TW201446287A - Rapidly disintegrating tablet suitable for administration to infants and simple production method therefor - Google Patents

Abstract

The present invention addresses the issue of providing: a suitable orally disintegrating tablet capable of being readily, reliably, and safely administered to infants; and a production method therefor whereby a suitable effective component amount in the orally disintegrating tablet can be readily adjusted. The present invention pertains to: a production method for an oral rapidly-disintegrating tablet for infants, including the addition of a pre-prepared disintegrating additive blend to a powdered pharmaceutical composition, mixing of same, and the preparation of tablets; and an oral rapidly-disintegrating tablet, etc., for infants, characterized by the time for oral disintegration being no more than 20 seconds.

Description

適合對兒童投予之快速崩解錠及其簡便之製造方法 Rapid disintegrating ingot for children and its simple manufacturing method

本發明係關於一種適合對兒童進行藥劑投予的口腔內快速崩解錠及其簡便之製法等。 The present invention relates to an intraoral rapid disintegrating ingot suitable for administering a medicament to a child, a simple method for producing the same, and the like.

對兒童投予經口藥時，由於兒童拒絕服藥，故而較為困難。無論錠劑、散劑、液劑均不咽下而被吐出等，因此大多不能成功投藥。於該情形時，會發生因強制服藥而越發拒絕此次之後之服藥的不良循環。 When a child is given oral medicine, it is more difficult because the child refuses to take the medicine. No matter whether the lozenge, the powder or the liquid agent is swallowed without being swallowed, most of them cannot be successfully administered. In this case, a bad cycle of taking the drug after the drug is more and more rejected due to compulsory medication.

散劑或液劑之投藥操作較為困難，另一方面，投藥操作相對容易之錠劑對兒童而言難以咽下，且噎到之危險性較高，因此不實用。有效成分量之調整較為困難亦為錠劑之缺點。既存之製劑中，針對兒童之按有效成分量設定規格者尚少而不充足。實際狀態為多數情況下使用成人用之製劑，並為了調整有效成分量而將錠劑分割、或擂碎進行粉末化而進行投藥。 It is difficult to administer a powder or a liquid. On the other hand, a tablet which is relatively easy to administer is difficult for a child to swallow, and the risk of sputum is high, so it is not practical. The difficulty in adjusting the amount of active ingredient is also a disadvantage of tablets. In the existing preparations, there are still few and insufficient specifications for the amount of active ingredients for children. In the actual state, a preparation for an adult is used in many cases, and in order to adjust the amount of the active ingredient, the tablet is divided or pulverized and powdered to be administered.

如上所述，關於兒童用之經口藥存在如下課題：先前並無可容易、確實、及安全地進行投藥之適當劑型，進而，難以調整適當之有效成分量。 As described above, there is a problem in the oral medicine for children that there is no suitable dosage form that can be easily, reliably, and safely administered, and it is difficult to adjust the appropriate amount of the active ingredient.

關於主要以成人為對象之口腔內崩解錠，先前已知如下技術。 Regarding the orally disintegrating ingot mainly for adults, the following technique has been known.

例如，專利文獻1中記載有使甘露醇、木糖醇、無機賦形劑、 崩解劑及羧甲纖維素(carmellose)於水之存在下均勻分散後進行乾燥而成的崩解性粒子組成物。該組成物之特徵在於：形成於甘露醇粒子中固體分散木糖醇而成之複合粒子，且無機賦形劑、崩解劑及羧甲纖維素分散於該複合粒子中。該崩解性粒子組成物可藉由對使該等各成分分散於水性介質中而成的分散液進行噴霧造粒、或噴霧於甘露醇等載體而製造。 For example, Patent Document 1 describes mannitol, xylitol, and inorganic excipients. A disintegrable particle composition in which a disintegrant and carmellose are uniformly dispersed in the presence of water and then dried. The composition is characterized in that composite particles in which xylitol is solid-dispersed in mannitol particles are formed, and an inorganic excipient, a disintegrant, and carboxymethylcellulose are dispersed in the composite particles. The disintegrable particle composition can be produced by spray granulating a dispersion obtained by dispersing the components in an aqueous medium or by spraying onto a carrier such as mannitol.

又，專利文獻2記載有含有有效成分及相對於全體為10%(w/w)以上之羧甲基纖維素(Carboxymethyl Cellulose)的口腔內崩解錠。該口腔內崩解錠係將各成分混合後以打錠機進行製備。 Further, Patent Document 2 discloses an orally disintegrating ingot containing an active ingredient and 10% (w/w) or more of carboxymethylcellulose (Carboxymethyl Cellulose). The orally disintegrating ingot is prepared by mixing the components and then using an ingot machine.

進而，專利文獻3中記載有含有作為藥效成分之氯雷他定(Loratadine)之口腔內崩解錠之製造方法。該製造方法之特徵在於：進行2階段造粒步驟，第1造粒步驟中，將氯雷他定與結合劑、賦形劑、崩解劑等之至少1種添加劑進行造粒，第2造粒步驟中，將第1造粒步驟中獲得之造粒物與和第1造粒步驟同樣之結合劑、賦形劑、崩解劑等之至少1種添加劑一併進一步進行造粒。作為崩解劑之一例，可列舉羧甲纖維素。 Further, Patent Document 3 describes a method for producing an orally disintegrating ingot containing loratadine as a medicinal ingredient. The production method is characterized in that a two-stage granulation step is carried out, and in the first granulation step, loratadine is granulated with at least one additive such as a binder, an excipient or a disintegrator, and the second granulation is carried out. In the granule step, the granules obtained in the first granulation step are further granulated together with at least one of a binder, an excipient, a disintegrator, and the like in the same manner as in the first granulation step. As an example of a disintegrating agent, carboxymethylcellulose is mentioned.

