 1 (before addition of acetic acid) (50% by mass of the granulated product obtained in Example 1) and 1204.7 g of glucose were mixed, and 145.3 g of acetic acid was added. Then, it became smooth and granular. Then, after adding 4457.6 g (50% by mass of the granulated product obtained in Example 1) of the remaining granulated product (before acetic acid addition) obtained in Example 1, and stirring and mixing for 5 minutes, The granulated product was taken out and sized to obtain granular and fine granular preparations.
[比較例1]
塩化ナトリウム7500.0g、塩化カリウム179.8g、酢酸ナトリウム891.1gを攪拌型混合造粒装置(深江パウテック株式会社製 ハイスピードミキサー FS−GS−25J)に添加し混合攪拌して混合物を得た。回転数70rpm(剪断力0.01kW/kg)で混合攪拌しながら、内温が40℃で、あらかじめ調製しておいた塩化マグネシウム122.4gと塩化カルシウム221.8gとを精製水162gに溶解した液温40℃の水溶液を添加した。添加した直後に、湿潤な粒子状であった内容物が、15分間混合攪拌するとサラサラとした顆粒状となった。一旦造粒物を取り出して、水分が0.5質量%以下になるまで80℃の温度条件下で乾燥した。得られた造粒物に酢酸145.3gを添加し、5分間混合攪拌した後に、造粒物を取り出し、整粒して顆粒状及び細粒状の製剤を得た。
[Comparative Example 1]
7500.0 g of sodium chloride, 179.8 g of potassium chloride, and 891.1 g of sodium acetate were added to a stirring type mixing granulator (High Speed Mixer FS-GS-25J, manufactured by Fukae Pautech Co., Ltd.) and mixed and stirred to obtain a mixture. . While mixing and stirring at a rotational speed of 70 rpm (shearing force 0.01 kW / kg), 122.4 g of magnesium chloride and 221.8 g of calcium chloride prepared in advance were dissolved in 162 g of purified water at an internal temperature of 40 ° C. An aqueous solution having a liquid temperature of 40 ° C. was added. Immediately after the addition, the contents, which were in the form of wet particles, turned into smooth granules when mixed and stirred for 15 minutes. The granulated product was once taken out and dried under a temperature condition of 80 ° C. until the water content became 0.5% by mass or less. After adding 145.3 g of acetic acid to the obtained granulated product and mixing and stirring for 5 minutes, the granulated product was taken out and sized to obtain granular and fine granular preparations.
[比較例2]
塩化カリウム24.0g、塩化マグネシウム16.3g、塩化カルシウム29.6g及び酢酸ナトリウム118.8gを精製水440.3gに溶解して水溶液を調製した。転動攪拌流動造粒装置(マルチプレックス MP−1 株式会社パウレック製)に、核粒子として塩化ナトリウム1000gを投入し、給気温度80℃、ローター回転数200rpm及び給気風量40m3/hrの条件下で、前記水溶液を噴霧すると同時に乾燥させた。得られた造粒物に酢酸19.4gを添加して顆粒状及び細粒状の製剤を得た。
[Comparative Example 2]
An aqueous solution was prepared by dissolving 24.0 g of potassium chloride, 16.3 g of magnesium chloride, 29.6 g of calcium chloride and 118.8 g of sodium acetate in 440.3 g of purified water. 1000 g of sodium chloride as a core particle is charged into a tumbling stirring fluidized granulator (Multiplex MP-1 manufactured by POWREC Co., Ltd.), a supply air temperature of 80 ° C., a rotor rotation speed of 200 rpm, and a supply air flow rate of 40 m 3 / hr. Below, the aqueous solution was sprayed and simultaneously dried. Acetic acid 19.4g was added to the obtained granulated material, and the granular and fine granular preparation was obtained.
