JP3170069B2 - Sustained release granules - Google Patents
Sustained release granulesInfo
- Publication number
- JP3170069B2 JP3170069B2 JP26739392A JP26739392A JP3170069B2 JP 3170069 B2 JP3170069 B2 JP 3170069B2 JP 26739392 A JP26739392 A JP 26739392A JP 26739392 A JP26739392 A JP 26739392A JP 3170069 B2 JP3170069 B2 JP 3170069B2
- Authority
- JP
- Japan
- Prior art keywords
- granules
- dissolution
- particle size
- elution
- coated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- Medicinal Preparation (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は顆粒からの薬物溶出性が
所定時間内において一定になるように制御された徐放性
顆粒剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release granule in which the dissolution of a drug from granules is controlled to be constant within a predetermined time.
【０００２】[0002]
【従来の技術】医薬品等の製剤より薬物を徐々に溶出さ
せて過剰の血中濃度上昇を防ぎ、投与回数を減少させる
ための試みが数多くなされている。製剤技術の進歩によ
り錠剤においては、所定時間一定の溶出性を維持するこ
とが可能となってきた。そして、顆粒剤の分野において
も、素顆粒に種々のコーティングを施して溶出速度をコ
ントロールする技術について多数報告されてきている。2. Description of the Related Art Many attempts have been made to gradually elute drugs from pharmaceutical preparations or the like to prevent an excessive increase in blood concentration and reduce the number of administrations. Advances in formulation technology have made it possible for tablets to maintain a constant dissolution property for a predetermined period of time. In the field of granules, many techniques have been reported for controlling the dissolution rate by applying various coatings to elementary granules.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、顆粒剤
の場合には、目的とする時間内において一定の溶出性、
すなわち０次溶出パターン（直線的溶出）は得られず、
初期に多量溶出し、後期に少量溶出するという一次溶出
パターンとなってしまう。かかる溶出パターンを制御す
る目的で、素顆粒を造粒するときの添加剤やコーティン
グ剤、さらにコーティング量の増減等の検討がなされて
いるが、未だ満足すべき結果は得られていないのが現状
である。従って、本発明の目的は所定時間内において一
定の薬物溶出性を維持するように制御された徐放性顆粒
剤を提供することにある。However, in the case of granules, a certain dissolution property within a target time,
That is, a zero-order elution pattern (linear elution) was not obtained,
A primary elution pattern occurs in which a large amount is eluted early and a small amount is eluted later. For the purpose of controlling such a dissolution pattern, additives and coating agents when granulating elementary granules, further increase and decrease of the coating amount, etc. have been examined, but satisfactory results have not yet been obtained. It is. Accordingly, an object of the present invention is to provide a sustained-release granule controlled so as to maintain a constant drug dissolution property within a predetermined time.
【０００４】[0004]
【課題を解決するための手段】そこで本発明者らは水不
溶性コーティングを施した顆粒個々の溶出パターンとそ
の集合体である一定の粒度分布をもった顆粒の溶出パタ
ーンとを比較研究したところ、個々の顆粒の溶出性は０
次溶出パターンを示すにもかかわらず、その顆粒集合体
は一次溶出パターンとなってしまうこと、さらに粒径の
小さいコーティング顆粒は溶出終了までの時間が短か
く、粒径の大きいコーティング顆粒は溶出終了までの時
間が長く、粒度分布の広い顆粒集合体では一次溶出パタ
ーンとなってしまうことを見出した。そして、かかる知
見に基づき、溶出性の制御手段について検討した結果、
平均粒径が異なり、粒度分布の狭いコーティング顆粒を
複数組み合せれば所定時間内において溶出パターンを０
次に制御し得ることを見出し、本発明を完成するに至っ
た。The present inventors conducted a comparative study on the dissolution pattern of each of the granules having a water-insoluble coating and the dissolution pattern of granules having a certain particle size distribution as an aggregate thereof. Dissolution of individual granules is 0
Despite showing the next elution pattern, the aggregate of granules will have a primary elution pattern, and coated granules with a small particle size will have a short time to complete elution, and coated granules with a large particle size will have completed elution It was found that the primary dissolution pattern was long in the case of a granule aggregate having a long particle size distribution and a wide particle size distribution. And based on such knowledge, as a result of examining the control means of dissolution,
If a plurality of coated granules having different average particle diameters and narrow particle size distributions are combined, the elution pattern becomes zero within a predetermined time.
Next, they found that control was possible, and completed the present invention.
【０００５】すなわち、本発明は、水不溶性コーティン
グが施された顆粒であって、相異なる平均粒径を有し、
かつそれぞれの顆粒集合体の粒度分布が２５０μｍ以下
の範囲である２種以上の顆粒集合体を混合したことを特
徴とする徐放性顆粒剤を提供するものである。[0005] That is, the present invention relates to granules provided with a water-insoluble coating, having different average particle sizes,
It is another object of the present invention to provide a sustained-release granule characterized in that two or more kinds of granules having a particle size distribution of 250 μm or less are mixed.
【０００６】本発明の徐放性顆粒剤は、２種以上の顆粒
を混合して得られるものであり、当該２種以上の顆粒は
それぞれ水不溶性コーティングを施された顆粒であり、
相異なる平均粒径を有し、かつ粒度分布が２５０μｍ以
下の範囲内にあるものである。ここで、当該２種以上の
顆粒は、例えば素顆粒を水不溶性コーティングを施し、
粒度分布が２５０μｍ以下となるように分級する、又は
素顆粒を粒度分布が２５０μｍ以下となるように分級し
た後水不溶性コーティングを施すことにより得られる。The sustained-release granules of the present invention are obtained by mixing two or more kinds of granules, and the two or more kinds of granules are water-insoluble coated granules, respectively.
It has a different average particle size and a particle size distribution within a range of 250 μm or less. Here, the two or more types of granules are, for example, subjected to water-insoluble coating on elementary granules,
It is obtained by classifying the particles so that the particle size distribution becomes 250 μm or less, or by classifying the elementary granules so that the particle size distribution becomes 250 μm or less and then applying a water-insoluble coating.
【０００７】素顆粒は、薬効成分、賦形剤、崩壊剤、結
合剤等を混合し、常法により造粒することにより得られ
る。ここで薬効成分としては、経口投与により薬効が期
待されるものであれば特に制限されない。その他、着色
剤、矯味剤、矯臭剤等を配合することもできる。[0007] Elementary granules are obtained by mixing a medicinal ingredient, an excipient, a disintegrant, a binder and the like and granulating the mixture by a conventional method. Here, the medicinal component is not particularly limited as long as the medicinal effect is expected by oral administration. In addition, a coloring agent, a flavoring agent, a flavoring agent, and the like can be blended.
【０００８】水不溶性コーティングに用いる成分として
は、水不溶性であれば特に制限されないが、エチルセル
ロースやアミノアルキルメタアクリレートコポリマー等
の造膜作用を有する水不溶性高分子；当該水不溶性高分
子とポリエチレングリコール、トリアセチル、クエン酸
トリエチル等の可塑剤等との混合物；ステアリン酸マグ
ネシウムやタルク等の水不溶性物質と水可溶性又は水不
溶性の結合剤や可塑剤等との混合物質等が挙げられる。The components used in the water-insoluble coating are not particularly limited as long as they are water-insoluble, but water-insoluble polymers having a film-forming action such as ethyl cellulose and aminoalkyl methacrylate copolymer; the water-insoluble polymer and polyethylene glycol; Mixtures with plasticizers such as triacetyl and triethyl citrate; and mixtures of water-insoluble substances such as magnesium stearate and talc with water-soluble or water-insoluble binders and plasticizers.
【０００９】得られたコーティング顆粒又は素顆粒の分
級は、粒度分布が２５０μｍ以下、好ましくは１５０μ
ｍ以下の範囲内となるようにふるい等を用いて行なわれ
る。粒度分布が２５０μｍを超える場合は、顆粒からの
薬物溶出パターンが一次的となり、溶出性が一定となら
ない。なお、粒度分布が２５０μｍ以下の範囲内の顆粒
は、通常の造粒手段では得られず、造粒後分級する必要
がある。In the classification of the obtained coated granules or elementary granules, the particle size distribution is 250 μm or less, preferably 150 μm.
This is performed using a sieve or the like so as to be within the range of m or less. When the particle size distribution exceeds 250 μm, the drug elution pattern from the granules becomes primary, and the elution property is not constant. Note that granules having a particle size distribution within a range of 250 μm or less cannot be obtained by ordinary granulation means, and must be classified after granulation.
【００１０】本発明の徐放性顆粒剤は、上記の如くして
得られた粒度分布の狭いコーティング顆粒であって、平
均粒径の異なる２種以上の顆粒を混合することにより、
所望の時間内において一定の薬物溶出性を達成し得る。
すなわち、粒度分布が狭く、平均粒径の小さなコーティ
ング顆粒は溶出終了時間の短かい０次溶出パターンを有
し、一方、粒度分布が狭く、平均粒径の大きなコーティ
ング顆粒は溶出終了時間の長い０次溶出パターンを有す
る。そこで、平均粒径の小さな素顆粒には溶出時間が長
くなるようなコーティングを施し、平均粒径の大きな顆
粒には溶出時間が短かくなるようなコーティングを施し
た後、これらを混合すれば所望時間内で０次溶出パター
ンを有する徐放性顆粒剤が得られる。また、それぞれ０
次溶出パターンを有するがその溶出速度が異なる２種の
コーティング顆粒を組み合せれば、投与直後は速やかに
薬物を溶出して血中濃度を速やかに上昇させ、その後は
徐々に一定速度で薬物を溶出して血中濃度を維持すると
いう特性を有する徐放性顆粒剤が得られる。ここで、コ
ーティングによる溶出速度の調整は、コーティング重
量、コーティング剤組成、コーティング方法等を変化さ
せることにより行なうことができる。またこれらのコー
ティング顆粒は２種を混合してもよく、３種以上を混合
してもよい。なお、これらの平均粒径は通常３５５μｍ
〜１４００μｍの中から選ばれる。The sustained-release granules of the present invention are coated granules having a narrow particle size distribution obtained as described above, and are obtained by mixing two or more types of granules having different average particle sizes.
A constant drug dissolution can be achieved within a desired time.
In other words, coated granules having a narrow particle size distribution and a small average particle size have a zero-order elution pattern with a short dissolution end time, while coated granules having a narrow particle size distribution and a large average particle size have a long dissolution end time. It has the following elution pattern. Therefore, it is desirable that the elementary granules having a small average particle diameter be coated so as to have a long dissolution time, and the granules having a large average particle diameter be coated so as to have a short dissolution time. A sustained-release granule having a zero-order elution pattern in time is obtained. In addition, 0
If two types of coated granules having the following dissolution patterns but different dissolution rates are combined, the drug is immediately eluted immediately after administration and the blood concentration is rapidly increased, and then the drug is gradually eluted at a constant rate. As a result, a sustained release granule having the property of maintaining the blood concentration is obtained. Here, the dissolution rate can be adjusted by changing the coating weight, the coating composition, the coating method, and the like. These coated granules may be used as a mixture of two kinds or as a mixture of three or more kinds. The average particle size of these particles is usually 355 μm.
４００1400 μm.
【００１１】本発明において、０次溶出パターンが得ら
れたのは、コーティング顆粒の溶出パターンを個々のコ
ーティング顆粒の溶出パターンに近づけたことにある。
従って、個々のコーティング顆粒が０次溶出パターンで
はないが、良好な溶出パターンを有する場合にも、本発
明が適用できる。In the present invention, the zero-order elution pattern was obtained because the elution pattern of the coated granules was close to the elution pattern of the individual coated granules.
Therefore, the present invention can be applied to a case where each coated granule does not have a zero-order elution pattern but has a good elution pattern.
【００１２】かくして得られる本発明の徐放性顆粒剤
は、そのまま顆粒剤として供給してもよいし、硬カプセ
ル剤皮に充填してカプセル剤とする等の加工を施して供
給してもよい。また、溶出速度の速い速放性顆粒との組
み合わせや他の薬効成分を含む素顆粒との組み合わせも
可能である。The sustained-release granule of the present invention thus obtained may be supplied as it is as a granule, or may be supplied after processing such as filling into a hard capsule shell to form a capsule. . Further, a combination with a quick-release granule having a high dissolution rate or a combination with an elementary granule containing another medicinal component is also possible.
【００１３】[0013]
【実施例】次に実施例を挙げて本発明を詳細に説明する
が、本発明はこれら実施例に何ら限定されるものではな
い。Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
【００１４】参考例１ アセトアミノフェンを表１の条件で遠心造粒して得た素
顆粒を表２の様にふるいにて分別し、Ｌ顆粒、Ｍ顆粒、
Ｓ顆粒及びＬＭＳ顆粒とした。次に、各顆粒を表３の条
件でコーティングし、それぞれのコーティング顆粒を得
た。Reference Example 1 Elementary granules obtained by centrifugal granulation of acetaminophen under the conditions shown in Table 1 were separated by sieving as shown in Table 2, and L granules, M granules,
These were S granules and LMS granules. Next, each granule was coated under the conditions shown in Table 3 to obtain each coated granule.
【００１５】[0015]
【表１】 [Table 1]
【００１６】[0016]
【表２】 [Table 2]
【００１７】[0017]
【表３】 [Table 3]
【００１８】（１）ＬＭＳ顆粒に２０％コーティングし
た顆粒（ＬＭＳ−２０％と記載し、他の顆粒についても
同様の表記をする）、アセトアミノフェン２２５mg相当
分を用い溶出試験を表４の条件で行なった。その結果、
図１に示すように、粒度分布の広いコーティング顆粒の
場合には、累積溶出率６０〜７０％（約２時間後）程度
まではほぼ０次溶出（パターンが直線）をするものの、
それ以降は溶出率が徐々に減少し曲線となる。また、３
時間目以降は極めて少量しか溶出しない。(1) LMS granules coated with 20% LMS granules (described as LMS-20%, other granules have the same notation), and a dissolution test using 225 mg of acetaminophen equivalent to the conditions in Table 4 Performed in as a result,
As shown in FIG. 1, in the case of coated granules having a wide particle size distribution, although almost zero-order elution (pattern is linear) up to a cumulative elution rate of about 60 to 70% (after about 2 hours),
Thereafter, the elution rate gradually decreases and forms a curve. Also, 3
Only very small amounts elute after the hour.
【００１９】[0019]
【表４】 [Table 4]
【００２０】（２）ＬＭＳ顆粒に２５％コーティングし
た顆粒を表２と同じ粒径幅に分級し、それぞれをＬＭＳ
−２５％Ｓ、ＬＭＳ−２５％Ｍ、ＬＭＳ−２５％Ｌとし
た。その３つの分画から１個をとり、溶出試験を表５の
条件で行なった。その結果、図２に示すように、顆粒１
個の溶出パターンは、１００％近く溶出するまで０次溶
出であり、粒径が小さいほど溶出速度が速く、粒径が大
きいほど溶出速度が遅いことがわかる。(2) The granules obtained by coating 25% of the LMS granules were classified into the same particle size width as in Table 2, and each was subjected to LMS.
-25% S, LMS-25% M, LMS-25% L. One of the three fractions was subjected to a dissolution test under the conditions shown in Table 5. As a result, as shown in FIG.
It can be seen that the elution pattern of the individual is zero-order elution until almost 100% is eluted, the smaller the particle size, the higher the elution speed, and the larger the particle size, the lower the elution speed.
【００２１】[0021]
【表５】 [Table 5]
【００２２】実施例１ 参考例１で作成したコーティング顆粒のＬ、Ｍ及びＳ顆
粒の各グループより溶出終了までの時間が近いＬ−１５
％、Ｍ−２５％及びＳ−３５％を選び重量比１：１：１
に混合し、参考例１（１）と同様にして溶出試験を行な
った。その結果、本発明顆粒剤は累積溶出率８０〜９０
％付近まで０次溶出し、長期間一定の溶出率が維持され
ていることがわかる。Example 1 L-15 of the coated granules prepared in Reference Example 1 which has a shorter time to the end of dissolution than each group of L, M and S granules
%, M-25% and S-35% by weight ratio 1: 1: 1
And a dissolution test was performed in the same manner as in Reference Example 1 (1). As a result, the granule of the present invention has a cumulative dissolution rate of 80 to 90.
%, And it can be seen that a constant elution rate was maintained for a long period of time.
【００２３】実施例２ 参考例１で作成したＬ−３０％及びＳ−１５％を重量比
１：１に混合して同じく溶出試験を行なった。その結果
は図４のように累積溶出率６０〜７０％付近まで速やか
に０次溶出し、その後９０％付近までゆっくりと０次溶
出するパターンとなった。得られた本発明顆粒剤は投与
直後には速やかに溶出して血中濃度を必要な値まで上
げ、その後は徐々に溶出してその血中濃度を維持するこ
とができる。Example 2 L-30% and S-15% prepared in Reference Example 1 were mixed at a weight ratio of 1: 1 and subjected to the same dissolution test. As a result, as shown in FIG. 4, the pattern eluted in the 0th order quickly until the cumulative elution rate reached around 60 to 70%, and then slowly eluted in the 0th order to around 90%. Immediately after administration, the obtained granules of the present invention are rapidly eluted to raise the blood concentration to a necessary value, and thereafter gradually elute to maintain the blood concentration.
【００２４】[0024]
【発明の効果】本発明の徐放性顆粒剤は所定の時間内に
おいて一定速度で薬物を放出するため、これを投与した
場合血中濃度の維持が容易となった。As described above, the sustained-release granules of the present invention release a drug at a constant rate within a predetermined period of time, so that administration thereof facilitates maintenance of blood concentration.
【図１】ＬＭＳ−２０％の溶出試験結果を示す図であ
る。FIG. 1 is a diagram showing the results of a dissolution test of LMS-20%.
【図２】ＬＭＳ−２５％Ｓ、ＬＭＳ−２５％Ｍ、ＬＭＳ
−２５％Ｌそれぞれのうちの顆粒１個の溶出試験結果を
示す図である。FIG. 2: LMS-25% S, LMS-25% M, LMS
It is a figure which shows the dissolution test result of one granule in each of -25% L.
【図３】Ｌ−１５％＋Ｍ−２５％＋Ｓ−３５％（１：
１：１）の溶出試験結果を示す図である。FIG. 3: L-15% + M-25% + S-35% (1:
It is a figure which shows the dissolution test result of 1: 1).
【図４】Ｌ−３０％、Ｓ−１５％及びＬ−３０％＋Ｓ−
１５％（１：１）の溶出試験結果を示す図である。FIG. 4: L-30%, S-15% and L-30% + S−
It is a figure which shows the dissolution test result of 15% (1: 1).
Claims (1)
あって、相異なる平均粒径を有し、かつそれぞれの顆粒
集合体の粒度分布が２５０μｍ以下の範囲である２種以
上の顆粒集合体を混合したことを特徴とする徐放性顆粒
剤。Claims 1. A granule provided with a water-insoluble coating, having two or more kinds of granules having different average particle diameters and a particle size distribution of each granule aggregate of 250 µm or less. Sustained-release granules characterized by being mixed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26739392A JP3170069B2 (en) | 1992-10-06 | 1992-10-06 | Sustained release granules |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26739392A JP3170069B2 (en) | 1992-10-06 | 1992-10-06 | Sustained release granules |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06116140A JPH06116140A (en) | 1994-04-26 |
| JP3170069B2 true JP3170069B2 (en) | 2001-05-28 |
Family
ID=17444230
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP26739392A Expired - Fee Related JP3170069B2 (en) | 1992-10-06 | 1992-10-06 | Sustained release granules |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3170069B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
| WO2006047493A2 (en) | 2004-10-21 | 2006-05-04 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
| US9161918B2 (en) | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| TWI415603B (en) * | 2005-05-20 | 2013-11-21 | Merck Sharp & Dohme | Formulations of suberoylanilide hydroxamic acid and methods for producing same |
| AU2007211210A1 (en) * | 2006-01-31 | 2007-08-09 | Teva Pharmaceutical Industries Ltd. | Oxcarbazepine pharmaceutical formulation and its method of preparation, wherein oxcarbazepine has a broad and multi-modal particle size distribution |
| AU2006337141A1 (en) * | 2006-01-31 | 2007-08-09 | Teva Pharmaceutical Industries Ltd. | Oxcarbazepine pharmaceutical formulation and its method of preparation, wherein oxcarbazepine has a broad and multi-modal particle size distribution |
| SI2120878T1 (en) * | 2007-02-09 | 2014-12-31 | Alphapharm Pty Ltd | A dosage form containing two active pharmaceutical ingredients in different physical forms |
| JP6084355B2 (en) * | 2010-05-06 | 2017-02-22 | 大正製薬株式会社 | Ambroxol-containing preparation particles |
| WO2018124282A1 (en) | 2016-12-28 | 2018-07-05 | 富山化学工業株式会社 | Pharmaceutical composition and method for producing same |
-
1992
- 1992-10-06 JP JP26739392A patent/JP3170069B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06116140A (en) | 1994-04-26 |
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