進而，專利文獻4中記載有口腔內崩解錠劑之製造方法。該製造方法包括：對賦形劑與藥物之混合物噴霧水溶性且親水性之崩解成分水懸濁液而獲得含藥物之造粒物A的步驟，對賦形劑噴霧同樣之崩解成分水懸濁液而獲得不含藥物之造粒物B的步驟，及將以上述方式獲得之造粒物A及造粒物B壓縮成形的步驟。 Further, Patent Document 4 describes a method for producing an orally disintegrating tablet. The manufacturing method comprises the steps of: spraying a water-soluble and hydrophilic disintegrating component aqueous suspension on a mixture of an excipient and a drug to obtain a drug-containing granulating A, and spraying the same disintegrating component water on the excipient; The step of obtaining the granule B containing no drug by the suspension, and the step of compression-molding the granule A and the granule B obtained in the above manner.

[先前技術文獻] [Previous Technical Literature] [專利文獻] [Patent Literature]

專利文獻1：國際公開手冊WO2011/019045 Patent Document 1: International Publication Manual WO2011/019045

專利文獻2：日本特開2008-285434號公報 Patent Document 2: Japanese Laid-Open Patent Publication No. 2008-285434

專利文獻3：日本特開2012-31138號公報 Patent Document 3: Japanese Laid-Open Patent Publication No. 2012-31138

專利文獻4：日本專利第4551627號說明書 Patent Document 4: Japanese Patent No. 4551627

本發明所欲解決之課題在於提供一種可對兒童容易、確實、及安全地進行投藥的適當之口腔內崩解錠、及可容易地調整該口腔內崩解錠中之適當之有效成分量的製造方法。 It is an object of the present invention to provide an appropriate orally disintegrating ingot which can be administered to children easily, reliably, and safely, and which can easily adjust the amount of an appropriate active ingredient in the orally disintegrating ingot. Production method.

更具體而言，本發明提供以下態樣。 More specifically, the present invention provides the following aspects.

[態樣1]一種兒童用口腔內快速崩解錠，其特徵在於：其口腔內崩解時間為20秒以內。 [Aspect 1] A rapid disintegrating ingot for oral use in children, characterized in that the intraoral disintegration time is within 20 seconds.

[態樣2]一種兒童用口腔內快速崩解錠之製造方法，其含有對粉末狀態之醫藥組成物添加預先製備之崩解性添加劑摻合物並進行混合、打錠。 [Aspect 2] A method for producing a rapidly disintegrating ingot for oral use in a child, which comprises adding a pre-prepared disintegrating additive blend to a pharmaceutical composition in a powder state, and mixing and tableting.

[態樣3]如態樣2記載之製造方法，其中，粉末狀態之醫藥組成物係藉由將固體狀醫藥組成物擂碎進行粉末化而獲得者。 [Aspect 3] The production method according to the aspect 2, wherein the pharmaceutical composition in a powder state is obtained by pulverizing the solid pharmaceutical composition and pulverizing the composition.

[態樣4]如態樣3記載之製造方法，其中，固體狀醫藥組成物為成人用錠劑或硬膠囊劑之固體內容物。 [Aspect 4] The production method according to Aspect 3, wherein the solid pharmaceutical composition is a solid content of an adult lozenge or a hard capsule.

[態樣5]如態樣2至4中任一態樣記載之製造方法，其中，不對醫藥組成物所含之有效成分進行分離、萃取而添加崩解性添加劑摻合物並進行混合、打錠。 [Aspect 5] The production method according to any one of the aspects 2 to 4, wherein the active ingredient contained in the pharmaceutical composition is not separated and extracted, and a disintegrating additive blend is added and mixed. ingot.

[態樣6]一種口腔內快速崩解錠，其係藉由如態樣2至5中任一態樣記載之製造方法所得之兒童用口腔內快速崩解錠，且其特徵在於：其口腔內崩解時間為20秒以內。 [Aspect 6] An intraorally rapidly disintegrating ingot obtained by a method for producing a method according to any one of the aspects 2 to 5, wherein the oral cavity is rapidly disintegrated, and characterized in that: The internal disintegration time is within 20 seconds.

本發明之口腔內快速崩解錠一旦被投予至口腔內即於極短 時間內開始崩解，因此噎到之危險性亦降低，且不會被吐出。其結果為，兒童對服藥難以拒絕，對服藥之抵抗感減弱。 The intraorally rapidly disintegrating ingot of the present invention is extremely short once it is administered into the oral cavity The disintegration begins in time, so the risk of getting it is reduced and it will not be spit out. As a result, it is difficult for children to refuse medication and the resistance to medication is weakened.

進而，於本發明之口腔內崩解錠之製造方法中，可容易地調整該口腔內崩解錠所含之有效成分量，以使之對利用先前之成人用錠劑之作為投予對象之兒童成為適當之投藥用量。 Further, in the method for producing an orally disintegrating tablet of the present invention, the amount of the active ingredient contained in the orally disintegrating tablet can be easily adjusted so as to be used as a target for administration of the previously used adult tablet. Children become appropriate doses for administration.

本發明之兒童用口腔內快速崩解錠之特徵在於：其口腔內崩解時間為20秒，較佳為15秒以內。其結果為，本發明之口腔內快速崩解錠於被投予之兒童之口腔內立即濕潤而開始崩解，且味覺及口感優異。又，口腔內快速崩解錠之硬度通常為15N以上，較佳為30N以上。 The intra-oral rapid disintegrating tablet for children of the present invention is characterized in that the intraoral disintegration time is 20 seconds, preferably 15 seconds or less. As a result, the intraorally rapidly disintegrating tablet of the present invention immediately wets in the oral cavity of the child to be administered and starts to disintegrate, and is excellent in taste and texture. Further, the hardness of the rapidly disintegrating ingot in the oral cavity is usually 15 N or more, preferably 30 N or more.

於醫藥品之用量設定中，通常多數情況下，所謂「兒童」係指約7歲以上但未達15歲，又，所謂「幼兒」係指約1歲以上但未達7歲，但於本說明書中，所謂「兒童」，表示大致1歲以上但未達15歲左右。當然，可否投藥、及應投藥之有效成分量應考慮藥劑之種類、年齡、體重、症狀等而判斷。 In the setting of the dosage of pharmaceuticals, in most cases, the term "child" means about 7 years old but not 15 years old. Moreover, the term "child" means about 1 year old or older but not 7 years old. In the manual, the term "child" means approximately one year old but not 15 years old. Of course, whether or not the drug can be administered and the amount of the active ingredient to be administered should be judged by considering the type, age, weight, and symptoms of the drug.