[比較例3]
塩化カリウム24.0g、塩化マグネシウム16.3g、塩化カルシウム29.6g及び酢酸ナトリウム118.8gを精製水440.3gに溶解して水溶液を調製した。転動攪拌流動造粒装置(マルチプレックス MP−1 株式会社パウレック製)に、核粒子として塩化ナトリウム1000gとブドウ糖160.6gとを投入し、給気温度60℃、ローター回転数200rpm及び給気風量40m3/hrの条件下で、前記水溶液を噴霧すると同時に乾燥させた。得られた造粒物に酢酸19.4gを添加して顆粒状及び細粒状の製剤を得た。
[Comparative Example 3]
An aqueous solution was prepared by dissolving 24.0 g of potassium chloride, 16.3 g of magnesium chloride, 29.6 g of calcium chloride and 118.8 g of sodium acetate in 440.3 g of purified water. 1000 g of sodium chloride and 160.6 g of glucose are introduced as core particles into a tumbling stirring fluidized granulator (Multiplex MP-1 manufactured by POWREC Co., Ltd.), the supply air temperature is 60 ° C., the rotor rotation speed is 200 rpm, and the supply air flow rate. The aqueous solution was sprayed and simultaneously dried under the condition of 40 m 3 / hr. Acetic acid 19.4g was added to the obtained granulated material, and the granular and fine granular preparation was obtained.
[試験例1]
実施例1で得られた製剤の顕微鏡写真(キーエンス社製)を図1に示す。この図より、実施例1で得た本製剤が、単独の粒子として存在したり、各母粒子の複数個が被覆層を介して結合した集合体として存在していることがわかる。また、同製剤の走査型電子顕微鏡(日立製作所製)による被覆層の構造を図2に示す。この図より、同製剤は被覆層を有していることが確認できる。更に、母粒子及び被覆層の元素分析結果(エネルギー分散型X線分析装置(EDX))を図3、図4、図5及び図6に夫々示す。これらの図より、母粒子として塩化ナトリウム、酢酸ナトリウム及び塩化カリウムが存在し、また、被覆層中には塩化マグネシウム、塩化カルシウム、塩化カリウム等が存在することが確認された。
[Test Example 1]
A photomicrograph (manufactured by Keyence Corporation) of the preparation obtained in Example 1 is shown in FIG. From this figure, it can be seen that the present preparation obtained in Example 1 exists as a single particle or as an aggregate in which a plurality of each mother particle is bonded via a coating layer. Moreover, the structure of the coating layer of the same preparation by a scanning electron microscope (manufactured by Hitachi, Ltd.) is shown in FIG. From this figure, it can be confirmed that the preparation has a coating layer. Furthermore, the elemental analysis results (energy dispersive X-ray analyzer (EDX)) of the mother particles and the coating layer are shown in FIGS. 3, 4, 5 and 6, respectively. From these figures, it was confirmed that sodium chloride, sodium acetate, and potassium chloride exist as mother particles, and that magnesium chloride, calcium chloride, potassium chloride, and the like exist in the coating layer.
[試験例2]
実施例2で得られた製剤の走査型電子顕微鏡(日立製作所製)による被覆層の構造を図7に示す。更に、母粒子及び被覆層の元素分析結果(エネルギー分散型X線分析装置(EDX))を図8及び図9に夫々示す。これらの図より、母粒子であるブドウ糖の表面に被覆層が形成され、被覆層中には塩化マグネシウム、塩化カルシウム、塩化カリウム等が存在することが確認された。
[Test Example 2]
FIG. 7 shows the structure of the coating layer of the preparation obtained in Example 2 using a scanning electron microscope (manufactured by Hitachi, Ltd.). Furthermore, elemental analysis results (energy dispersive X-ray analyzer (EDX)) of the mother particles and the coating layer are shown in FIGS. 8 and 9, respectively. From these figures, it was confirmed that a coating layer was formed on the surface of glucose as the mother particle, and magnesium chloride, calcium chloride, potassium chloride, etc. were present in the coating layer.
[試験例3]
実施例1で得られた製剤の薄膜X線回折の結果を図10及び図11に示す。また、実施例2で得られた製剤の薄膜X線回折の結果を図12及び図13に示し、比較例1で得られた製剤の薄膜X線回折の結果を図14及び図15に示し、比較例2で得られた製剤の薄膜X線回折の結果を図16及び図17に示す。
測定は、製剤の被覆層構造をより明確にするために、薄膜X線回折法を用い、薄膜X線回折装置(リガク社製)にて測定を行った。分析条件を下記に示す:
X線;Cu K−ALPHA1/50kV/300mA
発散スリット;1/2deg.
散乱スリット;open
受光スリット;open
走査モード;連続
スキャンスピード;2°/min.
