JP2016112062A - Producing method of granules used in dialysis agent a - Google Patents
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本発明は、透析用Ａ剤に使用される造粒物（以下、Ａ剤用造粒物）の製造方法に関する。より具体的には、本発明は、塩化ナトリウムを含まず、塩化カルシウム及び塩化マグネシウムを含み、優れた溶解性及び貯蔵安定性を備えるＡ剤用造粒物を簡便に製造する方法に関する。また、本発明は、当該製造方法で得られるＡ剤用造粒物、当該Ａ剤用造粒物を用いた透析用Ａ剤、及び当該透析用Ａ剤を用いた透析用剤に関する。 The present invention relates to a method for producing a granulated product used for dialysis agent A (hereinafter, granulated product for agent A). More specifically, the present invention relates to a method for easily producing a granulated product for agent A that does not contain sodium chloride, contains calcium chloride and magnesium chloride, and has excellent solubility and storage stability. The present invention also relates to a granule for agent A obtained by the production method, an agent A for dialysis using the granule for agent A, and a dialysis agent using the agent A for dialysis.
現在、透析用剤としては、重炭酸透析用剤が主に用いられており、塩化ナトリウムを含む多数の電解質成分及びブドウ糖を含むＡ剤と、重炭酸ナトリウムを含むＢ剤を合わせた２剤型の透析剤が一般的な透析剤として市販されている。 Currently, as a dialysis agent, a bicarbonate dialysis agent is mainly used, and a two-part type comprising a combination of many electrolyte components including sodium chloride and A agent containing glucose and B agent containing sodium bicarbonate. Are commercially available as common dialysis agents.
従来、透析用Ａ剤は、電解質成分を濃縮液形態で含む液状Ａ剤、電解質成分を固体状で含む固体状Ａ剤があったが、液状Ａ剤は、輸送コスト、病院等での保管スペース、病院内での作業性、使用後の容器の廃棄等の点で問題視されており、近年では、固体型の透析用Ａ剤が国内では主流となっている。また、固体状Ａ剤では、電解質成分、特に微量電解質成分（例えば、塩化カルシウム、塩化マグネシウム、酢酸ナトリウム等）が不均一に分布するのを防ぐために、電解質成分の全て又は一部が混合或いは造粒された状態で使用されている。一方、透析用Ｂ剤は、単一組成物であるため、粉末状態で使用されている。 Conventionally, the A agent for dialysis has the liquid A agent containing the electrolyte component in the form of a concentrated liquid and the solid A agent containing the electrolyte component in a solid state, but the liquid A agent is a transportation cost, storage space in a hospital, etc. In recent years, it has been regarded as a problem in terms of workability in hospitals, disposal of containers after use, etc. In recent years, solid-type dialysis agents A have become mainstream in Japan. In addition, in the solid A agent, in order to prevent uneven distribution of electrolyte components, particularly trace electrolyte components (for example, calcium chloride, magnesium chloride, sodium acetate, etc.), all or part of the electrolyte components are mixed or manufactured. Used in a grained state. On the other hand, since the dialysis agent B is a single composition, it is used in a powder state.
通常、透析用Ａ剤には、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、ｐＨ調節剤及びブドウ糖が含まれており、透析用Ｂ剤には重炭酸ナトリウムが含まれている。近年、塩化ナトリウム以外の電解質成分を含むＡ剤と、塩化ナトリウムを含むＳ剤と、重炭酸ナトリウムを含むＢ剤からなる３剤型透析用剤も提唱されている（特許文献１参照）。この３剤型透析用剤では、透析時にＳ剤とＢ剤の添加量の比率を調節することによって、患者の病態に応じて、透析中でも重炭酸イオン濃度を自在に変化させつつ、ナトリウム、カリウム、カルシウム、マグネシウム等の電解質濃度を一定に維持できる透析液を調製することが可能となる。 Usually, the dialysis agent A contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, a pH regulator and glucose, and the dialysis agent B contains sodium bicarbonate. In recent years, a three-agent dialysis agent comprising an agent A containing an electrolyte component other than sodium chloride, an agent S containing sodium chloride, and an agent B containing sodium bicarbonate has also been proposed (see Patent Document 1). This three-part dialysis agent adjusts the ratio of the amount of S agent and B agent added during dialysis, allowing sodium and potassium to freely change the bicarbonate ion concentration during dialysis, depending on the patient's condition. It is possible to prepare a dialysate that can maintain a constant electrolyte concentration of calcium, magnesium, and the like.
現在の国内外の一般的な透析装置、透析用剤、及び透析手法では、透析液中の重炭酸濃度を、患者間にある個体差、透析処置を開始する際の患者の状態、透析処置中に変化する患者の状態や病態等に応じて、個別に設定したり、経時的に変化させたりすることができないという欠点があるが、特許文献１で提唱されている３剤型透析用剤を使用すれば、これらの欠点を解消することが可能である。 In general dialysis machines, dialysis agents, and dialysis techniques in Japan and overseas, the bicarbonate concentration in the dialysate is different from patient to patient, the patient's condition when starting dialysis, and during dialysis. However, there is a drawback that it cannot be set individually or changed over time according to the patient's condition or disease state, etc. If used, these drawbacks can be eliminated.
しかしながら、特許文献１には、塩化ナトリウムを含まず、塩化カルシウム及び塩化マグネシウムを含む固体状透析用Ａ剤について、有機酸を含む場合に生じる固化の抑制、溶解性、貯蔵安定性、製造簡便性等の点については触れられておらず、更なる検討の余地が残っている。 However, Patent Document 1 does not contain sodium chloride, but includes solid dialysis agent A containing calcium chloride and magnesium chloride, which suppresses solidification that occurs when an organic acid is contained, solubility, storage stability, and ease of production. Such points are not mentioned, and there is room for further study.
塩化ナトリウムは、他の微量電解質成分（例えば、塩化カルシウム、塩化マグネシウム、酢酸ナトリウム等）に比べ化学的に不活性であり、安定であること、また結晶水を持たない硬質な結晶性粒子であり、流動性が良いことが知られている。塩化ナトリウムを含む固体状透析用Ａ剤では、電解質成分を造粒しても、７０重量％以上の塩化ナトリウムが含まれているため、固体状透析用Ａ剤内で塩化ナトリウムが緩衝剤のごとく働き、他の微量電解質同士の相互作用を抑制し、製造時に原料の粘性が大きくなるという不具合を防ぐことができる。 Sodium chloride is a hard crystalline particle that is chemically inert and stable compared to other trace electrolyte components (eg calcium chloride, magnesium chloride, sodium acetate, etc.) and has no water of crystallization. It is known that fluidity is good. In the solid dialysis agent A containing sodium chloride, even if the electrolyte component is granulated, sodium chloride is contained in the solid dialysis agent A because it contains 70% by weight or more of sodium chloride. It works, suppresses the interaction between other trace electrolytes, and prevents the problem that the viscosity of the raw material increases during the production.
一方、塩化ナトリウムを含まない造粒物では、このような塩化ナトリウムを造粒に供することによって得られる、様々な利点を受けることができないので、従来の製造方法では、塩化ナトリウムを含まない固体状透析用Ａ剤を製造しようとしても、製造時に他の微量電解質同士が相互作用して、原料の粘性が大きくなり、効率的な製造ができないという問題点がある。具体的には、塩化ナトリウムを配合せずに、塩化マグネシウムや塩化カルシウム、酢酸ナトリウムを含む造粒物を製造する場合、塩化マグネシウムと塩化カルシウムと酢酸ナトリウムの相互作用が生じ、これらに含まれる結晶水が一部遊離するため、原料の混合中に急激に粘性が増し、混合機内の壁面や撹拌翼に粒子が付着したり、混合機からの排出を困難にさせたりするという不具合がある。特に、この不具合は、湿式造粒を行う際に頻発し、微量電解質同士の相互作用の進行により粘性が大きく増すと、塊状の造粒物を与えたり、たとえ粘性が増さないように添加する水分量をコントロールして混合又は造粒したとしても、微量電解質同士の相互作用による物質の構造変化に伴い、一部原材料よりも細かい粒子が形成され、造粒物の粉化が発生したりする。更に、塩化ナトリウムを含まない造粒物を従来の製造方法で製造すると、貯蔵中に固化が生じ易くなったり、透析液調製のために水を添加した際に細かい粒子が凝集して溶解性不良を起こしたりする等の欠点もある。この場合の溶解性不良とは、透析液調製のために、透析用剤を溶解する際に生じる溶け残りを指し、溶解速度が遅い透析用剤ではその溶解性不良のリスクが増す。 On the other hand, a granulated product not containing sodium chloride cannot receive various advantages obtained by subjecting such sodium chloride to granulation. Even if it is going to manufacture the A agent for dialysis, there exists a problem that another trace electrolyte interacts at the time of manufacture, the viscosity of a raw material becomes large, and efficient manufacture cannot be performed. Specifically, when producing a granulated product containing magnesium chloride, calcium chloride, or sodium acetate without blending sodium chloride, the interaction between magnesium chloride, calcium chloride, and sodium acetate occurs, and the crystals contained in these Since part of the water is liberated, the viscosity rapidly increases during mixing of the raw materials, and there is a problem that particles adhere to the wall surface and stirring blade in the mixer or make it difficult to discharge from the mixer. In particular, this defect frequently occurs when wet granulation is performed, and if the viscosity greatly increases due to the progress of the interaction between the minute amounts of electrolytes, agglomerated granules are given or added so as not to increase the viscosity. Even if the amount of water is controlled or mixed or granulated, finer particles than the raw materials are formed due to the structural change of the substance due to the interaction between the minute amounts of electrolytes, and the granulated product may be pulverized. . Furthermore, when a granulated product that does not contain sodium chloride is produced by a conventional production method, solidification is likely to occur during storage, or fine particles aggregate when water is added for dialysate preparation, resulting in poor solubility. There are also drawbacks such as The poor solubility in this case refers to the undissolved residue that is generated when the dialysis agent is dissolved to prepare the dialysis solution, and the dialysis agent having a low dissolution rate increases the risk of poor solubility.