又，「口腔內崩解時間」係利用本說明書中以下記載之方法進行測定。 Moreover, the "intraoral disintegration time" is measured by the method described below in the present specification.

本發明之口腔內快速崩解錠係對應作為治療對象之疾患及症狀等含適當量從業者公知之任意藥效成分(化合物)作為有效成分，具有各種用途。作為該藥效成分，通常包括用於成人用者、成人與兒童共通使用者、及僅用於兒童者。 The intraorally rapidly disintegrating tablet of the present invention has various uses as an active ingredient in any pharmaceutically effective ingredient (compound) known to a proper amount as a therapeutic target, such as a disease or a symptom to be treated, and has various uses. As the medicinal ingredient, it is usually used for adults, for adults and children, and for children only.

例如，具有胃酸分泌抑制作用之H2受體拮抗劑尼紮替丁(NIZATIDINE)被認為尚未確定對兒童之投予安全性，因此難以獲得適於對兒童投予之製劑。但，於萬一因某些情況而判斷必須對兒童投予的情形時，可使用成人用之製劑製備所含有效成分量經減少之口腔內快速崩解錠。同樣地，具有過敏症狀緩解作用或睡眠改善作用之H1受體拮抗劑二苯胺明鹽酸鹽亦有副作用之虞，故而並不推薦對兒童投予，因此難以獲得適於對兒童投予之製劑。但，於萬一因某些情況而判斷必須對兒童投予之情形時，可使用成人用製劑製備有效成分量經減少之口腔內快速崩解錠。進而，作為可對兒童投予之劑型之經乾糖漿化的H1受體拮抗劑例如有依匹斯汀鹽酸鹽(Epinastine hydrochloride)，但以粉末方式投藥、或者進行液劑化後投藥均存在拒絕服藥之情況。作為投藥更簡便且更難拒絕服藥之劑型，口腔內快速崩解錠於被判斷為必需之情形時，同樣地可使用成人用製劑製備有效成分量經減少之口腔內快速崩解錠。 For example, the N2 receptor antagonist nizatidine (NIZATIDINE) having gastric acid secretion inhibitory action is considered to have not established safety for administration to children, and thus it is difficult to obtain a preparation suitable for administration to children. However, in the event that it is judged that the child must be administered in some cases, the adult preparation may be used to prepare a rapidly disintegrating ingot in the oral cavity having a reduced amount of the active ingredient. Similarly, the H1 receptor antagonist diphenylamine hydrochloride, which has an allergy symptom-relieving effect or a sleep-improving effect, has side effects, and is therefore not recommended for administration to children, so that it is difficult to obtain a preparation suitable for administration to children. . However, in the case where it is judged that the child must be administered in some cases, the adult preparation can be used to prepare a rapidly disintegrating ingot in the oral cavity having a reduced amount of the active ingredient. Further, as a dry syrup-forming H1 receptor antagonist which can be administered to a child, for example, Epinastine hydrochloride is administered as a powder or after liquefaction. Refusal to take the medicine. As a dosage form which is simpler and more difficult to refrain from taking the medicine, and in the case where the rapidly disintegrating tablet in the oral cavity is judged to be necessary, the adult preparation can be used to prepare a rapidly disintegrating ingot in the oral cavity having a reduced amount of the active ingredient.

進而，本發明之口腔內快速崩解錠中，除了相關有效成分及崩解劑(崩解性添加劑)成分，亦可視需要含有賦形劑、塑化劑、界面活性劑、潤滑劑、酸味料、甜味料、矯味劑、香料、著色劑、穩定化劑等醫藥上允許之其他任意成分。作為該等任意成分，例如，可使用醫藥品添加物辭典(藥事日報公司)、日本藥典中記載之適合成分。再者，該等各種任意成分之種類並無特別限制。又，只要可實現本發明之所需效果，則崩解劑成分、有效成分、及任意成分之摻合比率並無特別限制，從業者可酌情決定。如上所述之口腔內崩解錠劑可藉由打錠等從業者公知之任意方法而進行製劑化。 Further, in the intraorally rapidly disintegrating tablet of the present invention, in addition to the relevant active ingredient and the disintegrant (disintegrating additive) component, excipients, plasticizers, surfactants, lubricants, and sour materials may be contained as needed. Other sweet ingredients, sweeteners, flavoring agents, flavoring agents, coloring agents, stabilizers, and the like. As such an arbitrary component, for example, a suitable ingredient described in the Pharmaceutical Additive Dictionary (Pharmacy Daily) and the Japanese Pharmacopoeia can be used. Furthermore, the types of the various optional components are not particularly limited. Further, the blending agent component, the active ingredient, and the blending ratio of the optional component are not particularly limited as long as the desired effect of the present invention can be achieved, and the practitioner can make a discretion. The orally disintegrating tablet as described above can be formulated by any method known to a practitioner such as tableting.

本發明之口腔內快速崩解錠之製造方法並無特別限制，尤其以如下方法進行製造為佳。 The method for producing the intraorally rapidly disintegrating tablet of the present invention is not particularly limited, and it is particularly preferably produced by the following method.

即，本發明之口腔內快速崩解錠可利用包括如下操作之方法 進行製造：對粉末狀態之醫藥組成物添加預先製備之崩解性添加劑摻合物並進行混合、打錠。此處，粉末狀態之醫藥組成物之來源及製備方法並無特別限制，例如，可藉由將固體狀醫藥組成物擂碎進行粉末化而獲得，該醫藥組成物較佳為成人用之錠劑或硬膠囊劑之固體內容物。 That is, the intraorally rapidly disintegrating ingot of the present invention can utilize a method including the following operation Manufacture is carried out by adding a previously prepared disintegrating additive blend to a pharmaceutical composition in a powder state, and mixing and tableting. Here, the source and preparation method of the pharmaceutical composition in a powder state are not particularly limited, and for example, it can be obtained by pulverizing a solid pharmaceutical composition, which is preferably a tablet for adults. Or the solid content of a hard capsule.

粉末狀態之醫藥組成物與崩解性添加劑摻合物之混合(固體分散)及打錠可利用從業者公知之任意手段、方法實施。此時，可容易地調整該口腔內崩解錠中所含之有效成分量，以根據投予對象及投予目的等而成為適當之投藥用量。又，無需分離、萃取醫藥組成物中所含之有效成分。 The mixing (solid dispersion) and tableting of the pharmaceutical composition in a powder state with the disintegrating additive blend can be carried out by any means or method known to the practitioner. In this case, the amount of the active ingredient contained in the orally disintegrating tablet can be easily adjusted to be an appropriate dosage amount depending on the intended subject, the purpose of administration, and the like. Further, it is not necessary to separate and extract the active ingredient contained in the pharmaceutical composition.

大多情形時，適於對兒童投藥之有效成分量與成人相比較少，因此，藉由如上所述之粉末狀態之醫藥組成物與崩解性添加劑摻合物之混合(固體分散)操作可簡便且實用地製造本發明之口腔內快速崩解錠。 In most cases, the amount of the active ingredient suitable for administration to children is less than that of an adult, and therefore, it is easy to carry out the mixing (solid dispersion) operation of the pharmaceutical composition in a powder state as described above and the disintegrating additive blend. And the in-oral rapid disintegration ingot of the present invention is practically produced.

該粉末狀態之醫藥組成物並不具有快速崩解性，藉由與崩解性添加劑摻合物一併進行製劑化，而對本發明之口腔內快速崩解錠賦予優異之成型性及崩解性。 The pharmaceutical composition in the powder state does not have rapid disintegration property, and is formulated together with the disintegrating additive blend to impart excellent moldability and disintegration property to the intraorally rapidly disintegrating tablet of the present invention. .

作為錠劑等之崩解機制，有「Wicking(滲透)」、「Swelling(膨脹)」、「Deformation(變形)」及「Repulsion(排斥)」4種說法。其中，所謂Wicking，係水分經由錠劑中所含之崩解劑等成分而滲透，結果錠劑中所含之各粒子間結合力變弱而進行的崩解機制。作為對上述Wicking促進效果較高之崩解劑之代表例，已知有酸型羧甲基纖維素。又，所謂Swelling，係水滲透至崩解劑中，結果崩解劑自身膨潤而進行之崩解機制。 As a disintegration mechanism of a tablet or the like, there are four kinds of expressions: "Wicking", "Swelling", "Deformation", and "Repulsion". Here, Wicking is a disintegration mechanism in which water permeates through a component such as a disintegrant contained in a tablet, and the binding force between the particles contained in the tablet is weakened. As a representative example of the above-mentioned disintegrator having a high Wicking promoting effect, acid type carboxymethyl cellulose is known. Further, Swelling is a disintegration mechanism in which water permeates into a disintegrant and the disintegrant swells by itself.

因此，該崩解性添加劑摻合物中較佳為含有以下物質。 Therefore, it is preferred that the disintegrating additive blend contain the following materials.

首先，可列舉作為崩解劑成分被稱為羧甲纖維素之物質，即作為醫藥品添加劑而使用之酸型羧甲基纖維素。與酸型羧甲基纖維素同樣，例如羧甲基纖維素之鈣鹽及羧甲基纖維素鈉之交聯物均不溶於水，而 於錠劑等中被用作崩解劑。另一方面，羧甲基纖維素之鈉鹽為水溶性，可用於結合劑等目的。再者，亦有時將羧甲基纖維素之鹽記載為羧甲纖維素(Carmellose)。 First, a substance called carboxymethylcellulose as a component of a disintegrator, that is, an acid type carboxymethylcellulose used as a pharmaceutical additive can be mentioned. Like the acid type carboxymethyl cellulose, for example, the calcium salt of carboxymethyl cellulose and the crosslinked product of sodium carboxymethyl cellulose are insoluble in water, and It is used as a disintegrating agent in a tablet or the like. On the other hand, the sodium salt of carboxymethylcellulose is water-soluble and can be used for purposes such as a binder. Further, the salt of carboxymethylcellulose is sometimes referred to as Carmellose.

進而，作為第二崩解劑成分，可列舉酸型羧甲基纖維素以外之從業者公知之任意崩解劑。然而，為了獲得如上所示之不同崩解機制之複合效果，較佳為使用對Wicking以外之機制、例如Swelling之促進效果優異之崩解劑作為第二崩解劑成分。作為此種崩解劑之較佳例，可列舉：交聯聚維酮、交聯羧甲纖維素鈉、羧甲基澱粉鈉、低取代羥丙基纖維素、羧甲基纖維素鈣、羥丙基澱粉、及澱粉等。再者，交聯聚維酮為1-乙烯基-2-吡咯啶酮之交聯聚合物之通稱，交聯羧甲纖維素鈉為羧甲基纖維素鈉之交聯物之通稱。 Further, examples of the second disintegrant component include any disintegrator known to a practitioner other than the acid carboxymethylcellulose. However, in order to obtain the composite effect of the different disintegration mechanisms as described above, it is preferred to use a disintegrant excellent in the promotion effect other than Wicking, for example, Swelling, as the second disintegrator component. Preferred examples of such a disintegrant include crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, and hydroxy group. Propyl starch, and starch. Further, crospovidone is a general term for a crosslinked polymer of 1-vinyl-2-pyrrolidone, and croscarmellose sodium is a general term for a crosslinked product of sodium carboxymethylcellulose.

該等之中，較佳為選自交聯聚維酮、交聯羧甲纖維素鈉、羧甲基澱粉鈉、低取代羥丙基纖維素、或羧甲基纖維素鈣中之1種或2種以上之任意組合。 Among these, it is preferably one selected from the group consisting of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or carboxymethyl cellulose calcium or Any combination of two or more.

進而，作為第三成分，可含有從業者公知作為賦形劑之任意化合物。作為其代表例，可列舉：甘露醇、赤藻糖醇、山梨糖醇、D-葡萄糖醇(麥芽糖醇)、木糖醇、海藻糖、乳糖及麥芽糖等糖或糖醇。進而，作為較佳例，可列舉：甘露醇、赤藻糖醇、海藻糖、山梨糖醇、及D-葡萄糖醇(麥芽糖醇)。作為賦形劑，可使用適當選自該等之中之2種以上化合物。 Further, as the third component, any compound known to the practitioner as an excipient may be contained. Typical examples thereof include sugars or sugar alcohols such as mannitol, erythritol, sorbitol, D-glucitol (maltitol), xylitol, trehalose, lactose, and maltose. Further, preferred examples thereof include mannitol, erythritol, trehalose, sorbitol, and D-glucitol (maltitol). As the excipient, two or more kinds of compounds appropriately selected from the above may be used.

進而，上述崩解性添加劑摻合物中，例如，出於調整崩解力、結合力及錠劑之服用感等各特性之目的，亦可於無損由上述三種成分獲得之本發明之效果的範圍內酌情添加混合從業者公知之各種任意成分。作為上述成分之例，可列舉：塑化劑、無機賦形劑、甜味劑、香料及著色料等。 Further, in the above-mentioned disintegrating additive blend, for example, for the purpose of adjusting various properties such as disintegration power, binding strength, and feeling of taking of a tablet, the effects of the present invention obtained by the above three components may be impaired. Any of the various ingredients known to the practitioner are added as appropriate within the scope. Examples of the above components include plasticizers, inorganic excipients, sweeteners, perfumes, and coloring materials.

關於上述崩解性添加劑摻合物中之各成分之摻合量，從業者 可根據各成分之種類、成為混合之對象之醫藥組成物中的有效成分之種類及用途、最終製品即口腔內崩解錠之用途等而酌情決定。通常，相對於崩解性添加劑摻合物總重量，第一崩解劑成分為10~50重量%之範圍，第二崩解劑成分為1~20重量%之範圍，及賦形劑為30~89重量%之範圍。 Regarding the blending amount of each component in the above disintegrating additive blend, practitioner The type of each component, the type and use of the active ingredient in the pharmaceutical composition to be mixed, and the use of the final product, that is, the use of the orally disintegrating tablet, may be determined as appropriate. Generally, the first disintegrant component is in the range of 10 to 50% by weight, the second disintegrant component is in the range of 1 to 20% by weight, and the excipient is 30, based on the total weight of the disintegrating additive blend. ~89% by weight range.

再者，上述崩解性添加劑摻合物較佳為具有如下之物性。 Further, the above disintegrating additive blend preferably has the following physical properties.

(1)平均粒徑：50~200微米，(2)水分：0.5~3重量%。 (1) Average particle diameter: 50 to 200 μm, (2) Moisture: 0.5 to 3 wt%.

再者，該等物性值係利用以下之條件、方法進行測定。 Further, these physical property values were measured by the following conditions and methods.

平均粒徑：使用φ 75mm自動振盪篩器(M-2型、筒井理化學器械股份有限公司)對崩解性添加劑摻合物2g進行測定。 Average particle diameter: 2 g of the disintegrating additive blend was measured using a φ 75 mm automatic oscillating sieve (M-2 type, Tsutsui Chemical Instruments Co., Ltd.).

水分：使用鹵素水分測定器(HB43型、METTLER TOLEDO股份有限公司)對崩解性添加劑摻合物5g進行測定。 Moisture: 5 g of the disintegrating additive blend was measured using a halogen moisture analyzer (HB43 type, METTLER TOLEDO Co., Ltd.).

因此，上述崩解性添加劑摻合物之製造方法並無特別限制。例如，可藉由如下方法進行製造，該方法包括：使用該三種成分中之任意二種成分之第一濕式造粒步驟，及至少使用由第一濕式造粒步驟所獲得之造粒物、及第一濕式造粒步驟中未使用之剩餘的一種成分(或僅使用剩餘一種成分)的第二濕式造粒步驟。 Therefore, the method for producing the above disintegrating additive blend is not particularly limited. For example, it can be produced by a method comprising: a first wet granulation step using any two of the three components, and at least using the granulation obtained by the first wet granulation step And a second wet granulation step of the remaining one component (or only the remaining one component) not used in the first wet granulation step.

上述第一及第二造粒步驟係以藉由在水之存在下使各成分分散並進行乾燥而形成複合體的方法、即濕式造粒法進行。作為濕式造粒法之具體例，可列舉：噴霧乾燥、轉動造粒、攪拌造粒、及流體化床造粒等噴霧法、冷凍乾燥法、以及混練造粒等，可使用該等從業者公知之任意方法進行製造。 The first and second granulation steps are carried out by a wet granulation method in which a component is dispersed and dried in the presence of water to form a composite. Specific examples of the wet granulation method include spray drying, tumbling granulation, stirring granulation, and fluidized bed granulation, a spray method, a freeze-drying method, and kneading granulation, etc., and these practitioners can be used. Any method known in the art for manufacturing.

酸型羧甲基纖維素等崩解劑為親水性，因此利用濕式造粒，於水之存在下進行攪拌等施加物理力之操作，藉此，粒子會自乾燥粉末時之凝集狀態成為更分散之狀態。利用水噴霧進行分散化及乾燥之流體化床造粒、噴霧乾燥、轉動造粒及攪拌造粒等可最容易地進行分散，且乾燥速 度較快，因此該等方法較佳。 Since the disintegrant such as acid carboxymethylcellulose is hydrophilic, it is operated by wet granulation to apply a physical force such as stirring in the presence of water, whereby the particles become agglomerated from the dry powder. Dispersed state. The fluidized bed granulation, spray drying, tumbling granulation, stirring granulation, etc., which are dispersed and dried by water spray, can be most easily dispersed, and the drying speed is fast. The method is faster, so these methods are preferred.

該等之中，流體化床造粒法為一面以熱風吹刮起粉體一面噴霧水或含有結合劑之水溶液等而進行的造粒法，噴霧條件等之調節較為容易等，因此為最佳方法。 Among these, the fluidized bed granulation method is a granulation method in which the powder is sprayed with hot water or an aqueous solution containing a binder, and the like, and the spray conditions and the like are easily adjusted, and therefore it is optimal. method.

再者，上述崩解性添加劑摻合物可適當含有之、上述三種成分以外之從業者公知之各種任意成分可於第一及/或第二濕式造粒步驟中適當添加。或者，亦可進而設置第三步驟以後之濕式造粒步驟，並於該階段添加混合該等任意成分。 Further, any of the various components known to the practitioner other than the above-described three components which are appropriately contained in the above disintegrating additive mixture may be appropriately added in the first and/or second wet granulation step. Alternatively, a wet granulation step after the third step may be further provided, and the optional components are added and mixed at this stage.

進而，於第一及第二各濕式造粒步驟中，關於噴霧(spray)速度或空氣送氣溫度、排氣溫度、空氣送氣量等各條件，從業者可根據各成分之種類、量等而酌情決定。 Further, in the first and second wet granulation steps, the conditions of the spray rate, the air supply temperature, the exhaust gas temperature, and the air supply amount may be based on the type and amount of each component. And discretion.

於利用流體化床造粒法之第一濕式造粒步驟及第二濕式造粒步驟之任一者中，出於溶解槽或攪拌裝置之設置等裝置上之限制、及溶劑中溶解、懸浮有添加成分時添加成分之穩定性問題、以及為了設為無損崩解性成分之功能之造粒條件等理由，較佳為噴霧液中不含各三種成分之任一者。作為噴霧液之介質，只要為不對崩解性添加劑摻合物之特性造成影響、且為醫藥品或食品上允許之溶劑即可，例如可列舉水、乙醇、甲醇、丙酮等，尤佳為水。 In any of the first wet granulation step and the second wet granulation step using the fluidized bed granulation method, restrictions on the apparatus such as the dissolving tank or the stirring device, and dissolution in the solvent, It is preferable that the spray liquid does not contain any of the three components in order to solve the problem of the stability of the component to be added when the component is added, and the granulation conditions for the function of the component which does not impair the disintegrating component. The medium for the spray liquid is not particularly limited as long as it does not affect the properties of the disintegrating additive blend, and is a solvent acceptable for pharmaceuticals or foods, and examples thereof include water, ethanol, methanol, acetone, etc., and particularly preferably water. .

再者，本說明書中所引用之全部先前技術文獻之記載內容係作為參照而被組入本說明書中。 In addition, the contents of all the prior art documents cited in the present specification are incorporated herein by reference.

以下，利用實施例進而具體地對本發明進行說明，但本發明並不限定於該等實施例。 Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to the examples.

再者，於以下之實施例中，本發明之口腔內快速崩解錠之硬度(N)係使用數位硬度計(KHT-40N、藤原製作所股份有限公司)分別進行3次測定，並以其等之平均值作為測定結果。 Furthermore, in the following examples, the hardness (N) of the intraorally rapidly disintegrating tablet of the present invention was measured three times using a digital hardness tester (KHT-40N, Fujiwara Co., Ltd.), and the like. The average value is taken as the measurement result.

又，關於口腔內崩解時間，係測定將錠劑1錠含於口腔內並保持以不施加力之方式夾於舌與上顎間之狀態直至錠劑完全崩解的時間。令2名成年男子各實施2次，並以其等之平均值作為測定結果。 Further, regarding the intraoral disintegration time, it was measured that one tablet of the tablet was contained in the oral cavity and kept in a state of being sandwiched between the tongue and the upper jaw without applying a force until the tablet completely collapsed. Two adult men were each performed twice, and the average of them was used as the measurement result.

實施例1 Example 1

(用以由不具有快速崩解性之既存錠劑製造口腔內快速崩解錠的添加劑摻合物之製造方法) (Method for producing an additive blend for producing an orally rapidly disintegrating ingot from an existing tablet without rapid disintegration)

將羧甲纖維素(NS-300、五德藥品股份有限公司)100g、交聯聚維酮(Polyplasdone INF-10、ISP Japan)20g、甘露醇(D-甘露醇、Merck股份有限公司)375g投入至流體化床造粒機(LAB-1、Powrex股份有限公司)中，並噴霧純化水240g，藉此進行造粒，而獲得平均粒徑約100μm、水分約1%之造粒物(崩解性添加劑摻合物)。 100 g of carboxymethylcellulose (NS-300, Wude Pharmaceutical Co., Ltd.), 20 g of crospovidone (Polyplasdone INF-10, ISP Japan), and 375 g of mannitol (D-mannitol, Merck Co., Ltd.) were put. Into a fluidized bed granulator (LAB-1, Powrex Co., Ltd.), and 240 g of purified water was sprayed, granulation was carried out to obtain granules having an average particle diameter of about 100 μm and a moisture content of about 1% (disintegration). Additive blend).

實施例2 Example 2

(自不具有快速崩解性之含尼紮替丁錠劑減少有效成分量而得之口腔內快速崩解錠的製造方法) (Method for producing a rapidly disintegrating ingot in the oral cavity obtained by reducing the amount of active ingredient in a nizatidine tablet containing no rapid disintegration)

對每1錠含有75mg尼紮替丁(H2受體拮抗劑：胃酸分泌抑制作用)作為有效成分的成人用既存錠劑(Zeria新藥工業股份有限公司「Acinon錠75mg」、錠劑重量108mg、作為添加物而含有部分α化澱粉、結晶纖維素、羥丙基纖維素、交聯聚維酮、硬脂酸鎂、羥丙甲纖維素、氧化鈦、巴西棕櫚蠟)2錠添加輕質矽酸酐(Adsolider、Freund產業股份有限公司)10mg，此後以研缽擂碎，獲得含有尼紮替丁150mg之粉末226mg。於其中添加以實施例1之方法獲得之造粒物1764mg、蔗糖素(San-Ei Gen F.F.I.股份有限公司)10mg，於聚乙烯製的袋中充分混合。使用簡易錠劑成形機(HANDTAB-100、市橋精機股份有限公司)於打錠壓縮力5kN及3kN下將該混合粉末打錠，獲得直徑8.0mm、平面斜角、重量200mg、每1錠尼紮替丁含量15mg之口腔內快速崩解錠。該含尼紮替丁口腔內快速崩解錠 (消化管運動改善劑)於打錠壓縮力為5kN及3kN之情形時，錠劑厚度分別為3.56mm及3.85mm，錠劑硬度分別為30N及16N，口腔內崩解時間(成年男性)分別為15秒及13秒。再者，本實施例中所獲得之口腔內快速崩解錠所含的尼紮替丁量為每1錠降低至成人1次用量(例如150mg)之1/10左右(15mg)，因此較容易考慮被投藥之兒童之年齡、體重、症狀而設定投藥量。 An existing preservative for adults containing 75 mg of nizatidine (H2 receptor antagonist: gastric acid secretion inhibitory action) per tablet (Zeria New Drug Industry Co., Ltd. "Acinon ingot 75 mg", tablet weight 108 mg, as Additives containing partially gelatinized starch, crystalline cellulose, hydroxypropylcellulose, crospovidone, magnesium stearate, hypromellose, titanium oxide, carnauba wax) 2 ingots added light phthalic anhydride (Adsolider, Freund Industries Co., Ltd.) 10 mg, and thereafter mashed to obtain 226 mg of a powder containing 150 mg of nizatidine. 1764 mg of granules obtained by the method of Example 1 and 10 mg of sucralose (San-Ei Gen F.F.I. Co., Ltd.) were added thereto, and the mixture was thoroughly mixed in a polyethylene bag. The mixed powder molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.) was used to ingot the mixed powder at a compression force of 5 kN and 3 kN to obtain a diameter of 8.0 mm, a plane bevel angle, a weight of 200 mg, and a Niza per 1 spindle. A rapid disintegration ingot in the oral cavity with a content of 15 mg. Rapid disintegration ingot containing nizatidine (Digestive tube movement improver) When the compression force of the tablet is 5kN and 3kN, the thickness of the tablet is 3.56mm and 3.85mm, the hardness of the tablet is 30N and 16N respectively, and the intraoral disintegration time (adult male) respectively It is 15 seconds and 13 seconds. Furthermore, the amount of nizatidine contained in the intraorally rapidly disintegrating tablet obtained in the present embodiment is reduced to about 1/10 (15 mg) per one dose of the adult (for example, 150 mg), which is easy. The dosage is set in consideration of the age, weight, and symptoms of the child to be administered.

實施例3 Example 3

(自不具有快速崩解性之含二苯胺明鹽酸鹽錠劑減少有效成分量而得之口腔內快速崩解錠的製造方法) (Method for producing a rapidly disintegrating ingot in the oral cavity obtained by reducing the amount of active ingredient in a diphenylamine-containing hydrochloride tablet containing no rapid disintegration)

將每1錠含25mg二苯胺明鹽酸鹽(H1受體拮抗劑)作為有效成分的成人用既存錠劑(SS製藥股份有限公司「Drewell」、錠劑重量265mg、作為添加物而含有交聯羧甲纖維素鈉、矽酸酐、纖維素、乳糖、羥丙基纖維素、羥丙甲纖維素、聚乙烯二醇、硬脂酸鎂、滑石、氧化鈦)3錠以研缽擂碎，而獲得含有二苯胺明鹽酸鹽75mg之粉末795mg。於其中添加以實施例1之方法獲得之造粒物2190mg、蔗糖素(San-Ei Gen F.F.I.股份有限公司)15mg，於聚乙烯製的袋中充分混合。使用簡易錠劑成形機(HANDTAB-100、市橋精機股份有限公司)以打錠壓縮力5kN將該混合粉末進行打錠，獲得直徑8.0mm、平面斜角、重量200mg、每1錠二苯胺明鹽酸鹽含量5mg之口腔內快速崩解錠。該含二苯胺明鹽酸鹽口腔內快速崩解錠之錠劑厚度為3.27mm，錠劑硬度為28N，口腔內崩解時間(成年男性)為17秒。再者，本實施例中所獲得之口腔內快速崩解錠所含的二苯胺明鹽酸鹽為每1錠降低至成人1次用量(例如50mg)之1/10左右(5mg)，因此較容易考慮被投藥之兒童之年齡、體重、症狀而設定投藥量。 A preservative tablet for adult use (Drewell, SS Pharmaceutical Co., Ltd., 265 mg of tablet weight, containing cross-linking as an additive) containing 25 mg of diphenylamine hydrochloride (H1 receptor antagonist) per serving as an active ingredient Carboxymethylcellulose sodium, phthalic anhydride, cellulose, lactose, hydroxypropylcellulose, hypromellose, polyethylene glycol, magnesium stearate, talc, titanium oxide) 3 ingots to grind, and 795 mg of a powder containing 75 mg of diphenylamine hydrochloride was obtained. To the mixture, 2190 mg of the granules obtained by the method of Example 1 and 15 mg of sucralose (San-Ei Gen F.F.I., Ltd.) were added, and the mixture was sufficiently mixed in a bag made of polyethylene. The mixed powder was ingots by a simple tablet molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.) at a spindle compression force of 5 kN to obtain a diameter of 8.0 mm, a plane bevel angle, a weight of 200 mg, and a perylene diphenylamine salt. A rapidly disintegrating ingot in the oral cavity with a salt content of 5 mg. The tablet containing diphenylamineamine hydrochloride in the mouth rapidly disintegrating ingot has a thickness of 3.27 mm, a tablet hardness of 28 N, and an intraoral disintegration time (adult male) of 17 seconds. Furthermore, the diphenylamine hydrochloride hydrochloride contained in the orally rapidly disintegrating tablet obtained in the present embodiment is reduced to about 1/10 (5 mg) per one dose of the adult (for example, 50 mg) per one tablet, and thus It is easy to consider the age, weight, and symptoms of the child being administered and set the dosage.