スキャンステップ;0.01°又は0.02°
入射角;1°
次に、試料作製方法について説明する。試料は各製剤から約0.5gを取り、打錠機を用いて厚みが一様な円盤状に圧縮成型した。打錠圧力は製剤の母粒子が破砕しない程度とし、試料の大きさは直径約20mm、厚さは約2mmとした。
この図より、塩化カルシウムと酢酸ナトリウムとに由来する高次化合物を示すピークが2θ=10.2°付近に検出されていることがわかる。
[Test Example 3]
The results of thin film X-ray diffraction of the preparation obtained in Example 1 are shown in FIGS. Moreover, the result of the thin film X-ray diffraction of the formulation obtained in Example 2 is shown in FIG. 12 and FIG. 13, the result of the thin film X-ray diffraction of the formulation obtained in Comparative Example 1 is shown in FIG. 14 and FIG. The results of thin film X-ray diffraction of the preparation obtained in Comparative Example 2 are shown in FIGS.
The measurement was carried out using a thin film X-ray diffraction method (manufactured by Rigaku Corporation) using a thin film X-ray diffraction method in order to clarify the coating layer structure of the preparation. The analysis conditions are shown below:
X-ray; Cu K-ALPHA 1 / 50kV / 300mA
Divergent slit; 1/2 deg.
Scattering slit; open
Light receiving slit; open
Scan mode; continuous scan speed; 2 ° / min.
Scan step; 0.01 ° or 0.02 °
Incident angle: 1 °
Next, a sample preparation method will be described. About 0.5 g of the sample was taken from each preparation, and compression-molded into a disk having a uniform thickness using a tableting machine. The tableting pressure was such that the mother particles of the preparation were not crushed, the sample size was about 20 mm in diameter, and the thickness was about 2 mm.
From this figure, it can be seen that a peak indicating a higher order compound derived from calcium chloride and sodium acetate is detected in the vicinity of 2θ = 10.2 °.
[試験例4]
実施例1及び比較例1で得られた製剤からランダムに6箇所サンプリングを行い、それぞれの検体についてサンプル8.5206gを水に溶かして正確に200mlとし、これを50倍希釈してNa+、K+、Mg2+、Ca2+、Cl−、CH3COO−の各電解質濃度を東ソー社製イオンクロマトグラフにより測定した。分析方法を下記に示す。また、実施例1の測定結果を表1、比較例1の測定結果を表2に示す。
アニオン測定
装置;TOSOH ION CHROMATOGRAPH
カラム;TSKguardcolumn SuperIC−AP Super IC−AP
カラム温度;40℃
サンプル量;30μL
溶離液;0.3mmol/L Na2B407・10H2O+2.1mmol/L NaHCO3+2.5mmol/L Na2CO3
流量;0.80ml/min
カチオン測定
装置;TOSOH ION CHROMATOGRAPH
カラム;TSKguardcolumn SuperIC−C Super IC−Cation
カラム温度;40℃
サンプル量;30μL
溶離液;2.5mmol/L HNO3+0.5mmol/L L−ヒスチジン
流量;1.00ml/min
[Test Example 4]
Six samples were randomly sampled from the preparations obtained in Example 1 and Comparative Example 1, and 8.5206 g of each specimen was dissolved in water to make exactly 200 ml, and this was diluted 50 times to obtain Na + , K The electrolyte concentrations of + , Mg 2+ , Ca 2+ , Cl − , and CH 3 COO − were measured by an ion chromatograph manufactured by Tosoh Corporation. The analysis method is shown below. The measurement results of Example 1 are shown in Table 1, and the measurement results of Comparative Example 1 are shown in Table 2.