透析液調製時に透析用剤の溶け残りが発生すると、調製される透析液中の各電解質濃度が予め設定された濃度とならず、濃度異常を生じる。この濃度異常の発生している透析液を用いて透析を行うと、体内の電解質が正常な範囲内に是正されず、場合によっては重篤な電解質濃度異常を引き起こす可能性がある。これを防止するために、透析用剤の溶解装置や透析装置には安全装置が備え付けられているが、そもそも安全装置を作動させること自体が望ましくない。そのため、溶解性不良を起こさないためには、溶解性の良い（溶解速度の良好な）製剤を使用することが重要であり、既存の溶解装置に設定されている溶解所要時間内に、使用する透析用剤全量が確実に溶解するように設計されていることが必要である。透析施設で広く使用されている溶解装置として、例えば、全自動溶解装置ＤＡＤ−５０ＮＸ−ＳＴ（日機装株式会社製）があり、当該溶解装置では、溶解所要時間が約４分という短時間に設定されている。また、Ａ剤溶解装置ＡＨＩ-５０２（東亜ディーケーケー株式会社製）も溶解装置として広く普及しており、当該溶解装置では、装置内に溜められた所定量の水に、透析用剤を少しずつ添加し、透析液が定められた電導度に達すると自動的に添加を停止するシステムを採用しており、溶解所要時間は約９分に設定されている。この溶解装置に、溶解性が不良な（溶解速度の遅い）透析用剤が使用された場合、透析液が所定の電導度に達し透析用剤の添加が停止した後に、溶け残った透析用剤が遅れて溶解するために濃度異常が発生してしまう。このように、一般的に臨床で使用されている溶解装置においては、用いられる透析用剤の溶解性が悪い場合には、得られる透析液の品質、並びに調製効率に大きな影響を及ぼすことが懸念される。 If undissolved dialysis agent is generated during dialysate preparation, the concentration of each electrolyte in the dialysate to be prepared does not become a preset concentration, resulting in a concentration abnormality. When dialysis is performed using a dialysate in which this concentration abnormality occurs, the electrolyte in the body is not corrected within the normal range, and in some cases, a serious electrolyte concentration abnormality may be caused. In order to prevent this, a dialysis agent dissolving apparatus and dialysis apparatus are provided with a safety device, but it is not desirable to operate the safety device in the first place. Therefore, in order not to cause poor solubility, it is important to use a preparation with good solubility (good dissolution rate) and use it within the required dissolution time set in the existing dissolution apparatus. It is necessary to ensure that the entire amount of dialysis agent is dissolved. As a dissolution apparatus widely used in dialysis facilities, for example, there is a fully automatic dissolution apparatus DAD-50NX-ST (manufactured by Nikkiso Co., Ltd.), and the dissolution time is set to a short time of about 4 minutes. ing. In addition, A agent dissolution apparatus AHI-502 (manufactured by Toa DKK Co., Ltd.) is also widely used as a dissolution apparatus. In this dissolution apparatus, a dialysis agent is added little by little to a predetermined amount of water stored in the apparatus. In addition, a system is adopted in which the addition is automatically stopped when the dialysate reaches a predetermined conductivity, and the time required for dissolution is set to about 9 minutes. When a dialysis agent with poor solubility (slow dissolution rate) is used in this dissolution apparatus, the dialysis solution that remains undissolved after the dialysate reaches the prescribed conductivity and the addition of the dialysis agent is stopped Concentration abnormalities occur because of a delayed dissolution. Thus, in the dissolution apparatus generally used in clinical practice, when the solubility of the dialysis agent used is poor, there is a concern that the quality of the resulting dialysate and the preparation efficiency may be greatly affected. Is done.
また、塩化ナトリウムを含まない固体状透析用Ａ剤では、原料全体に占める塩化カルシウム及び塩化マグネシウムの割合が、塩化ナトリウムを含む固体状透析用Ａ剤の場合に比べ相対的に高くなるため、それに伴い、原料中に含まれる絶対的な水分量（結晶水量）も高くなり、固化、溶解性不良、ブドウ糖の貯蔵安定性の問題がより顕著になるという欠点がある。特に、ブドウ糖の貯蔵安定性に関しては、ブドウ糖が固体状透析用Ａ剤中に含まれる場合、相対的な水分含有量の増加の影響の他に、塩化ナトリウムが含まれていない分、ブドウ糖と、ブドウ糖の分解を促す塩化カルシウム、塩化マグネシウム及び他の微量電解質との接触面積が大きくなるために、ブドウ糖がより不安定化し易くなるという問題点もある。 In addition, in the solid dialysis agent A that does not contain sodium chloride, the proportion of calcium chloride and magnesium chloride in the total raw material is relatively higher than in the case of the solid dialysis agent A that contains sodium chloride. Along with this, there is a drawback that the absolute water content (crystal water content) contained in the raw material is also increased, and the problems of solidification, poor solubility and storage stability of glucose become more remarkable. In particular, regarding the storage stability of glucose, when glucose is included in the solid dialysis agent A, in addition to the effect of an increase in relative water content, the amount of glucose that is not included in sodium chloride, Since the contact area with calcium chloride, magnesium chloride, and other microelectrolytes that promote the degradation of glucose increases, there is also a problem that glucose is more likely to become unstable.
一方、特許文献２には、塩化ナトリウムの一部又は全部を除いた状態で、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を含むＡ剤用造粒物を、飽和水蒸気量又はそれ以下に加湿された加湿気体を用いて湿式造粒する方法が開示されている。特許文献２に記載の湿式造粒法では、電解質成分同士の相互作用が生じるが、加湿気体の湿度をコントロールすることで粘性の増加を抑え、収率よく透析用固体Ａ剤を製造できる。しかしながら、特許文献２に記載の湿式造粒法では、湿式造粒する際の加湿気体の湿度コントロールが必要とされ、更に造粒と乾燥を別工程で行うため、簡易な製造方法といえるものではない。また、塩化カルシウムや塩化マグネシウムに加湿気体を吹き付けることによりそれらを発熱させるといった造粒方法は、連続製造には適さない。即ち、このような造粒方法では、バッチ間における装置内の温湿度管理が求められると共に、製造を重ねるにつれて原料の発熱の程度が変化し、一定の生産条件で一定の品質の製品を製造することが困難となる。更に、特許文献２では、前記湿式造粒法で得られるＡ剤用造粒物の溶解性や貯蔵安定性については検討されていない。更に、特許文献２に記載の湿式造粒法で得られるＡ剤用造粒物は、最終的には、塩化ナトリウムと混合した後に透析用Ａ剤として使用される。そのため、特許文献２では、前述するような塩化ナトリウム非存在下で生じるブドウ糖の不安定化等については問題になっておらず、ブドウ糖の安定性に配慮したＡ剤用造粒物の製造技術を開示するものではない。 On the other hand, Patent Document 2 discloses a granulated product for agent A containing potassium chloride, calcium chloride, magnesium chloride, and sodium acetate, with some or all of sodium chloride removed, to a saturated water vapor amount or less. A method of wet granulation using a humidified humidified gas is disclosed. In the wet granulation method described in Patent Document 2, the interaction between the electrolyte components occurs, but by controlling the humidity of the humidified gas, the increase in viscosity can be suppressed and the solid A agent for dialysis can be produced with high yield. However, in the wet granulation method described in Patent Document 2, it is necessary to control the humidity of the humidified gas during wet granulation, and further granulation and drying are performed in separate steps. Absent. Moreover, the granulation method of generating heat by spraying humidified gas on calcium chloride or magnesium chloride is not suitable for continuous production. That is, in such a granulation method, temperature and humidity management in the apparatus between batches is required, and the degree of heat generation of the raw material changes as production is repeated, and a product of constant quality is manufactured under constant production conditions. It becomes difficult. Further, Patent Document 2 does not discuss the solubility and storage stability of the granulated product for agent A obtained by the wet granulation method. Furthermore, the granule for agent A obtained by the wet granulation method described in Patent Document 2 is finally used as the agent A for dialysis after being mixed with sodium chloride. Therefore, in Patent Document 2, there is no problem with the destabilization of glucose that occurs in the absence of sodium chloride as described above, and the manufacturing technique of the granule for agent A in consideration of the stability of glucose is disclosed. It is not disclosed.
また、塩化ナトリウムを含まないＡ剤用造粒物の製造を試みて、たとえ乾式造粒をしようとしても、バインダーの役割を果たす自由水が含まれていないため、粒子同士が結合せず、造粒されないという別の不具合が生じる。 In addition, even when trying to produce a granulated product for agent A that does not contain sodium chloride, even if dry granulation is attempted, free water that serves as a binder is not included, so the particles do not bond together and Another problem of not being grained occurs.
本発明の目的は、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含むＡ剤用造粒物を、従来行われている造粒及び乾燥という各操作を、別の工程として行わず、簡便に製造できる方法を提供することである。また、本発明の目的は、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含み、且つ優れた溶解性を備えており、また、貯蔵時に生じる固化を低減することができ、更にブドウ糖と共存させてもブドウ糖の劣化を抑制する効果を備えるＡ剤用造粒物、当該Ａ剤用造粒物を用いた透析用Ａ剤、及び当該透析用Ａ剤を用いた透析用剤を提供することである。 The object of the present invention is not to include sodium chloride, but to perform granulation for agent A containing magnesium chloride and calcium chloride, without performing each of the conventional operations of granulation and drying as separate steps. It is to provide a method that can be manufactured. In addition, the object of the present invention is that it does not contain sodium chloride, contains magnesium chloride and calcium chloride, has excellent solubility, can reduce solidification that occurs during storage, and further coexists with glucose. However, by providing the granule for agent A having the effect of suppressing the deterioration of glucose, the agent A for dialysis using the granule for agent A, and the agent for dialysis using the agent A for dialysis. is there.
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含むＡ剤用造粒物の製造方法において、少なくとも塩化マグネシウム及び塩化カルシウムを含む電解質原料を１１０℃以上の温度条件で加熱して造粒物を得る方法を採用することにより、電解質原料の粘度の上昇を抑制し、装置内への付着を抑制するとともに、製品排出を容易にし、更には従来別工程で行われている造粒と乾燥を同時に進行させることができるので、効率的にＡ剤用造粒物が得られることを見出した。また、本発明者は、前記製造方法で得られたＡ剤用造粒物は、優れた溶解性を備えており、透析液の調製の簡便化が図れることを見出した。更に、本発明者は、前記製造方法で得られたＡ剤用造粒物は、貯蔵時の固化が抑制され、更にブドウ糖と共存させてもブドウ糖の劣化を抑制でき、優れた貯蔵安定性をも備えていることを見出した。本発明は、これらの知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventor has intensively studied to solve the above-mentioned problems. As a result, in the method for producing a granulated product for agent A containing no sodium chloride but containing magnesium chloride and calcium chloride, at least magnesium chloride and calcium chloride are included. By adopting a method of heating the electrolyte raw material at a temperature condition of 110 ° C. or more to obtain a granulated product, the increase in the viscosity of the electrolyte raw material is suppressed, the adhesion to the apparatus is suppressed, and the product discharge is facilitated. Furthermore, it has been found that granulation for agent A can be efficiently obtained because granulation and drying, which are conventionally performed in separate steps, can proceed simultaneously. Further, the present inventor has found that the granule for agent A obtained by the above production method has excellent solubility and simplifies the preparation of the dialysate. Furthermore, the present inventor has shown that the granulated product for agent A obtained by the above production method is suppressed in solidification at the time of storage, and can suppress deterioration of glucose even when coexisting with glucose, and has excellent storage stability. I found out that it also has. The present invention has been completed by further studies based on these findings.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． 塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含む、透析用Ａ剤に使用される造粒物の製造方法であって、
少なくとも塩化マグネシウム及び塩化カルシウムを含む電解質原料を１１０℃以上の温度条件で加熱して造粒物を得る工程を含むことを特徴とする、製造方法。
項２． 前記塩化マグネシウムの少なくとも一部が、水和物の形態である、項１に記載の製造方法。
項３． 前記電解質原料の水分含量が、塩化マグネシウムの無水物重量換算１００重量部当たり、３５０重量部以下である、項１又は２に記載の製造方法。
項４． 前記電解質原料に自由水が実質的に含まれていない、項１〜３のいずれかに記載の製造方法。
項５． 前記加熱が、Ａ剤用造粒物の水分含量が塩化マグネシウムの無水物重量換算１００重量部当たり２５０重量部以下になるように行われる、項１〜４のいずれかに記載の製造方法。
項６． 前記加熱後に得られた造粒物に有機酸を添加する工程を含む、項１〜５のいずれかに記載の製造方法。
項７． 項１〜６のいずれかに記載の製造方法で得られる、透析用Ａ剤に使用される造粒物。
項８． 項７に記載の造粒物を含む、透析用Ａ剤。
項９． 更にブドウ糖を含む、項８に記載の透析用Ａ剤。
項１０． 更に塩化ナトリウムを含む、項８又は９に記載の透析用Ａ剤。
項１１． 項８〜１０のいずれかに記載の透析用Ａ剤、及び重炭酸ナトリウムを含む透析用Ｂ剤を含む、透析用剤。
項１２． 前記透析用Ａ剤が塩化ナトリウムを含んでおらず、
更に塩化ナトリウムを含む透析用Ｓ剤を含み、
前記透析用Ａ剤、前記透析用Ｂ剤、及び前記透析用Ｓ剤からなる３剤型の透析用剤である、項１１に記載の透析用Ａ剤。
項１３． 前記透析用Ａ剤が塩化ナトリウムを含み、
前記透析用Ａ剤、及び前記透析用Ｂ剤からなる２剤型の透析用剤である、項１１に記載の透析用剤。
That is, this invention provides the invention of the aspect hung up below.