實施例4 Example 4

(自不具有快速崩解性之含依匹斯汀鹽酸鹽錠劑減少有效成 分量而成的口腔內快速崩解錠之製造方法) (Efficient formation of Epstein-based hydrochloride tablets without rapid disintegration Method for manufacturing a rapidly disintegrating ingot in the oral cavity)

將每1錠含10mg依匹斯汀鹽酸鹽(H1受體拮抗劑)作為有效成分的成人用既存錠劑(SS製藥股份有限公司「Alesion 10」、錠劑重量88mg、作為添加物而含有矽酸酐、乳糖、羥丙甲纖維素、聚乙烯吡咯啶酮、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、聚乙烯二醇、聚矽氧樹脂、硬脂酸鎂、滑石、氧化鈦、玉米澱粉)1錠以研缽擂碎，而獲得含有依匹斯汀鹽酸鹽10mg之粉末88mg。於其中添加以實施例1之方法獲得之造粒物712mg、蔗糖素(San-Ei Gen F.F.I.股份有限公司)8mg，於聚乙烯製的袋中充分混合。使用簡易錠劑成形機(HANDTAB-100、市橋精機股份有限公司)以打錠壓縮力7kN將該混合粉末進行打錠，獲得直徑8.0mm、平面斜角、重量200mg、每1錠依匹斯汀鹽酸鹽含量2.5mg之口腔內快速崩解錠。該含依匹斯汀鹽酸鹽口腔內快速崩解錠之錠劑厚度為3.37mm，錠劑硬度為30N，口腔內崩解時間(成年男性)為11秒。再者，本實施例中所獲得之口腔內快速崩解錠所含的依匹斯汀鹽酸鹽量為每1錠降低至兒童1日標準服用量上限(10mg)之1/4(2.5mg)，因此較容易考慮被投藥之兒童之年齡、體重、症狀而設置投藥量。 An adult preservative tablet (SS Apharmaceutical Co., Ltd. "Alesion 10", a tablet weight of 88 mg, containing 10 mg of eplesine hydrochloride (H1 receptor antagonist) as an active ingredient, is contained as an additive. Phthalic anhydride, lactose, hypromellose, polyvinylpyrrolidone, ethyl acrylate-methyl methacrylate copolymer, polyethylene glycol, polyoxyl resin, magnesium stearate, talc, titanium oxide, corn One tablet of starch was ground in a mortar to obtain 88 mg of a powder containing 10 mg of eplesine hydrochloride. To the mixture, 712 mg of granules obtained by the method of Example 1 and 8 mg of sucralose (San-Ei Gen F. F. I. Co., Ltd.) were added and thoroughly mixed in a bag made of polyethylene. The mixed powder was tableted by a simple tablet molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.) at a spindle compression force of 7 kN to obtain a diameter of 8.0 mm, a plane bevel angle, a weight of 200 mg, and one tablet per epoxide. A rapidly disintegrating ingot in the oral cavity having a hydrochloride content of 2.5 mg. The tablet containing the epitopin hydrochloride rapid disintegration tablet has a thickness of 3.37 mm, a tablet hardness of 30 N, and an intraoral disintegration time (adult male) of 11 seconds. Furthermore, the amount of eplesine hydrochloride contained in the orally rapidly disintegrating ingot obtained in the present example is 1/4 of the upper limit (10 mg) of the standard daily dose of 1 day (2.5 mg per child). Therefore, it is easier to consider the age, weight, and symptoms of the child to be administered and set the dosage.

[產業上之可利用性] [Industrial availability]

根據本發明，可提供一種可容易、確實且安全地進行對兒童之投予、且有效成分量可適當調整之口腔內快速崩解錠，及由容易獲得之既存不具有快速崩解性之成人用錠劑簡便地製造該口腔內崩解錠之實用性製法。 According to the present invention, it is possible to provide an orally rapidly disintegrating ingot which can be administered to a child easily, reliably and safely, and which can appropriately adjust the amount of the active ingredient, and an adult which is easily obtained and which does not have rapid disintegration A practical method for easily producing the orally disintegrating ingot by a tablet.

Claims (6)

一種兒童用口腔內快速崩解錠，其口腔內崩解時間為20秒以內。 A rapid disintegrating ingot in a child's mouth, which has an intraoral disintegration time of less than 20 seconds. 一種兒童用口腔內快速崩解錠之製造方法，其含有對粉末狀態之醫藥組成物添加預先製備之崩解性添加劑摻合物並進行混合、打錠。 A method for producing a rapidly disintegrating ingot in a child's oral cavity, which comprises adding a pre-prepared disintegrating additive blend to a pharmaceutical composition in a powder state, and mixing and tableting. 如申請專利範圍第2項之製造方法，其中，粉末狀態之醫藥組成物係藉由將固體狀醫藥組成物擂碎進行粉末化而獲得者。 The production method of the second aspect of the invention, wherein the pharmaceutical composition in a powder state is obtained by pulverizing a solid pharmaceutical composition. 如申請專利範圍第3項之製造方法，其中，固體狀醫藥組成物為成人用錠劑或硬膠囊劑之固體內容物。 The manufacturing method of claim 3, wherein the solid pharmaceutical composition is a solid content of an adult lozenge or a hard capsule. 如申請專利範圍第2至4項中任一項之製造方法，其中，不對醫藥組成物所含之有效成分進行分離、萃取而添加崩解性添加劑摻合物並進行混合、打錠。 The production method according to any one of claims 2 to 4, wherein the active ingredient contained in the pharmaceutical composition is not separated and extracted, and a disintegrating additive blend is added and mixed and tableted. 一種口腔內快速崩解錠，其係藉由申請專利範圍第2至5項中任一項之製造方法所獲得的兒童用口腔內快速崩解錠；其口腔內崩解時間為20秒以內。 An intra-oral rapid disintegrating tablet obtained by the method of any one of claims 2 to 5, wherein the oral disintegration time is within 20 seconds.