Anion measurement equipment; TOSOH ION CHROMATOGRAPH
Column; TSK guard column Super IC-AP Super IC-AP
Column temperature: 40 ° C
Sample volume: 30 μL
Eluent: 0.3 mmol / L Na 2 B 4 0 7 · 10H 2 O + 2.1 mmol / L NaHCO 3 +2.5 mmol / L Na 2 CO 3
Flow rate: 0.80 ml / min
Cation measuring device; TOSOH ION CHROMATOGRAPH
Column; TSK guard column Super IC-C Super IC-Cation
Column temperature: 40 ° C
Sample volume: 30 μL
Eluent: 2.5 mmol / L HNO 3 +0.5 mmol / L L-histidine Flow rate: 1.00 ml / min
[試験例5]
実施例1と比較例1と比較例2とで得られた製剤をそれぞれ5gずつシャーレに採り、25℃、60%RHの条件下で20分間放置し吸湿試験を行った。試料の試験前後の質量変化より吸湿度を求めた。尚、吸湿度は以下の式より算出した。
吸湿度〔質量%〕={(試験後質量〔g〕−試験前質量〔g〕)/試験前質量〔g〕}×100
また、吸湿試験後、結晶が見掛け上サラサラとした状態を○、湿潤な結晶状態を×とした。測定結果を表3に示す。
[Test Example 5]
5 g of each of the preparations obtained in Example 1, Comparative Example 1 and Comparative Example 2 were placed in a petri dish, and left for 20 minutes under the conditions of 25 ° C. and 60% RH to conduct a moisture absorption test. The moisture absorption was determined from the change in mass of the sample before and after the test. The moisture absorption was calculated from the following formula.
Hygroscopicity [% by mass] = {(mass after test [g] −mass before test [g]) / mass before test [g]} × 100
Further, after the moisture absorption test, the state that the crystal was apparently smooth was marked with ◯, and the wet crystal state was marked with ×. Table 3 shows the measurement results.
[試験例6]
実施例1、比較例1及び比較例2で得られた製剤240gを量り取り、それぞれ130mm×85mmのアルミニウムラミネート製包材に充填し、ヒートシールした後に、60℃、90%RHの条件下で固結状態を観察した。固結試験の結果を表4に示す。サンプルは、所定の時間経過した後に開封し、9メッシュ(目開き2mm)のふるいで軽く篩過してふるい残の量を測定した。また、篩上のふるい残を10回手で軽く振とうさせ、固結強度についても測定をした。ふるい残が15質量%以内の場合は◎、15〜40質量%の場合は○、40〜70質量%以上の場合は△、70質量%以上の場合は×で表した。
[Test Example 6]
240 g of the preparations obtained in Example 1, Comparative Example 1 and Comparative Example 2 were weighed, filled into 130 mm × 85 mm aluminum laminate packaging materials, heat sealed, and then subjected to conditions of 60 ° C. and 90% RH. The consolidated state was observed. The results of the consolidation test are shown in Table 4. The sample was opened after a lapse of a predetermined time, and lightly sieved with a 9 mesh (2 mm mesh) sieve, and the amount of the sieve residue was measured. Moreover, the sieve residue on the sieve was lightly shaken 10 times by hand, and the caking strength was also measured. When the sieve residue is 15% by mass or less, ◎, when it is 15 to 40% by mass, Δ when it is 40 to 70% by mass or more, and × when it is 70% by mass or more.
[試験例7]
実施例1と比較例1との造粒時における機器への粉体付着量の比較を行った。結果を表5に示す。
[Test Example 7]
Example 1 and Comparative Example 1 were compared in terms of the amount of powder adhered to the equipment during granulation. The results are shown in Table 5.
[試験例8]
実施例2と比較例2との製剤をアルミニウムラミネート製包材に充填し、ヒートシールした後に、40℃(75%RH)の条件下で安定性試験を実施した。ブドウ糖の分解率を測定するため第14改正日本薬局方に記載されているブドウ糖注射液の純度試験の吸光度測定に基づき吸光度の測定を行った。その結果を表6に示す。
[Test Example 8]
After the preparations of Example 2 and Comparative Example 2 were filled in an aluminum laminate packaging material and heat-sealed, a stability test was performed under conditions of 40 ° C. (75% RH). In order to measure the degradation rate of glucose, the absorbance was measured based on the absorbance measurement in the purity test of the glucose injection solution described in the 14th revision Japanese Pharmacopoeia. The results are shown in Table 6.