Item 1. A method for producing a granulated product used for dialysis agent A, which does not contain sodium chloride but contains magnesium chloride and calcium chloride,
The manufacturing method characterized by including the process of heating the electrolyte raw material containing at least magnesium chloride and calcium chloride on the temperature conditions of 110 degreeC or more, and obtaining a granulated material.
Item 2. Item 2. The production method according to Item 1, wherein at least a part of the magnesium chloride is in the form of a hydrate.
Item 3. Item 3. The production method according to Item 1 or 2, wherein the water content of the electrolyte material is 350 parts by weight or less per 100 parts by weight of magnesium chloride anhydride.
Item 4. Item 4. The production method according to any one of Items 1 to 3, wherein the electrolyte material is substantially free of free water.
Item 5. Item 5. The production method according to any one of Items 1 to 4, wherein the heating is performed such that the moisture content of the granule for agent A is 250 parts by weight or less per 100 parts by weight of magnesium chloride anhydride.
Item 6. The manufacturing method in any one of claim | item 1-5 including the process of adding an organic acid to the granulated material obtained after the said heating.
Item 7. The granulated material used for the A agent for dialysis obtained with the manufacturing method in any one of claim | item 1 -6.
Item 8. Item A dialysis agent comprising the granulated product according to Item 7.
Item 9. Item 9. The dialysis agent A according to Item 8, further comprising glucose.
Item 10. Item 10. The dialysis agent A according to Item 8 or 9, further comprising sodium chloride.
Item 11. Item 11. A dialysis agent comprising the dialysis agent A according to any one of items 8 to 10 and a dialysis agent B containing sodium bicarbonate.
Item 12. The dialysis agent A does not contain sodium chloride,
In addition, it contains S-dialysis agent containing sodium chloride,
Item 12. The dialysis agent A according to item 11, which is a three-agent dialysis agent comprising the dialysis agent A, the dialysis agent B, and the dialysis agent S.
Item 13. The dialysis agent A contains sodium chloride,
Item 12. The dialysis agent according to Item 11, which is a two-agent dialysis agent comprising the dialysis agent A and the dialysis agent B.
本発明によれば、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含むＡ剤用造粒物の製造において、電解質原料を１１０℃以上の温度条件で加熱して造粒物を得る方法を採用することにより、造粒時の電解質原料の粘度の上昇を抑制し、造粒時に造粒装置内の壁面や撹拌翼に原料が付着するのを抑制できるので、簡便且つ効率的にＡ剤用造粒物を製造することが可能になる。また、本発明によれば、造粒時の加熱によって乾燥も同時に進行させることができるので、工程を簡略化して効率的にＡ剤用造粒物を製造することもできる。 According to the present invention, a method of obtaining a granulated product by heating an electrolyte raw material under a temperature condition of 110 ° C. or higher in the production of a granulated product for agent A containing magnesium chloride and calcium chloride without containing sodium chloride. As a result, the increase in the viscosity of the electrolyte raw material during granulation can be suppressed, and the raw material can be prevented from adhering to the wall surface and stirring blade in the granulator during granulation. It becomes possible to produce granules. Moreover, according to this invention, since drying can also be simultaneously advanced by the heating at the time of granulation, the process can be simplified and the granule for A agent can also be manufactured efficiently.
また、本発明で得られるＡ剤用造粒物は、優れた溶解性を備えており、一般的に用いられている溶解装置を使用し、透析液を調製する際に、迅速に溶解することで溶け残りを防ぐと同時に、透析液濃度異常のリスクを低減することができ、安全な透析液を安定的に、且つ効率的に供給することが可能となる。更に、本発明で得られるＡ剤用造粒物は、貯蔵時の固化が抑制され、更にブドウ糖と共存させてもブドウ糖の劣化を抑制でき、貯蔵安定性の点でも優れている。 In addition, the granule for agent A obtained in the present invention has excellent solubility, and dissolves quickly when preparing a dialysate using a commonly used dissolution apparatus. In addition to preventing undissolved residue, the risk of an abnormal dialysate concentration can be reduced, and a safe dialysate can be supplied stably and efficiently. Furthermore, the granule for agent A obtained in the present invention is suppressed in solidification at the time of storage, and further, even when it coexists with glucose, it can suppress the deterioration of glucose and is excellent in terms of storage stability.
１．Ａ剤用造粒物の製造方法
本発明の製造方法は、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含むＡ剤用造粒物の製造方法であって、少なくとも塩化マグネシウム及び塩化カルシウムを含む電解質原料を加熱して造粒物を１１０℃以上の温度条件で加熱して造粒物を得る工程を含むことを特徴とする。以下、本発明の製造方法について詳述する。
1. Method for producing granulated product for agent A The production method of the present invention is a method for producing a granulated product for agent A containing magnesium chloride and calcium chloride without containing sodium chloride, and includes at least magnesium chloride and calcium chloride. The method includes a step of heating the electrolyte raw material and heating the granulated material under a temperature condition of 110 ° C. or higher to obtain the granulated product. Hereafter, the manufacturing method of this invention is explained in full detail.
電解質原料
本発明の製造方法では、塩化ナトリウムを含まず、少なくとも塩化マグネシウム及び塩化カルシウムを含む電解質原料を使用して造粒する。
Electrolyte Raw Material In the production method of the present invention, granulation is performed using an electrolyte raw material which does not contain sodium chloride but contains at least magnesium chloride and calcium chloride.
電解質原料に用いられる塩化マグネシウムは、水和物又は無水物のいずれを使用してもよいが、塩化マグネシウムの一部又は全てが水和物の形態であることが好ましい。塩化マグネシウムの水和物を使用すると、造粒時の加熱によって塩化マグネシウムの水和物に含まれる結晶水の少なくとも一部が離脱してバインダーとしての役割を果たし、電解質原料を効率的に造粒させることが可能になる。 Magnesium chloride used for the electrolyte raw material may be either a hydrate or an anhydride, but it is preferable that part or all of the magnesium chloride is in the form of a hydrate. When magnesium chloride hydrate is used, at least part of the water of crystallization contained in the magnesium chloride hydrate is removed by heating during granulation, and it acts as a binder to efficiently granulate the electrolyte raw material. It becomes possible to make it.
塩化マグネシウムの水和物としては、具体的には、塩化マグネシウム二水和物、塩化マグネシウム四水和物、塩化マグネシウム六水和物、塩化マグネシウム八水和物、塩化マグネシウム十二水和物等の１〜１２水和物が挙げられる。これらの塩化マグネシウムの水和物の中でも、好ましくは塩化マグネシウム六水和物が挙げられる。これらの塩化マグネシウムの水和物は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of magnesium chloride hydrate include magnesium chloride dihydrate, magnesium chloride tetrahydrate, magnesium chloride hexahydrate, magnesium chloride octahydrate, magnesium chloride dodecahydrate, etc. 1 to 12 hydrates. Among these magnesium chloride hydrates, magnesium chloride hexahydrate is preferable. These magnesium chloride hydrates may be used alone or in combination of two or more.
また、前記電解質原料において、塩化マグネシウムの一部又は全部を水和物の形態で含有させる場合、電解質原料に含まれる塩化マグネシウムの総量当たりに占める塩化マグネシウムの水和物の割合については、塩化カルシウム及び／又は塩化マグネシウムに含まれる結晶水が電解質原料中で占める割合が後述する範囲を充足するように適宜設定すればよいが、電解質原料に含まれる塩化マグネシウム総量１００重量部当たり、例えば、六水和物形態の塩化マグネシウムが４０〜１００重量部、好ましくは７０〜１００重量部、更に好ましくは１００重量部となる割合が挙げられる。ここで、塩化マグネシウムの総量とは、塩化マグネシウムが水和物の形態の場合には、結晶水（水和物中の水分子）の重量を含めて算出される総重量である。 In the electrolyte raw material, when a part or all of magnesium chloride is contained in the form of hydrate, the ratio of magnesium chloride hydrate to the total amount of magnesium chloride contained in the electrolyte raw material is about calcium chloride. And / or may be set as appropriate so that the proportion of crystal water contained in the magnesium chloride in the electrolyte raw material satisfies the range described later, for example, six water is included per 100 parts by weight of the total amount of magnesium chloride contained in the electrolyte raw material. The proportion of magnesium chloride in the form of a hydrate is 40 to 100 parts by weight, preferably 70 to 100 parts by weight, and more preferably 100 parts by weight. Here, the total amount of magnesium chloride is the total weight calculated including the weight of water of crystallization (water molecules in the hydrate) when the magnesium chloride is in the form of a hydrate.
また、塩化マグネシウムの一部又は全部を水和物の形態で使用する場合、前記電解質原料において、塩化マグネシウムに含まれる結晶水（水和物中の水分子）の総量については、例えば１〜４０重量％、好ましくは２〜３０重量％、更に好ましくは４〜２０重量％を占めていることが望ましい。このような割合で塩化マグネシウムの結晶水を含むことによって、造粒時に電解質原料の粘度の上昇抑制効果を高めてＡ剤用造粒物の製造効率化をより一層向上させると共に、溶解性の向上、貯蔵時の固化抑制、及びブドウ糖安定化を一層効果的に図ることが可能になる。 Moreover, when using a part or all of magnesium chloride in the form of a hydrate, about the total amount of the crystal water (water molecule in a hydrate) contained in magnesium chloride in the said electrolyte raw material, it is 1-40, for example. It is desirable to occupy 2% by weight, preferably 2 to 30% by weight, and more preferably 4 to 20% by weight. By containing magnesium chloride crystallization water at such a ratio, the effect of suppressing the increase in the viscosity of the electrolyte raw material during granulation is enhanced to further improve the production efficiency of the granulated product for agent A and improve the solubility. In addition, it is possible to more effectively achieve solidification suppression during storage and glucose stabilization.
また、前記電解質原料における塩化マグネシウムの含有量については、透析用Ａ剤によって調製される透析液のマグネシウムイオン濃度が０．５〜２．０ｍＥｑ／Ｌ、好ましくは０．７５〜１．５ｍＥｑ／ｌとなるように、Ａ剤用造粒物に必要に応じて含まれる他のマグネシウム塩の含有量等を勘案して適宜設定すればよいが、例えば、前記電解質原料の総量１００重量部当たり、塩化マグネシウムの無水物重量換算で１〜５０重量部、好ましくは１〜２５重量部、更に好ましくは１〜１５重量部が挙げられる。本発明において、「電解質原料の総量」とは、必要に応じて含まれる結晶水及び自由水も含めた総重量を指し、「塩化マグネシウムの無水物重量換算」とは、塩化マグネシウムが水和物の形態の場合には、結晶水（水和物中の水分子）の重量を除いて、無水物の重量に換算して求められる値である。 Moreover, about content of magnesium chloride in the said electrolyte raw material, the magnesium ion density | concentration of the dialysate prepared with the dialysis agent A is 0.5-2.0 mEq / L, Preferably it is 0.75-1.5 mEq / l. It may be set as appropriate in consideration of the content of other magnesium salts contained in the granule for agent A as necessary. For example, per 100 parts by weight of the total electrolyte raw material, 1 to 50 parts by weight, preferably 1 to 25 parts by weight, and more preferably 1 to 15 parts by weight in terms of magnesium anhydride. In the present invention, "total amount of electrolyte raw material" refers to the total weight including crystal water and free water contained as necessary, and "in terms of anhydrous magnesium chloride weight" means that magnesium chloride is a hydrate In the case of this form, it is a value obtained by converting to the weight of the anhydride, excluding the weight of crystal water (water molecules in the hydrate).