このように、本発明の透析用固形剤は、表1に示す通りに理論値に極めて近い組成の製剤になっており、それぞれの成分において含量均一性が充分であることが分かる。これに対し、本発明の範囲外の透析用固形剤は、表2に示す通りに、表1に比べて理論値からの変動が大きい。また、本発明の透析用固形剤は、吸湿性試験の結果を表3に示す通りに防湿性に優れたものであり、表4に示す通りに固結試験の結果も良好であり、長期の保存が可能な製剤であることが分かる。更に、ブドウ糖の安定性の結果も表6に示す通りに優れた製剤となっている。また、表5より明らかな通りに、微粉末懸濁液を用いる本発明の製造方法に従えば、造粒時における機器への粉体付着が少ないため、生産性が向上し、工業的に好ましい実施態様であることが分かる。 Thus, the solid preparation for dialysis of the present invention is a preparation having a composition very close to the theoretical value as shown in Table 1, and it is understood that the content uniformity is sufficient for each component. On the other hand, as shown in Table 2, the dialysis solid agent outside the range of the present invention has a large variation from the theoretical value as compared with Table 1. In addition, the solid preparation for dialysis of the present invention is excellent in moisture resistance as shown in Table 3 for the hygroscopicity test, and the result of the consolidation test is good as shown in Table 4 for a long time. It turns out that it is a formulation which can be preserve | saved. Furthermore, the stability results of glucose are excellent as shown in Table 6. Further, as is apparent from Table 5, according to the production method of the present invention using a fine powder suspension, since the powder adhesion to the device during granulation is small, the productivity is improved, which is industrially preferable. It can be seen that this is an embodiment.
腎不全患者の透析療法に使用される重炭酸透析液調製用の透析用固形剤として用いることができる。 It can be used as a solid agent for dialysis for preparing bicarbonate dialysate used for dialysis therapy of patients with renal failure.
Claims (10)
〔1〕原料成分である粉体及び/又は粒体の塩化ナトリウム、塩化カリウム、塩化カルシウム、酢酸ナトリウムを混合し;
〔2〕電解質組成物全体の質量に対して0.3〜3.2質量%の水に、電解質組成物中の塩化カリウム全体の質量に対して4〜84質量%の塩化カリウムを溶解して水溶液にし;
〔3〕工程〔2〕の水溶液に、電解質組成物中の酢酸ナトリウム全体の質量に対して5〜50質量%の酢酸ナトリウムを攪拌下で添加し、懸濁液を調製し;
〔4〕工程〔3〕の懸濁液に、電解質組成物中の塩化マグネシウム全量を攪拌下で添加し、微粉末懸濁液を調製し;
〔5〕工程〔1〕の混合物に、工程〔4〕の微粉末懸濁液を添加し、50℃以下の温度で攪拌混合して混合物を得;
〔6〕工程〔5〕の混合物を、該混合物1kg当り0.001kW/kg以上の剪断力下、50℃以下の温度で1分間以上攪拌造粒して顆粒状及び/又は細粒状の造粒物を得;
〔7〕工程〔6〕の造粒物を乾燥し;
〔8〕工程〔7〕の造粒物に、pH調整剤を混合する。 A method for producing a solid preparation for dialysis comprising an electrolyte composition containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and a pH adjuster as raw materials, comprising the following steps [1] to [8]: Method:
[1] Mixing powder and / or granule sodium chloride, potassium chloride, calcium chloride, sodium acetate as raw material components;
[2] Dissolving 4 to 84% by mass of potassium chloride with respect to the total mass of potassium chloride in the electrolyte composition in 0.3 to 3.2% by mass of water based on the total mass of the electrolyte composition. In aqueous solution;
[3] To the aqueous solution of step [2], 5 to 50% by mass of sodium acetate based on the total mass of sodium acetate in the electrolyte composition is added with stirring to prepare a suspension;
[4] To the suspension of step [3], the whole amount of magnesium chloride in the electrolyte composition is added with stirring to prepare a fine powder suspension;
[5] Add the fine powder suspension of step [4] to the mixture of step [1] and stir and mix at a temperature of 50 ° C. or lower to obtain a mixture;
[6] Granules and / or fine granules obtained by stirring and granulating the mixture of step [5] for 1 minute or more at a temperature of 50 ° C. or less under a shearing force of 0.001 kW / kg or more per 1 kg of the mixture. Get things;
[7] Dry the granulated product of step [6];
[8] A pH adjuster is mixed with the granulated product in the step [7].