電解質原料に用いられる塩化カルシウムは、水和物又は無水物のいずれを使用してもよいが、塩化カルシウムの一部又は全てが水和物の形態であることが好ましい。塩化カルシウムの水和物を使用すると、造粒時の加熱条件によっては、塩化カルシウムの水和物に含まれる結晶水の少なくとも一部が離脱してバインダーとしての役割を果たすこともある。 The calcium chloride used for the electrolyte raw material may be either a hydrate or an anhydride, but it is preferable that a part or all of the calcium chloride is in the form of a hydrate. When calcium chloride hydrate is used, depending on the heating conditions at the time of granulation, at least a part of the crystal water contained in the calcium chloride hydrate may be released to serve as a binder.
塩化カルシウムの水和物としては、具体的には、塩化カルシウム一水和物、塩化カルシウム二水和物、塩化カルシウム四水和物、塩化カルシウム六水和物等の１〜６水和物が挙げられる。これらの塩化カルシウムの水和物の中でも、好ましくは塩化カルシウム二水和物が挙げられる。これらの塩化カルシウムの水和物は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of calcium chloride hydrates include 1 to 6 hydrates such as calcium chloride monohydrate, calcium chloride dihydrate, calcium chloride tetrahydrate, and calcium chloride hexahydrate. Can be mentioned. Among these calcium chloride hydrates, calcium chloride dihydrate is preferable. These calcium chloride hydrates may be used singly or in combination of two or more.
前記電解質原料において、塩化カルシウムの一部又は全部を水和物の形態で含有させる場合、電解質原料に含まれる塩化カルシウムの総量当たりに占める塩化カルシウムの水和物の割合については、特に制限されないが、例えば、電解質原料に含まれる塩化カルシウム総量１００重量部当たり、例えば、二水和物形態の塩化カルシウムが４０〜１００重量部、好ましくは７０〜１００重量部、更に好ましくは１００重量部となる割合が挙げられる。ここで、塩化カルシウムの総量とは、塩化カルシウムが水和物の形態の場合には、結晶水（水和物中の水分子）の重量を含めて算出される総重量である。 When a part or all of calcium chloride is contained in the electrolyte raw material in the form of a hydrate, the ratio of the calcium chloride hydrate to the total amount of calcium chloride contained in the electrolyte raw material is not particularly limited. For example, per 100 parts by weight of the total amount of calcium chloride contained in the electrolyte raw material, for example, the proportion of dihydrate calcium chloride is 40 to 100 parts by weight, preferably 70 to 100 parts by weight, more preferably 100 parts by weight. Is mentioned. Here, the total amount of calcium chloride is the total weight calculated including the weight of crystal water (water molecules in the hydrate) when calcium chloride is in the form of a hydrate.
前記電解質原料における塩化カルシウムの含有量については、透析用Ａ剤によって調製される透析液のカルシウムイオン濃度が１．５〜４．５ｍＥｑ／ｌ、好ましくは２．５〜３．５ｍＥｑ／ｌとなるように、Ａ剤用造粒物に必要に応じて含まれる他のカルシウム塩の含有量等を勘案して適宜設定すればよいが、例えば、前記電解質原料の総量１００重量部当たり、塩化カルシウムの無水物重量換算で１〜７５重量部、好ましくは５〜５０重量部、更に好ましくは１０〜３５重量部が挙げられる。本発明において、「塩化カルシウムの無水物重量換算」とは、塩化カルシウムが水和物の形態の場合には、結晶水（水和物中の水分子）の重量を除いて、無水物の重量に換算して求められる値である。 Regarding the content of calcium chloride in the electrolyte raw material, the calcium ion concentration of the dialysate prepared by the dialysis agent A is 1.5 to 4.5 mEq / l, preferably 2.5 to 3.5 mEq / l. Thus, the content of other calcium salts contained in the granule for agent A may be set as appropriate, for example. For example, per 100 parts by weight of the total electrolyte raw material, 1-75 weight part in conversion of an anhydride weight, Preferably it is 5-50 weight part, More preferably, 10-35 weight part is mentioned. In the present invention, “calcium chloride anhydrous weight conversion” means that when calcium chloride is in the form of hydrate, the weight of anhydride is excluded except for the weight of crystal water (water molecules in the hydrate). It is a value obtained by converting to.
前記電解質原料は、粉体状であることを限度として、必要に応じて自由水が含まれていてもよい。本発明の製造方法において、塩化マグネシウムの少なくとも一部が水和物の形態である場合、造粒時の加熱によって塩化マグネシウムに含まれる結晶水が離脱して、バインダーとして機能するため、自由水が含まれていなくてもよいが、塩化マグネシウムとして水和物の形態のものを使用しない場合には、バインダーとして自由水を添加しておくことが好ましい。また、塩化マグネシウムとして水和物の形態のものを使用する場合であっても、造粒時の加熱によって離脱する結晶水以外に、バインダーとして機能する水分を補充するために、自由水を添加しておいてもよい。本発明において、「自由水」とは、電解質原料において水和物形態で含まれる結晶水とは別に、他の分子とは結びつきがない状態で添加される水である。 The electrolyte raw material may contain free water as necessary, as long as it is in a powder form. In the production method of the present invention, when at least a part of magnesium chloride is in the form of hydrate, the water of crystallization contained in magnesium chloride is released by heating during granulation and functions as a binder. Although it does not need to be contained, it is preferable to add free water as a binder when the hydrate form of magnesium chloride is not used. In addition, even when using hydrated form of magnesium chloride, free water is added to replenish moisture that functions as a binder in addition to crystal water that is released by heating during granulation. You may keep it. In the present invention, “free water” refers to water that is added in a state in which it is not associated with other molecules, apart from crystallization water contained in a hydrate form in the electrolyte raw material.
前記電解質原料における自由水の含有量については、水和物形態の塩化マグネシウムの含有量等に応じて適宜設定すればよいが、例えば、塩化マグネシウムの無水物重量換算１００重量部に対して０〜１５０重量部、好ましくは０〜１００重量部、更に好ましくは０〜５０重量部が挙げられる。電解質原料における自由水の含有量を前記範囲に調節することによって、造粒時に電解質原料の粘度の上昇を抑制してＡ剤用造粒物をより一層効率的に製造できると共に、水への溶解性をより一層向上させ、更には貯蔵時の固化抑制及びブドウ糖の安定化をより一層向上させて、格段に優れた貯蔵安定性を備えさせることが可能になる。 The content of free water in the electrolyte raw material may be appropriately set according to the content of magnesium chloride in the form of hydrate, etc., for example, 0 to 100 parts by weight in terms of anhydrous magnesium chloride 150 parts by weight, preferably 0 to 100 parts by weight, more preferably 0 to 50 parts by weight. By adjusting the content of free water in the electrolyte raw material to the above range, it is possible to more efficiently produce the granulated product for agent A by suppressing the increase in the viscosity of the electrolyte raw material during granulation, and to dissolve in water It is possible to further improve the storage property, further improve the suppression of solidification during storage and the stabilization of glucose, and provide storage stability that is significantly superior.
また、前記電解質原料における水分含量については粉体状であることを限度として特に制限されず、前述する塩化マグネシウムに含まれる結晶水の量、自由水の添加量等に応じて適宜設定すればよいが、例えば、塩化マグネシウムの無水物重量換算１００重量部当たり、３５０重量部以下が挙げられる。本発明において、「電解質原料における水分含量」とは、水和物の形態で含まれる結晶水と、添加される自由水の合計量である。Ａ剤用造粒物の製造効率化及び貯蔵安定性をより一層向上させるという観点から、前記電解質原料における水分含量として、塩化マグネシウムの無水物換算重量１００重量部当たり、好ましくは１００〜３００重量部、更に好ましくは１５０〜２５０重量部が挙げられる。 Further, the water content in the electrolyte raw material is not particularly limited as long as it is in powder form, and may be appropriately set according to the amount of crystallization water contained in the magnesium chloride, the amount of free water added, and the like. However, 350 weight part or less is mentioned per 100 weight part of anhydride weight conversion of magnesium chloride, for example. In the present invention, the “water content in the electrolyte raw material” is the total amount of crystal water contained in the form of hydrate and free water added. From the viewpoint of further improving the production efficiency and storage stability of the granulated product for agent A, the water content in the electrolyte raw material is preferably 100 to 300 parts by weight per 100 parts by weight of magnesium chloride in terms of anhydride. More preferred is 150 to 250 parts by weight.
更に、前記電解質原料には、塩化カルシウム及び塩化マグネシウム以外に、必要に応じて、カルシウムイオン、マグネシウムイオン、ナトリウムイオン、カリウムイオン、塩化物イオン、酢酸イオン、クエン酸イオン、乳酸イオン、グルコン酸イオン、コハク酸イオン、リンゴ酸イオン等の供給源となる有機酸塩及び／又は無機塩が含まれていてもよい。 Furthermore, in addition to calcium chloride and magnesium chloride, the electrolyte raw material may be calcium ion, magnesium ion, sodium ion, potassium ion, chloride ion, acetate ion, citrate ion, lactic acid ion, gluconate ion as necessary. Organic acid salts and / or inorganic salts serving as a supply source of succinic acid ions, malic acid ions, and the like may be included.
カルシウムイオンの供給源となる化合物としては、例えば、酢酸カルシウム、乳酸カルシウム、クエン酸カルシウム、グルコン酸カルシウム、コハク酸カルシウム、リンゴ酸カルシウム等の有機酸のカルシウム塩が挙げられる。これらの有機酸のカルシウム塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 Examples of the compound serving as a source of calcium ions include calcium salts of organic acids such as calcium acetate, calcium lactate, calcium citrate, calcium gluconate, calcium succinate, and calcium malate. These calcium salts of organic acids may be used alone or in combination of two or more.
マグネシウムイオンの供給源となる化合物としては、例えば、酢酸マグネシウム、乳酸マグネシウム、クエン酸マグネシウム、グルコン酸マグネシウム、コハク酸マグネシウム、リンゴ酸マグネシウム等のマグネシウムの有機酸塩が挙げられる。これらのマグネシウムの有機酸塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 Examples of the compound serving as a supply source of magnesium ions include magnesium organic acid salts such as magnesium acetate, magnesium lactate, magnesium citrate, magnesium gluconate, magnesium succinate, and magnesium malate. One of these organic acid salts of magnesium may be used alone, or two or more thereof may be used in combination.
ナトリウムイオンの供給源となる化合物としては、例えば、酢酸ナトリウム、乳酸ナトリウム、クエン酸ナトリウム、グルコン酸ナトリウム、コハク酸ナトリウム、リンゴ酸ナトリウム等のナトリウムの有機酸塩が挙げられる。これらのナトリウムの有機酸塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 Examples of the compound serving as the supply source of sodium ions include sodium organic acid salts such as sodium acetate, sodium lactate, sodium citrate, sodium gluconate, sodium succinate, and sodium malate. These organic acid salts of sodium may be used alone or in combination of two or more.
カリウムイオンの供給源となる化合物としては、例えば、塩化カリウム、酢酸カリウム、乳酸カリウム、クエン酸カリウム、グルコン酸カリウム、コハク酸カリウム、リンゴ酸カリウム等のカリウムの無機塩及び／又は有機酸塩が挙げられる。これらのカリウムの無機塩及び／又は有機酸塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 Examples of the compound serving as a source of potassium ions include potassium chloride, potassium acetate, potassium lactate, potassium citrate, potassium gluconate, potassium succinate, potassium malate, and other inorganic salts and / or organic acid salts of potassium. Can be mentioned. These inorganic salts and / or organic acid salts of potassium may be used singly or in combination of two or more.
酢酸イオンの供給源となる化合物としては、例えば、酢酸ナトリウム、酢酸カリウム等の酢酸のアルカリ金属塩；二酢酸ナトリウム、二酢酸カリウム等の二酢酸アルカリ金属塩が挙げられる。これらの酢酸のアルカリ金属塩及び二酢酸アルカリ金属塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 Examples of the compound serving as a supply source of acetate ions include alkali metal salts of acetic acid such as sodium acetate and potassium acetate; alkali metal diacetates such as sodium diacetate and potassium diacetate. One of these alkali metal salts of acetic acid and alkali metal diacetate may be used alone, or two or more thereof may be used in combination.
塩化物イオンの供給源となる化合物としては、例えば、塩化カリウム等が挙げられる。 Examples of the compound serving as a supply source of chloride ions include potassium chloride.
これらの有機酸塩及び／又は無機酸塩については、最終的に調製される透析液に含有させるべき各種イオンの種類に応じて適宜選択すればよいが、好ましくは、カリウムの無機塩及び／又は有機酸塩と酢酸のアルカリ金属塩、更に好ましくは塩化カリウムと酢酸ナトリウムが挙げられる。 These organic acid salts and / or inorganic acid salts may be appropriately selected according to the type of various ions to be contained in the dialysate to be finally prepared, preferably potassium inorganic salts and / or Alkali metal salts of organic acid salts and acetic acid, more preferably potassium chloride and sodium acetate.
電解質原料において、これらの有機酸塩及び／又は無機塩の含有量については、最終的に調製される透析液に備えさせる各イオン濃度に応じて適宜設定される。具体的には、Ａ剤に含まれる電解質成分の含有量は、Ａ剤用造粒物以外に含まれる電解質成分量等を勘案し、最終的に調製される透析液が下記表１に示す各イオン濃度を満たすよう、適宜設定すればよい。 In the electrolyte raw material, the content of these organic acid salt and / or inorganic salt is appropriately set according to each ion concentration provided in the dialysate finally prepared. Specifically, the content of the electrolyte component contained in the agent A takes into consideration the amount of the electrolyte component contained other than the granule for agent A, and the dialysate finally prepared is shown in Table 1 below. What is necessary is just to set suitably so that ion concentration may be satisfy | filled.
電解質原料を用いた造粒
本発明の製造方法では、前記電解質原料に加熱を行うことによって造粒する。前記電解質原料を加熱することによって、塩化カルシウム、塩化マグネシウム、及び必要に応じて添加される他の電解質成分が結合して、優れた溶解性及び貯蔵安定性を備えるＡ剤用造粒物を形成することが可能になる。また、前記電解質原料は、水分量が少ないため、造粒時に電解質原料の粘度が上昇するのを抑制し、効率的にＡ剤用造粒物を製造することが可能になる。更に、前記電解質原料を１１０℃以上の温度条件で加熱することによって、造粒と共に乾燥も同時に進行するので、従来の湿式造粒のように造粒後に乾燥処理を行わなくてよく、Ａ剤用造粒物の簡便な製造が可能になる。
Granulation using electrolyte raw material In the production method of the present invention, the electrolyte raw material is granulated by heating. By heating the electrolyte raw material, calcium chloride, magnesium chloride, and other electrolyte components added as needed are combined to form a granule for agent A having excellent solubility and storage stability. It becomes possible to do. Moreover, since the said electrolyte raw material has little moisture content, it becomes possible to suppress that the viscosity of an electrolyte raw material raises at the time of granulation, and to manufacture the granulated material for A agent efficiently. Furthermore, by heating the electrolyte raw material at a temperature of 110 ° C. or higher, drying proceeds simultaneously with granulation, so that it is not necessary to perform a drying treatment after granulation as in conventional wet granulation. The granulated product can be easily produced.
造粒する際の加温条件については、１１０℃以上であることを限度として特に制限されないが、Ａ剤用造粒物の製造効率化及び貯蔵安定性をより一層向上させるという観点から、好ましくは１１０〜２００℃、更に好ましくは１３０〜１７０℃が挙げられる。 The heating condition for granulation is not particularly limited as long as it is 110 ° C. or higher, but from the viewpoint of further improving the production efficiency and storage stability of the granulated product for agent A, preferably 110-200 degreeC, More preferably, 130-170 degreeC is mentioned.
また、加熱時間については、加熱温度、造粒に供する電解質原料の量、製造されるＡ剤用造粒物の水分含量等を勘案して適宜設定すればよいが、例えば、１〜４５分間、好ましくは５〜３０分間、更に好ましくは１０〜２５分間が挙げられる。 In addition, the heating time may be appropriately set in consideration of the heating temperature, the amount of electrolyte raw material to be subjected to granulation, the moisture content of the granulated product for agent A to be produced, etc., for example, 1 to 45 minutes, Preferably it is 5 to 30 minutes, more preferably 10 to 25 minutes.
加熱後に得られるＡ剤用造粒物の水分含量については、特に制限されないが、例えば、製造されるＡ剤用造粒物の水分含量が塩化マグネシウムの無水物換算重量１００重量部に対して０〜２５０重量部程度であればよい。このような水分含量になる程度まで加熱することによって、優れた溶解性及び貯蔵安定性を備えるＡ剤用造粒物を得ることが可能になる。より一層優れた溶解性及び貯蔵安定性を備えるＡ剤用造粒物を得るという観点から、前記電解質原料に対する加熱は、製造されるＡ剤用造粒物の水分含量が、塩化マグネシウムの無水物換算重量１００重量部に対して、好ましくは１０〜２００重量部、更に好ましくは５０〜１６０重量部となる程度に行うことが望ましい。 The water content of the granule for agent A obtained after heating is not particularly limited. For example, the moisture content of the granule for agent A to be produced is 0 with respect to 100 parts by weight of magnesium chloride in terms of anhydride. It may be about ~ 250 parts by weight. By heating to such a water content level, it becomes possible to obtain a granulated product for agent A having excellent solubility and storage stability. From the viewpoint of obtaining a granulated product for agent A having even better solubility and storage stability, the heating to the electrolyte raw material is an anhydrous magnesium chloride having a moisture content of the granulated material for agent A to be produced. The amount is preferably 10 to 200 parts by weight, more preferably 50 to 160 parts by weight with respect to 100 parts by weight of the converted weight.
造粒時の加熱方法については、特に制限されず、例えば、前記電解質原料の調製に使用した混合機を加温しながら必要に応じて撹拌する方法；送風定温乾燥機を用いて静置加熱する方法；流動層乾燥機（転動流動層乾燥機、振動流動層乾燥機等含む）を用いて電解質原料の流動層を形成して加熱する方法等が挙げられる。これらの加熱方法の中でも、好ましくは流動層乾燥機を用いて加熱する方法が挙げられる。１１０℃以上での加熱を流動層乾燥機にて行うことによって、粒径１８０μｍ以下の微細な粒子が生じるのを抑制し、粒径が１８０〜１７００μｍ程度のＡ剤用造粒物を効率的に得ることが可能になる。 The heating method at the time of granulation is not particularly limited, and for example, a method of stirring as necessary while heating the mixer used for the preparation of the electrolyte raw material; Method: A method in which a fluidized bed of an electrolyte raw material is formed using a fluidized bed dryer (including a rolling fluidized bed dryer, a vibrating fluidized bed dryer, etc.) and heated. Among these heating methods, a method of heating using a fluidized bed dryer is preferable. By performing heating at 110 ° C. or higher with a fluidized bed dryer, the generation of fine particles having a particle size of 180 μm or less is suppressed, and the granule for agent A having a particle size of about 180 to 1700 μm is efficiently produced. It becomes possible to obtain.
有機酸（ｐＨ調節剤）の添加
本発明の製造方法で得られるＡ剤用造粒物には、最終的に調製される透析液のｐＨを調整するために、有機酸が含まれていてもよい。従来のＡ剤用造粒物では、ｐＨ調節剤として有機酸（特に酢酸）を添加すると、貯蔵時に固化を進行させ易くなる傾向を示すが、本発明の製造方法で得られるＡ剤用造粒物では有機酸を添加しても、固化を十分に抑制でき、優れた貯蔵安定性を備えることができる。
Addition of organic acid (pH adjuster) The granulated product for agent A obtained by the production method of the present invention may contain an organic acid in order to adjust the pH of the dialysate finally prepared. Good. In the conventional granulated product for agent A, when an organic acid (particularly acetic acid) is added as a pH adjuster, solidification tends to proceed during storage, but granulation for agent A obtained by the production method of the present invention. Even if an organic acid is added to the product, solidification can be sufficiently suppressed and excellent storage stability can be provided.
Ａ剤用造粒物に含まれる有機酸の種類については、透析用剤に使用できることを限度として特に制限されないが、例えば、酢酸、クエン酸、乳酸、リンゴ酸、フマル酸、コハク酸、マロン酸、グルコン酸等が挙げられる。これらの有機酸の中でも、好ましくは酢酸、クエン酸、更に好ましくは酢酸（特に、氷酢酸）が挙げられる。これらの有機酸は、１種単独で使用してもよく、また２種以上組み合わせて使用してもよい。 The type of organic acid contained in the granulated product for agent A is not particularly limited as long as it can be used as a dialysis agent. For example, acetic acid, citric acid, lactic acid, malic acid, fumaric acid, succinic acid, malonic acid And gluconic acid. Among these organic acids, acetic acid and citric acid are preferable, and acetic acid (particularly glacial acetic acid) is more preferable. These organic acids may be used alone or in combination of two or more.
Ａ剤用造粒物における有機酸の含有量は、最終的に調製される透析液に備えさせるｐＨ、有機酸の種類等に応じて適宜設定される。具体的には、Ａ剤用造粒物における有機酸の含有量は、最終的に調製される透析液のｐＨが７．２〜７．６、好ましくは７．２〜７．５となるように適宜設定すればよい。 The content of the organic acid in the granule for agent A is appropriately set according to the pH, the type of the organic acid, etc. provided in the finally prepared dialysate. Specifically, the content of the organic acid in the granule for agent A is such that the pH of the finally prepared dialysate is 7.2 to 7.6, preferably 7.2 to 7.5. May be set as appropriate.
有機酸の添加タイミングについては、特に制限されないが、造粒時の加熱による有機酸の分解を抑制するという観点から、造粒後に添加することが好ましい。 The addition timing of the organic acid is not particularly limited, but it is preferably added after granulation from the viewpoint of suppressing decomposition of the organic acid due to heating during granulation.
Ａ剤用造粒物
前記製造方法で得られたＡ剤用造粒物は、透析用Ａ剤の添加原料として使用される。
Granule for agent A The granule for agent A obtained by the above production method is used as an additive raw material for agent A for dialysis.
また、本発明の製造方法によれば、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含むＡ剤用造粒物に対して、従来技術では実現し得ない優れた溶解性を備えさせることができる。即ち、本発明では、更に、塩化ナトリウムを含まず、塩化マグネシウム及び塩化カルシウムを含むＡ剤用造粒物であって、以下の条件での溶解時間が２３０秒以内、好ましくは５０〜２２０秒という溶解特性を備えるＡ剤用造粒物が提供される。
（溶解条件）
１Ｌ容ビーカー（底面積５０ｃｍ2）中に半径１５ｍｍの撹拌子を７５０ｒｐｍで回転させた状態で、造粒物４４．１３ｇを投入した後に、２０℃の精製水を流速６６７ｇ／分の速度で９０秒間ビーカーの上部から壁を伝わらせて添加して、精製水の添加終了後から造粒物が完全に溶解するまでの溶解時間を目視にて計測する。
In addition, according to the production method of the present invention, it is possible to provide excellent solubility that cannot be achieved by the prior art for the granule for agent A containing no sodium chloride but containing magnesium chloride and calcium chloride. it can. That is, in this invention, it is a granule for A agent which does not contain sodium chloride but contains magnesium chloride and calcium chloride, and the dissolution time under the following conditions is within 230 seconds, preferably 50 to 220 seconds. A granule for agent A having dissolution characteristics is provided.
(Dissolution conditions)
In a state where a stirrer having a radius of 15 mm was rotated at 750 rpm in a 1 L beaker (bottom area 50 cm 2 ), 44.13 g of the granulated product was added, and then purified water at 20 ° C. was added at a flow rate of 667 g / min. It is added along the wall from the top of the beaker for 2 seconds, and the dissolution time from the end of the addition of purified water to the complete dissolution of the granulated product is visually measured.
２．透析用Ａ剤
本発明の透析用Ａ剤は、前記Ａ剤用造粒物を含有する。本発明の透析用Ａ剤は、前記Ａ剤用造粒物のみからなるものであってもよく、また、必要に応じて、透析用剤に使用される他の化合物が含まれていてもよい。
2. A agent for dialysis The A agent for dialysis of the present invention contains the granulated product for the A agent. The dialysis agent A of the present invention may be composed only of the granulated product for the agent A, and may contain other compounds used in the dialysis agent as necessary. .
例えば、本発明の透析用Ａ剤には、患者の血糖値の維持の目的で、前記Ａ剤用造粒物と共にブドウ糖を含んでいてもよい。ブドウ糖は、塩化カルシウム、塩化マグネシウム等の電解質との接触によって不安定化される傾向があるが、本発明の透析用Ａ剤では、前記Ａ剤用造粒物を使用することによってブドウ糖を含有させても、ブドウ糖を安定に維持することができる。 For example, the dialysis agent A of the present invention may contain glucose together with the granule for agent A for the purpose of maintaining the blood glucose level of the patient. Glucose tends to be destabilized by contact with electrolytes such as calcium chloride and magnesium chloride. However, in the dialysis agent A of the present invention, glucose is contained by using the granule for the agent A. However, glucose can be maintained stably.
本発明の透析用Ａ剤中のブドウ糖の含有量は、最終的に調製される透析液に備えさせるブドウ糖濃度に応じて適宜設定される。具体的には、本発明の透析用Ａ剤中のブドウ糖の含有量は、最終的に調製される透析液におけるブドウ糖濃度が０〜２．５ｇ／ｌ、好ましくは１．０〜１．５ｇ／ｌとなるように適宜設定すればよい。 The content of glucose in the dialysis agent A of the present invention is appropriately set according to the glucose concentration provided in the finally prepared dialysate. Specifically, the content of glucose in the dialysis agent A of the present invention is such that the glucose concentration in the finally prepared dialysate is 0 to 2.5 g / l, preferably 1.0 to 1.5 g / l. What is necessary is just to set suitably so that it may become l.
また、本発明の透析用Ａ剤は、必要に応じて、塩化ナトリウムが含まれていてもよい。透析用Ａ剤に塩化ナトリウムが含まれている場合には、本発明の透析用Ａ剤は、重炭酸ナトリウムを含むＢ剤と共に、２剤型の透析用剤として使用される。 Further, the dialysis agent A of the present invention may contain sodium chloride, if necessary. When sodium chloride is contained in the dialysis agent A, the dialysis agent A of the present invention is used as a two-part dialysis agent together with the B agent containing sodium bicarbonate.
本発明の透析用Ａ剤における塩化ナトリウムの含有量については、透析用Ａ剤中のナトリウム塩の量等を勘案し、最終的に調製される透析液が前記表１に示す各イオン濃度を満たすように適宜設定すればよい。 Regarding the content of sodium chloride in the dialysis agent A of the present invention, the dialysis solution to be finally prepared satisfies each ion concentration shown in Table 1 in consideration of the amount of sodium salt in the dialysis agent A and the like. What is necessary is just to set suitably.
本発明の透析用Ａ剤は、重炭酸ナトリウムを含む透析用Ｂ剤と共に、重炭酸透析液を調製するための透析用剤として使用される。 The dialysis agent A of the present invention is used as a dialysis agent for preparing a bicarbonate dialysis solution together with a dialysis agent B containing sodium bicarbonate.
３．透析用剤
本発明の透析用剤は、前記透析用Ａ剤、及び重炭酸ナトリウムを含む透析用Ｂ剤を含有する。
3. Dialysis Agent The dialysis agent of the present invention contains the dialysis agent A and the dialysis agent B containing sodium bicarbonate.
前記透析用Ｂ剤には、必要に応じてブドウ糖が含まれていてもよい。前記透析用Ｂ剤にブドウ糖を含有させる場合、その含有量は、最終的に調製される透析液におけるブドウ糖濃度が０〜２．５ｇ／ｌ、好ましくは１．０〜１．５ｇ／ｌとなるように適宜設定すればよい。但し、前記透析用Ｂ剤は、重炭酸ナトリウム以外の電解質成分が含まれていないことが望ましく、含有成分が実質的に重炭酸ナトリウムからなるものが好適である。透析用Ｂ剤は、輸送や保管の観点から固形状であることが望ましい。また、固形状の透析用Ｂ剤の形状としては、具体的には粉末剤、顆粒剤等が挙げられる。 The dialysis agent B may contain glucose as necessary. When glucose is contained in the dialysis agent B, the content thereof is such that the glucose concentration in the dialysate to be finally prepared is 0 to 2.5 g / l, preferably 1.0 to 1.5 g / l. What is necessary is just to set suitably. However, it is desirable that the dialysis agent B does not contain an electrolyte component other than sodium bicarbonate, and it is preferable that the component is substantially composed of sodium bicarbonate. The dialysis agent B is preferably solid from the viewpoint of transportation and storage. Specific examples of the shape of the solid dialysis agent B include powders and granules.
前記透析用Ｂ剤の使用量は、最終的に調製される透析液中の重炭酸イオンが２０〜４０ｍＥｑ／ｌ、好ましくは２５〜３５ｍＥｑ／ｌとなるように適宜設定すればよい。 What is necessary is just to set the usage-amount of the said B agent for dialysis suitably so that the bicarbonate ion in the dialysate finally prepared may be 20-40 mEq / l, Preferably it is 25-35 mEq / l.
前記透析用Ａ剤に塩化ナトリウムが含まれている場合には、本発明の透析用剤は、前記透析用Ａ剤、及び重炭酸ナトリウムを含む透析用Ｂ剤からなる２剤型の透析用剤として使用される。 When sodium chloride is contained in the dialysis agent A, the dialysis agent of the present invention is a two-part dialysis agent comprising the dialysis agent A and a dialysis agent B containing sodium bicarbonate. Used as.
また、前記透析用Ａ剤に塩化ナトリウムが含まれていない場合には、本発明の透析用剤は、前記透析用Ａ剤、塩化ナトリウムを含む透析用Ｓ剤、及び重炭酸ナトリウムを含む透析用Ｂ剤からなる３剤型の透析用剤として使用される。当該３剤型の透析用剤は、特許文献１に記載されているように、透析時に透析用Ｓ剤と透析用Ｂ剤の添加量の比率を調節することによって、患者の病態に応じて、透析中でも重炭酸イオン濃度を自在に変化させつつ、ナトリウム、カリウム、カルシウム、マグネシウム等の電解質濃度を一定に維持できる透析液を調製することが可能になる。 When sodium chloride is not contained in the dialysis agent A, the dialysis agent of the present invention is the dialysis agent A, dialysis agent S containing sodium chloride, and dialysis agent containing sodium bicarbonate. It is used as a three-part dialysis agent consisting of B agent. As described in Patent Document 1, the three-part dialysis agent is adjusted according to the patient's condition by adjusting the ratio of the addition amount of the dialysis agent S and the dialysis agent B during dialysis. It is possible to prepare a dialysate that can maintain a constant electrolyte concentration such as sodium, potassium, calcium, magnesium, etc. while freely changing the bicarbonate ion concentration even during dialysis.
前記透析用Ｓ剤には、必要に応じてブドウ糖が含まれていてもよい。前記透析用Ｓ剤にブドウ糖を含有させる場合、その含有量は、最終的に調製される透析液におけるブドウ糖濃度が０〜２．５ｇ／ｌ、好ましくは１．０〜１．５ｇ／ｌとなるように適宜設定すればよい。但し、前記透析用Ｓ剤は、塩化ナトリウム以外の電解質成分が含まれていないことが望ましく、含有成分が実質的に塩化ナトリウムからなるものが好適である。前記透析用Ｓ剤は、輸送や保管の観点から固形状であることが望ましい。また、固形状の透析用Ｓ剤の形状としては、具体的には粉末剤、顆粒剤等が挙げられる。 The dialysis agent S may contain glucose as necessary. When glucose is contained in the dialysis agent S, the content thereof is 0 to 2.5 g / l, preferably 1.0 to 1.5 g / l, as the glucose concentration in the dialysate finally prepared. What is necessary is just to set suitably. However, it is desirable that the dialysis agent S does not contain any electrolyte component other than sodium chloride, and it is preferable that the contained component substantially consists of sodium chloride. The dialysis agent S is preferably solid from the viewpoint of transportation and storage. Specific examples of the shape of the solid S-dialysis agent include powders and granules.
前記透析用Ｓ剤の使用量は、前記透析用Ａ剤中のナトリウム塩の量等を勘案し、最終的に調製される透析液が前記表１に示すナトリウム濃度を満たすように適宜設定すればよい。 The use amount of the dialysis S agent is appropriately set so that the dialysate finally prepared satisfies the sodium concentration shown in Table 1 in consideration of the amount of sodium salt in the dialysis agent A and the like. Good.
本発明の透析用剤は、重炭酸透析液を調製するために使用される。具体的には、前記透析用Ａ剤、前記透析用Ｂ剤、及び前記透析用Ａ剤に塩化ナトリウムが含まれていない場合には前記透析用Ｓ剤を、所定量の水（好ましくは精製水）に混合し希釈させることによって、重炭酸透析液が調製される。 The dialysis agent of the present invention is used to prepare a bicarbonate dialysate. Specifically, when sodium chloride is not contained in the dialysis agent A, the dialysis agent B, and the dialysis agent A, the dialysis agent S is added to a predetermined amount of water (preferably purified water). The bicarbonate dialysate is prepared by mixing and diluting.
以下、実施例を挙げて本発明を具体的に説明する。但し、本発明は以下の実施例に限定して解釈されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not construed as being limited to the following examples.
試験例１
（１）自由水の未添加でのＡ剤用造粒物の製造
実施例１〜７及び比較例１〜４
塩化カリウム６．２６ｋｇ、塩化カルシウム二水和物９．２６ｋｇ、塩化マグネシウム六水和物４．２７ｋｇ、及び酢酸ナトリウム２７．５６ｋｇをナウタミキサ（製造元：ホソカワミクロン株式会社、型番：ＮＸ−２Ｊ）で１時間撹拌混合し、電解質原料（塩化マグネシウムの無水物換算重量１００重量部当たりの水分含量は２２７重量部）を得た。この電解質原料３ｋｇを流動層乾燥機（製造元：株式会社長門電機工作所、型番：１０Ｆ型）で、表２に示す条件で加熱して造粒と共に乾燥を行った。得られた造粒物を目開き１．７ｍｍの篩で篩過し、Ａ剤用造粒物を得た（実施例１〜６及び比較例１〜３）。また、前記電解質原料２ｋｇを金属製バットに乗せ送風定温乾燥機（製造元：株式会社アドバンテック、型式：ＤＲＳ４２０ＤＡ）で、表２に示す条件で加熱して造粒と共に乾燥を行い、目開き１．７ｍｍの篩で篩過し、Ａ剤用造粒物を得た（実施例７及び比較例４）。この結果、自由水を添加しなくても、１１０℃以上の加熱によって造粒物を形成できることが確認された。
Test example 1
(1) Manufacture of granules for agent A without free water
Examples 1-7 and Comparative Examples 1-4
Potassium chloride 6.26 kg, calcium chloride dihydrate 9.26 kg, magnesium chloride hexahydrate 4.27 kg, and sodium acetate 27.56 kg with Nauta mixer (manufacturer: Hosokawa Micron Corporation, model number: NX-2J) for 1 hour The mixture was stirred and mixed to obtain an electrolyte raw material (moisture content per 100 parts by weight of anhydrous magnesium chloride was 227 parts by weight). 3 kg of the electrolyte raw material was heated in a fluidized bed dryer (manufacturer: Nagato Electric Works Co., Ltd., model number: 10F type) under the conditions shown in Table 2 and dried together with granulation. The obtained granulated material was sieved with a sieve having a mesh opening of 1.7 mm to obtain a granulated product for agent A (Examples 1 to 6 and Comparative Examples 1 to 3). In addition, 2 kg of the electrolyte raw material was placed on a metal bat and dried with granulation by heating in a constant temperature dryer (manufacturer: Advantech Co., Ltd., model: DRS420DA) under the conditions shown in Table 2, with an opening of 1.7 mm The resulting mixture was passed through a sieve to obtain granules for agent A (Example 7 and Comparative Example 4). As a result, it was confirmed that a granulated product could be formed by heating at 110 ° C. or higher without adding free water.
比較例５
塩化カリウム０.２６４ｋｇ、塩化カルシウム二水和物０.３９１ｋｇ、塩化マグネシウム六水和物０.１８０ｋｇ、及び酢酸ナトリウム１．１６４ｋｇを混合し、電解質混合物（塩化マグネシウムの無水物換算重量１００重量部当たりの水分含量は２２７重量部）を得た。この混合物を転動流動層造粒コーティング装置（製造元：株式会社パウレック、型番ＦＤ−ＭＰ-０１Ｓ型）に投入し、撹拌翼とロータディスクを３００ｒｐｍで回転させ、温度３０℃、湿度２７％ＲＨの空気を０．８ｍ3／分の流量で吹き付けて２５分間混合・撹拌を行い造粒した。この吹付条件では、電解質原料に塩化マグネシウムの無水物重量換算１００重量部当たり、１９４重量部の自由水が供給された状態で造粒されていた。造粒後に、８０℃、相対湿度０．７６％ＲＨの乾燥エアーを用いて２．０ｍ3／分の流量で１５分間乾燥を行い、目開き１．７ｍｍの篩で篩過することによって、Ａ剤用造粒物を得た。
Comparative Example 5
0.264 kg of potassium chloride, 0.391 kg of calcium chloride dihydrate, 0.180 kg of magnesium chloride hexahydrate and 1.164 kg of sodium acetate were mixed, and the electrolyte mixture (per 100 parts by weight of magnesium chloride in terms of anhydride) The water content was 227 parts by weight). This mixture is put into a rolling fluidized bed granulation coating apparatus (manufacturer: POWREC Co., Ltd., model number FD-MP-01S type), and the stirring blade and the rotor disk are rotated at 300 rpm, at a temperature of 30 ° C. and a humidity of 27% RH. Air was blown at a flow rate of 0.8 m 3 / min to mix and stir for 25 minutes for granulation. Under this spraying condition, the electrolyte material was granulated in a state where 194 parts by weight of free water was supplied per 100 parts by weight in terms of anhydrous magnesium chloride. After granulation, drying is performed for 15 minutes at a flow rate of 2.0 m 3 / min using dry air at 80 ° C. and a relative humidity of 0.76% RH, and sieved with a sieve having an opening of 1.7 mm. A granulated product was obtained.
比較例６
造粒後の乾燥条件を、１１０℃、相対湿度０．７６％ＲＨの乾燥エアーを使用して乾燥時間を１８分間に変更したこと以外は、前記比較例５と同条件でＡ剤用造粒物を得た。
Comparative Example 6
Granulation for agent A under the same conditions as in Comparative Example 5 except that the drying conditions after granulation were changed to 110 minutes using dry air with a relative humidity of 0.76% RH and the drying time was changed to 18 minutes. I got a thing.
比較例７
造粒後の乾燥条件を、１３０℃、相対湿度０．４０％ＲＨの乾燥エアーを使用して乾燥時間を１２分間に変更したこと以外は、前記比較例５と同条件でＡ剤用造粒物を得た。
Comparative Example 7
Granulation for agent A under the same conditions as in Comparative Example 5 except that the drying conditions after granulation were changed to 12 minutes using 130 ° C. dry air with a relative humidity of 0.40% RH. I got a thing.
比較例８
塩化カリウム０.２６４ｋｇ、塩化カルシウム二水和物０.３９１ｋｇ、塩化マグネシウム六水和物０.１８０ｋｇ、及び酢酸ナトリウム１．１６４ｋｇを混合し、Ａ剤用混合物（塩化マグネシウムの無水物換算重量１００重量部当たりの水分含量は２２７重量部）を得た。
Comparative Example 8
0.264 kg of potassium chloride, 0.391 kg of calcium chloride dihydrate, 0.180 kg of magnesium chloride hexahydrate, and 1.164 kg of sodium acetate were mixed, and the mixture for agent A (an anhydrous equivalent weight of magnesium chloride of 100 weight) The water content per part was 227 parts by weight).
（２）Ａ剤用造粒物又はＡ剤用混合物の収率、水分含量、及び粒度分布
得られた各Ａ剤用造粒物及びＡ剤用混合物の収率、水分含量及び粒度分布を求めた。収率は、実施例１〜７及び比較例１〜４については、加熱造粒乾燥に供した電解質原料の重量に対して得られた、１．７ｍｍ以下の粒径を持つＡ剤用造粒物重量の割合を算出することによって求め、比較例５〜７については、造粒に供した電解質原料の重量に対して、造粒及び乾燥を経て得られた、１．７ｍｍ以下の粒径を持つＡ剤用造粒物重量の割合を算出することによって求めた。水分含量は、カールフィッシャー水分計（製造元：平沼産業、型番ＡＶＱ-６）を用いて測定した。粒度分布はＡ剤用造粒物１０ｇをロボットシフター（製造元：株式会社セイシン企業、型番：ＲＰＳ-１０５）を用いて、音波強度２０、音波周波数５１Ｈz、分級時間５分、スイープ時間０．３分、パルス間隔１秒の測定条件により、１０ｇ中に含まれる、粒径１７５μｍ以下の粒子の割合を算出した。
(2) Yield, moisture content, and particle size distribution of granule for A agent or mixture for A agent Obtain the yield, moisture content, and particle size distribution of each obtained granule for A agent and mixture for A agent. It was. Yield is granulated for agent A having a particle diameter of 1.7 mm or less obtained with respect to the weight of the electrolyte raw material subjected to heating granulation drying for Examples 1 to 7 and Comparative Examples 1 to 4. It calculates | requires by calculating the ratio of an object weight, and about Comparative Examples 5-7, with respect to the weight of the electrolyte raw material with which it granulated, the particle size of 1.7 mm or less obtained through granulation and drying was obtained. It calculated | required by calculating the ratio of the granulated material weight for A agent to have. The moisture content was measured using a Karl Fischer moisture meter (manufacturer: Hiranuma Sangyo, model number AVQ-6). The particle size distribution is 10 g of granulated product for agent A using a robot shifter (manufacturer: Seishin Co., Ltd., model number: RPS-105), sound intensity 20, sound frequency 51 Hz, classification time 5 minutes, sweep time 0.3 minutes. The ratio of particles having a particle size of 175 μm or less contained in 10 g was calculated according to the measurement conditions with a pulse interval of 1 second.
得られた結果を表３に示す。実施例１〜７の条件では、いずれも加熱時に電解質原料の粘度上昇が抑えられ、流動層乾燥機内への電解質原料の付着を抑制できており、９７％以上という高い収率でＡ剤用造粒物を製造できた。また、実施例１〜７で得られた造粒物の水分含量は、いずれも６．７％未満であり、十分に水分量を低減できていた。更に、粒径１８０μｍ以下の粒子の割合については、実施例１〜７では、比較例１〜８に比して、十分に低値であり、微粉の発生が抑制されていた。 The obtained results are shown in Table 3. Under the conditions of Examples 1 to 7, any increase in the viscosity of the electrolyte raw material was suppressed during heating, and the adhesion of the electrolyte raw material into the fluidized bed dryer could be suppressed. Granules could be produced. Moreover, the moisture content of the granulated material obtained in Examples 1-7 was all less than 6.7%, and the moisture content was fully reduced. Furthermore, about the ratio of the particle diameter of 180 micrometers or less, in Examples 1-7, compared with Comparative Examples 1-8, it was a sufficiently low value, and generation | occurrence | production of the fine powder was suppressed.
（３）有機酸を含むＡ剤用造粒物の製造及び性能評価
前記で得られたＡ剤用造粒物及びＡ剤用混合物各１ｋｇに対し、ｐＨ調節剤として酢酸をそれぞれ０．１１７ｋｇの割合で添加、混合し、酢酸含有Ａ剤用造粒物及び酢酸含有Ａ剤用混合物を得た（実施例８〜１４及び比較例９〜１６）。
(3) Production and performance evaluation of granulated product for agent A containing organic acid For each 1 kg of the granulated product for agent A and the mixture for agent A obtained above, 0.117 kg of acetic acid was used as a pH regulator. It added and mixed in the ratio and the granule for acetic acid containing A agents and the mixture for acetic acid containing A agents were obtained (Examples 8-14 and Comparative Examples 9-16).
酢酸含有Ａ剤用造粒物及び酢酸含有Ａ剤用混合物の製造において、各Ａ剤用造粒物又はＡ剤用混合物と酢酸と混合した際の流動性について、以下の判定基準に従って評価した。
＜流動性の判定基準＞
○：流動性が高く、混合を容易且つ十分に行うことができる。
△：流動性がやや低く、十分な混合を行い難い。
×：流動性が低く、十分な混合を行うことができない。
In the production of the granulated product for acetic acid-containing agent A and the mixture for acetic acid-containing agent A, the fluidity when mixed with each granule for agent A or the mixture for agent A and acetic acid was evaluated according to the following criteria.
<Criteria for liquidity>
○: High fluidity and easy and sufficient mixing.
(Triangle | delta): Fluidity is slightly low and it is difficult to perform sufficient mixing.
X: The fluidity is low and sufficient mixing cannot be performed.
また、酢酸含有Ａ剤用造粒物及び酢酸含有Ａ剤用混合物をポリエチレン袋に包装後、３０ｋｇの重りの下で２０℃、４０％ＲＨの環境下で１日間保存した。保存後の酢酸含有Ａ剤用造粒物及び酢酸含有Ａ剤用混合物を、自然落下にて目開き１．７ｍｍの篩に通過させ、篩上に残った固化物の重量比を固化率として算出した。 Further, the granulated product for acetic acid-containing agent A and the mixture for acetic acid-containing agent A were packaged in a polyethylene bag, and then stored for 1 day in an environment of 20 ° C. and 40% RH under a weight of 30 kg. The granulated product for acetic acid-containing agent A and the mixture for acetic acid-containing agent A after storage are passed through a sieve having a mesh opening of 1.7 mm by natural dropping, and the weight ratio of the solidified material remaining on the sieve is calculated as the solidification rate. did.
また、保存後に目開き１．７ｍｍの篩で、固化がほとんど生じていない酢酸含有Ａ剤用造粒物（実施例１〜７及び比較例１４、１５）はそのまま、保存後に固化の割合が多かった酢酸含有Ａ剤用造粒物及び酢酸含有Ａ剤用混合物（比較例１〜５、８）については、軽く砕いてから、目開き１．７ｍｍの篩を通過させたものを用いて、水への溶解性を測定した。具体的には、空の底面積５０ｃｍ3１Ｌビーカー中に半径１５ｍｍの撹拌子を７５０ｒｐｍで回転させておき、篩過した酢酸含有Ａ剤用造粒物４４．１３ｇを投入し、２０℃の精製水を流速６６７ｇ／分の速度で９０秒間ビーカーの上部から壁を伝わらせて添加した。目視にて酢酸含有Ａ剤用造粒物が、精製水の添加終了後から完全に溶解するまでの時間を溶解時間として求めた。 In addition, the acetic acid-containing granule for agent A (Examples 1 to 7 and Comparative Examples 14 and 15), which has a sieve having an opening of 1.7 mm after storage and hardly solidified, has a high solidification ratio after storage. The acetic acid-containing granule for agent A and the mixture for acetic acid-containing agent A (Comparative Examples 1 to 5, 8) were crushed lightly and then passed through a sieve having a mesh size of 1.7 mm. The solubility in was measured. Specifically, a stirrer having a radius of 15 mm was rotated at 750 rpm in an empty bottom area 50 cm 3 1 L beaker, and 44.13 g of the granulated product for acetic acid-containing agent A was passed through, and purified at 20 ° C. Water was added along the wall from the top of the beaker for 90 seconds at a flow rate of 667 g / min. The time from the completion of the addition of purified water to the complete dissolution of the granulated product for acetic acid-containing agent A was determined as the dissolution time.
得られた結果を表４に示す。この結果から、実施例８〜１４の酢酸含有Ａ剤用造粒物では、製造時の流動性が高く、製造が容易に行われ、しかも保存後の固化も十分に抑制できていた。また、実施例８〜１４の酢酸含有Ａ剤用造粒物では、優れた溶解性も備えていた。一方、比較例１３〜１５の酢酸含有Ａ剤用造粒物では、それぞれ酢酸含有前の水分含量が実施例１、３、及び５と同程度であるにも拘わらず、保存後に全体、又は一部が固化していたことから、従来法で製造されるＡ剤用造粒物では貯蔵安定性が不十分であることが分かり、また比較例１３〜１５の酢酸含有Ａ剤用造粒物は溶解性の点でも、劣っていた。 Table 4 shows the obtained results. From these results, the granules for acetic acid-containing agent A of Examples 8 to 14 had high fluidity during production, were easily produced, and solidification after storage could be sufficiently suppressed. Moreover, the acetic acid containing granule for A agent of Examples 8-14 was also equipped with the outstanding solubility. On the other hand, in the granulated product for acetic acid-containing agent A of Comparative Examples 13 to 15, the water content before acetic acid content was almost the same as in Examples 1, 3, and 5, respectively, but after the storage, Since the part was solidified, it was found that the storage stability of the granule for agent A produced by the conventional method was insufficient, and the granules for acetic acid-containing agent A of Comparative Examples 13 to 15 were It was inferior also in the solubility point.
試験例３
（１）透析用Ａ剤の調製
試験例１で得られた実施例８〜１４及び比較例９〜１６の各酢酸含有Ａ剤用造粒物及び酢酸含有Ａ剤用混合物１０４．４ｇと、ブドウ糖８７．５０ｇを混合し、透析用Ａ剤（実施例１５〜２１及び比較例１７〜２４）を得た。
Test example 3
(1) Preparation of dialysis agent A 104.4 g of each granule for acetic acid-containing agent A and the mixture for acetic acid-containing agent A in Examples 8 to 14 and Comparative Examples 9 to 16 obtained in Test Example 1, and glucose 87.50 g was mixed to obtain a dialysis agent A (Examples 15 to 21 and Comparative Examples 17 to 24).
（２）１７５倍濃縮Ａ剤溶液のｐＨ
上記で得られた各透析用Ａ剤を、ポリエチレンテレフタレート製フィルムとアルミニウム箔とポリエチレン製フィルムが積層されている積層体で形成されたラミネート袋（透湿度は実質的に０ｇ／ｍ2・２４ｈ）に収容して密封し、４０℃、相対湿度７５％ＲＨで１４日間保存した。
(2) pH of 175-fold concentrated agent A solution
Each dialysis agent A obtained above is a laminated bag formed of a laminate in which a polyethylene terephthalate film, an aluminum foil, and a polyethylene film are laminated (moisture permeability is substantially 0 g / m 2 · 24 h). And sealed for 14 days at 40 ° C. and a relative humidity of 75% RH.
保存５日後に、各透析用Ａ剤を収容したポリエチレン製袋を開封し、各透析用Ａ剤の固化の有無を確認した。この場合の固化とは、粒径が１．７ｍｍ以上の凝集物の有無で判定した。 After 5 days of storage, the polyethylene bag containing each dialysis agent A was opened, and the presence or absence of solidification of each dialysis agent A was confirmed. Solidification in this case was determined by the presence or absence of aggregates having a particle size of 1.7 mm or more.
また、上記で得られた保存前、保存５日後、及び保存１４日後の各透析用Ａ剤１９１．９ｇを精製水に溶解して透析液の３５倍濃縮Ａ剤溶液を調製し、０．２μｍフィルターでろ過した液について分光光度計を用いて、波長２８４ｎｍにおける吸光度を測定することによって溶液中の５−ヒドロキシメチルフルフラール（以下、５−ＨＭＦと記載）量を測定した。なお、５−ＨＭＦはブドウ糖の分解によって生じる化合物であり、上記吸光度が低値である程、ブドウ糖が安定に維持されていることを示す。 In addition, a 19-fold concentrated A-agent solution of dialysis solution was prepared by dissolving 191.9 g of each A-dialysis agent obtained before, 5 days after storage, and 14 days after storage in purified water. The amount of 5-hydroxymethylfurfural (hereinafter referred to as 5-HMF) in the solution was measured by measuring the absorbance at a wavelength of 284 nm using a spectrophotometer for the liquid filtered through the filter. 5-HMF is a compound produced by the decomposition of glucose, and the lower the absorbance, the more stably glucose is maintained.
得られた結果を表５に示す。この結果、実施例１５〜２１の透析用Ａ剤は、いずれも、保存後に固化を生じておらず、しかも５−ＨＭＦ量の上昇が抑制されており、保存前の値と同程度であることから、優れた貯蔵安定性を備えていることが確認された。また、比較例２１では、酢酸含有前の水分含量が実施例１５と同程度であるにも関わらず、保存後に固化が生じ、更に５−ＨＭＦ量が多くなっており、従来法で製造されるＡ剤用造粒物では貯蔵安定性が不良であることが確認できる。 The results obtained are shown in Table 5. As a result, none of the dialysis agents A of Examples 15 to 21 was solidified after storage, and the increase in the amount of 5-HMF was suppressed, which was comparable to the value before storage. From this, it was confirmed that it had excellent storage stability. Moreover, in Comparative Example 21, although the water content before acetic acid content is about the same as that in Example 15, solidification occurs after storage, and the amount of 5-HMF is increased, which is produced by the conventional method. It can be confirmed that the granule for agent A has poor storage stability.
Claims (13)
少なくとも塩化マグネシウム及び塩化カルシウムを含む電解質原料を１１０℃以上の温度条件で加熱して造粒物を得る工程を含むことを特徴とする、製造方法。 A method for producing a granulated product used for dialysis agent A, which does not contain sodium chloride but contains magnesium chloride and calcium chloride,
The manufacturing method characterized by including the process of heating the electrolyte raw material containing at least magnesium chloride and calcium chloride on the temperature conditions of 110 degreeC or more, and obtaining a granulated material.
更に塩化ナトリウムを含む透析用Ｓ剤を含み、
前記透析用Ａ剤、前記透析用Ｂ剤、及び前記透析用Ｓ剤からなる３剤型の透析用剤である、請求項１１に記載の透析用Ａ剤。 The dialysis agent A does not contain sodium chloride,
In addition, it contains S-dialysis agent containing sodium chloride,
The dialysis agent A according to claim 11, which is a three-part dialysis agent comprising the dialysis agent A, the dialysis agent B, and the dialysis agent S.
前記透析用Ａ剤、及び前記透析用Ｂ剤からなる２剤型の透析用剤である、請求項１１に記載の透析用剤。 The dialysis agent A contains sodium chloride,
The dialysis agent according to claim 11, which is a two-part dialysis agent comprising the dialysis agent A and the dialysis agent B.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6312957B1 (en) * | 2016-10-28 | 2018-04-18 | 富田製薬株式会社 | Agent A for hemodialysis |
| JP6366214B1 (en) * | 2016-10-28 | 2018-08-01 | 富田製薬株式会社 | Agent A for hemodialysis |
| WO2023063306A1 (en) * | 2021-10-12 | 2023-04-20 | 富田製薬株式会社 | Granulated material to be used in hemodialysis agent, and hemodialysis agent a and hemodialysis agent containing same |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0940562A (en) * | 1995-08-02 | 1997-02-10 | Tomita Seiyaku Kk | Solid agent for dialysis and its production |
| JPH11114054A (en) * | 1997-10-13 | 1999-04-27 | Nikkiso Co Ltd | Solid dialysis agent |
| JP2012105964A (en) * | 2010-10-25 | 2012-06-07 | Nikkiso Co Ltd | Dialysis agent, and method for manufacturing the same |
| JP2013048895A (en) * | 2011-07-29 | 2013-03-14 | Nikkiso Co Ltd | Dialysis agent and method for manufacturing the same |
| JP2013048894A (en) * | 2011-07-29 | 2013-03-14 | Nikkiso Co Ltd | Dialysis agent and method for manufacturing the same |
| WO2013092284A1 (en) * | 2011-12-21 | 2013-06-27 | Gambro Lundia Ab | Dialysis precursor composition |
| WO2014057966A1 (en) * | 2012-10-10 | 2014-04-17 | 富田製薬株式会社 | Dialysis a agent comprising acetic acid and acetate, and two-part dialysis agent using same |
| JP5517322B1 (en) * | 2013-10-02 | 2014-06-11 | 富田製薬株式会社 | Three-part dialysis agent containing acetic acid and acetate |
-
2014
- 2014-12-11 JP JP2014251259A patent/JP6562336B2/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0940562A (en) * | 1995-08-02 | 1997-02-10 | Tomita Seiyaku Kk | Solid agent for dialysis and its production |
| JPH11114054A (en) * | 1997-10-13 | 1999-04-27 | Nikkiso Co Ltd | Solid dialysis agent |
| JP2012105964A (en) * | 2010-10-25 | 2012-06-07 | Nikkiso Co Ltd | Dialysis agent, and method for manufacturing the same |
| JP2013048895A (en) * | 2011-07-29 | 2013-03-14 | Nikkiso Co Ltd | Dialysis agent and method for manufacturing the same |
| JP2013048894A (en) * | 2011-07-29 | 2013-03-14 | Nikkiso Co Ltd | Dialysis agent and method for manufacturing the same |
| WO2013092284A1 (en) * | 2011-12-21 | 2013-06-27 | Gambro Lundia Ab | Dialysis precursor composition |
| WO2014057966A1 (en) * | 2012-10-10 | 2014-04-17 | 富田製薬株式会社 | Dialysis a agent comprising acetic acid and acetate, and two-part dialysis agent using same |
| JP5517322B1 (en) * | 2013-10-02 | 2014-06-11 | 富田製薬株式会社 | Three-part dialysis agent containing acetic acid and acetate |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6312957B1 (en) * | 2016-10-28 | 2018-04-18 | 富田製薬株式会社 | Agent A for hemodialysis |
| JP6366214B1 (en) * | 2016-10-28 | 2018-08-01 | 富田製薬株式会社 | Agent A for hemodialysis |
| JP2018168147A (en) * | 2016-10-28 | 2018-11-01 | 富田製薬株式会社 | Agent a for hemodialysis |
| WO2023063306A1 (en) * | 2021-10-12 | 2023-04-20 | 富田製薬株式会社 | Granulated material to be used in hemodialysis agent, and hemodialysis agent a and hemodialysis agent containing same |
| JP7372001B2 (en) | 2021-10-12 | 2023-10-31 | 富田製薬株式会社 | Granules used in hemodialysis agents, hemodialysis agents A and hemodialysis agents containing the granules |
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