The manufacturing method according to claim 5, wherein the dialysis solid agent is the dialysis solid agent according to any one of claims 1 to 4 and claim 9.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006200391A JP4878233B2 (en) | 2006-07-24 | 2006-07-24 | Dialysis solid preparation and method for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006200391A JP4878233B2 (en) | 2006-07-24 | 2006-07-24 | Dialysis solid preparation and method for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2008023146A true JP2008023146A (en) | 2008-02-07 |
JP4878233B2 JP4878233B2 (en) | 2012-02-15 |
Family
ID=39114394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006200391A Active JP4878233B2 (en) | 2006-07-24 | 2006-07-24 | Dialysis solid preparation and method for producing the same |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP4878233B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015072494A1 (en) * | 2013-11-12 | 2015-05-21 | 扶桑薬品工業株式会社 | Novel sodium diacetate crystal and solid dialysis preparation comprising said crystal |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2987488B2 (en) * | 1995-08-02 | 1999-12-06 | 富田製薬株式会社 | Solid dialysis agent and method for producing the same |
-
2006
- 2006-07-24 JP JP2006200391A patent/JP4878233B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2987488B2 (en) * | 1995-08-02 | 1999-12-06 | 富田製薬株式会社 | Solid dialysis agent and method for producing the same |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015072494A1 (en) * | 2013-11-12 | 2015-05-21 | 扶桑薬品工業株式会社 | Novel sodium diacetate crystal and solid dialysis preparation comprising said crystal |
JPWO2015072494A1 (en) * | 2013-11-12 | 2017-03-16 | 扶桑薬品工業株式会社 | Novel sodium diacetate crystal and solid dialysis preparation containing the crystal |
US9840452B2 (en) | 2013-11-12 | 2017-12-12 | Fuso Pharmaceutical Industries, Ltd. | Sodium diacetate crystal and solid dialysis preparation comprising said crystal |
US10822296B2 (en) | 2013-11-12 | 2020-11-03 | Fuso Pharmaceutical Industries, Ltd. | Sodium diacetate crystal and solid dialysis preparation comprising said crystal |
Also Published As
Publication number | Publication date |
---|---|
JP4878233B2 (en) | 2012-02-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4760381B2 (en) | Solid preparation for dialysis and production method thereof | |
TWI516284B (en) | Solid preparation for dialysis | |
JP4647953B2 (en) | Single agent type solid preparation for bicarbonate dialysis and method for producing the same | |
JP4603977B2 (en) | Dialysis solid preparation and method for producing the same | |
JP2987488B2 (en) | Solid dialysis agent and method for producing the same | |
JP4989876B2 (en) | Dialysis solid preparation and method for producing the same | |
JP3530235B2 (en) | Hemodialysis agent | |
JP3647898B2 (en) | Sodium bicarbonate dialysis agent and method for producing the same | |
JP4878233B2 (en) | Dialysis solid preparation and method for producing the same | |
JP5550778B1 (en) | Dialysis agent and method for producing dialysis agent | |
JP6467285B2 (en) | Granules for agent A for dialysis and method for producing the same | |
JP5028122B2 (en) | Single-agent dialysis solid preparation and method for producing the same | |
JP6562336B2 (en) | Method for producing granulated material used for dialysis agent A | |
JP2005230361A (en) | Solid agent for dialysis and manufacturing method therefor | |
JP5548301B1 (en) | Dialysis agent and method for producing dialysis agent | |
WO2004066977A1 (en) | Solid agent for dialysis and process for producing the same | |
JP4561978B2 (en) | Solid dialysis agent and method for producing the same | |
JP5830341B2 (en) | Dialysis agent and method for producing dialysis agent | |
JP4370729B2 (en) | Solid dialysis agent and method for producing the same | |
JPH0724061A (en) | Prepation for hemodialysis | |
JP2003093502A (en) | Solid dialysing agent and method for manufacturing the same | |
EP1086700A2 (en) | A solid pharmaceutical composition for dialysate containing sodium bicarbonate and a process for producing the same | |
JP5548300B1 (en) | Dialysis agent and method for producing dialysis agent | |
JP2007130165A (en) | Odorless solid agent for dialysis and its manufacturing method | |
JP2005314295A (en) | Solid preparation for dialysis and method for producing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090602 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20110324 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110329 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110525 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20111122 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20111125 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4878233 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20141209 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |