JPH03148215A - Laminated formulation - Google Patents
Laminated formulationInfo
- Publication number
- JPH03148215A JPH03148215A JP28704889A JP28704889A JPH03148215A JP H03148215 A JPH03148215 A JP H03148215A JP 28704889 A JP28704889 A JP 28704889A JP 28704889 A JP28704889 A JP 28704889A JP H03148215 A JPH03148215 A JP H03148215A
- Authority
- JP
- Japan
- Prior art keywords
- flavoxate hydrochloride
- sustained release
- release
- sustained
- granules
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title abstract description 20
- 238000009472 formulation Methods 0.000 title abstract description 10
- 238000013268 sustained release Methods 0.000 claims abstract description 61
- 239000012730 sustained-release form Substances 0.000 claims abstract description 61
- XOEVKNFZUQEERE-UHFFFAOYSA-N flavoxate hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 XOEVKNFZUQEERE-UHFFFAOYSA-N 0.000 claims abstract description 55
- 229960003064 flavoxate hydrochloride Drugs 0.000 claims abstract description 50
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims abstract description 9
- 229920002472 Starch Polymers 0.000 claims abstract description 6
- 239000008107 starch Substances 0.000 claims abstract description 6
- 235000019698 starch Nutrition 0.000 claims abstract description 6
- 238000010030 laminating Methods 0.000 claims abstract 2
- 239000000463 material Substances 0.000 claims description 34
- 239000002702 enteric coating Substances 0.000 claims description 28
- 238000009505 enteric coating Methods 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 27
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 15
- 229940079593 drug Drugs 0.000 abstract description 22
- 239000003814 drug Substances 0.000 abstract description 22
- 239000000126 substance Substances 0.000 abstract description 17
- 235000019658 bitter taste Nutrition 0.000 abstract description 6
- 238000002156 mixing Methods 0.000 abstract description 5
- 239000008187 granular material Substances 0.000 description 41
- 230000000052 comparative effect Effects 0.000 description 30
- 238000012360 testing method Methods 0.000 description 24
- 239000011248 coating agent Substances 0.000 description 23
- 238000000576 coating method Methods 0.000 description 23
- 229920002261 Corn starch Polymers 0.000 description 14
- 239000008120 corn starch Substances 0.000 description 14
- 229940099112 cornstarch Drugs 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000003405 delayed action preparation Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000454 talc Substances 0.000 description 9
- 229910052623 talc Inorganic materials 0.000 description 9
- -1 etc. Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000007922 dissolution test Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000036325 urinary excretion Effects 0.000 description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 229960000855 flavoxate Drugs 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 239000007931 coated granule Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000005484 gravity Effects 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 230000007721 medicinal effect Effects 0.000 description 3
- 230000027939 micturition Effects 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- KMMBBZOSQNLLMN-UHFFFAOYSA-N 3-methylflavone-8-carboxylic acid Chemical compound O1C2=C(C(O)=O)C=CC=C2C(=O)C(C)=C1C1=CC=CC=C1 KMMBBZOSQNLLMN-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Abstract
Description
本発明は、徐放部分の外側に速放部分が形成される積層
タイプの塩酸フラポキサート徐放性製剤に関する。
更に詳しくは、胃において速やかに溶出する速放部分と
胃では溶出しにくく腸に至って溶出するように放出制御
された徐放部分とが一体となっており、経口的に人に投
与された場合に当該成分の放出を長時間に渡って持続せ
しめ、治療効果を有効にするものである。
従って本発明は医薬品の分野において利用される。The present invention relates to a laminated type sustained release preparation of frapoxate hydrochloride in which an immediate release part is formed outside the sustained release part. More specifically, it consists of an immediate-release portion that dissolves quickly in the stomach and a controlled-release portion that is difficult to dissolve in the stomach and reaches the intestines, and when administered orally to humans. This allows the release of the component to be sustained over a long period of time, thereby making the therapeutic effect effective. Therefore, the present invention finds use in the pharmaceutical field.
従来より塩酸フラボキサート製剤に関しては白糖等を施
した糖衣錠、あるいはヒドロキシプロピルセルロース、
ヒドロキシプロピルメチルセルロース等の皮膜を施した
フィルムコーティング錠、または頚粒が市販され幅広く
使用されている。
これらの塩酸フラボキサート製剤は優れた頻尿および残
尿感治療効果が得られているが、消化管からの吸収がす
みやかでありかつ生物学的半減期が１．２時間と短いこ
とから、薬効持続時間が４〜５時間と短く、従って１日
３回分服する用法にならざるを得ない状況にある。
このために特にこの種の薬物を服用する対象として老人
が多いことを考慮すれば、夜間頻尿による睡眠妨害等の
苦痛を伴うことになる。
このような状況から服用後速やかに薬効を発揮し、しか
も薬効の持続時間が長い塩酸フラボキサート製剤が要望
されているがいまだ有用な製剤の出現を見ていない。
特開昭６３−１５４６１９号公報には塩酸フラボキサー
トを含む速放性顆粒とこれに腸溶性皮膜物質を施した顆
粒を一定の比率で混合し徐放性製剤とする旨の記載がな
されている。
しかしながら本発明者らの詳細な研究によれば、塩酸フ
ラボキサートとほとんどの腸溶性皮膜物質との間には両
者の相互作用による皮膜の不溶化現象が認められ、その
結果腸溶性皮膜物質が溶解する条件下においても皮膜本
来のスムーズな溶解が妨げられ、従って塩酸フラボキサ
ートの放出性に問題を生じることが判明しており、必ず
しも満足すべき徐放性製剤とはいい難い。
またこのタイプの製剤の欠点として両顆粒の投与単位に
おける組成割合が一定し難く幅広いバラツキが見られる
ことが公知の事実として挙げられる。
原因は両顆粒の比重、大きさ、表面状態の違い、帯電性
の違い等の要因からくる混合操作に難しさがあるものと
思われるが、いずれにしても組成割合のバラツキは徐放
性製剤の信頼性、有用性を損なう欠陥である。
更に、周知のように塩酸フラボキサートは強い苦味を有
していることから、服用時のマスキングについても充分
な配慮が必要である。Conventionally, flavoxate hydrochloride preparations are sugar-coated tablets coated with sucrose, etc., or hydroxypropylcellulose,
Film-coated tablets or tablets coated with hydroxypropyl methylcellulose or the like are commercially available and widely used. These flavoxate hydrochloride preparations have been shown to have excellent therapeutic effects on frequent urination and residual urination; however, they are rapidly absorbed from the gastrointestinal tract and have a short biological half-life of 1.2 hours, so their efficacy may not last long. The time required is short, 4 to 5 hours, and the situation is such that the drug must be taken three times a day. For this reason, especially considering that there are many elderly people who take this type of drug, they are accompanied by pain such as sleep disturbance due to nocturnal urination. Under these circumstances, there is a demand for a hydrochloric acid flavoxate preparation that exerts its medicinal effect immediately after administration and has a long duration of medicinal effect, but no useful preparation has yet appeared. JP-A-63-154619 describes that immediate-release granules containing flavoxate hydrochloride and granules coated with an enteric coating material are mixed in a fixed ratio to prepare a sustained-release preparation. However, according to the detailed research conducted by the present inventors, an insolubilization phenomenon of the film due to the interaction between flavoxate hydrochloride and most enteric coating substances has been observed, and as a result, the conditions under which the enteric coating substance dissolves are observed. It has been found that the original smooth dissolution of the film is hindered even at lower temperatures, resulting in problems with the release properties of flavoxate hydrochloride, and it is difficult to say that this is a sustained release preparation that is necessarily satisfactory. Furthermore, it is a known fact that a drawback of this type of preparation is that the composition ratio of both granules in a dosage unit is difficult to maintain and can vary widely. The reason seems to be that there is difficulty in the mixing operation due to factors such as differences in specific gravity, size, surface condition, and chargeability of both granules, but in any case, the variation in composition ratio is due to the difference in the specific gravity, size, surface condition, and chargeability of the two granules. This is a defect that impairs the reliability and usefulness of Furthermore, as is well known, flavoxate hydrochloride has a strong bitter taste, so sufficient consideration must be given to masking when taking it.
本発明者らは以上のような塩酸フラボキサートに係わる
事情に鑑みて、鋭意研究を重ねた結果、塩酸フラボキサ
ートと腸溶性皮膜物質との接触を回避するための特別の
膜層及び特定の腸溶性皮膜物質の組成を見い出したこと
により皮膜物質の不溶化及び薬物の放出性に関する問題
を解消したこと、速放部分と徐放部分を一体化すること
によって組成割合のバラツキに関する問題を解消したこ
と、及び酸可溶性皮膜物質を被覆することによって苦味
等のコンプライアンスに関する問題を改善することがで
き、本発明を完成するに至った。
即ち本発明の目的は上記の塩酸フラボキサートに係わる
諸問題を解消し、服用時あるいは服用後のコンプライア
ンスに関する問題のないしかも安定した治療効果を有す
る塩酸フラボキサート徐放性製剤を提供することにある
。In view of the above circumstances related to flavoxate hydrochloride, the present inventors have conducted intensive research and have developed a special membrane layer and a specific enteric coating to avoid contact between flavoxate hydrochloride and enteric coating material. By discovering the composition of the substance, problems related to insolubilization of the coating material and drug release properties were solved; problems related to variations in composition ratio were solved by integrating the immediate release part and sustained release part; By coating with a soluble coating substance, compliance-related problems such as bitterness can be improved, leading to the completion of the present invention. That is, the purpose of the present invention is to solve the above-mentioned problems associated with flavoxate hydrochloride, and to provide a sustained release preparation of flavoxate hydrochloride that does not have problems with compliance during or after administration and has a stable therapeutic effect.
本発明において速放部分とは投与後胃内において速やか
に薬物を放出し初期の薬効を呈する部分であり、徐放部
分とは胃内では放出せず小腸上部以降のｐＨに至って薬
物を放出し薬効を呈する部分である。
以下に顆粒タイプの側稜を主体に本発明の詳細な説明す
る。但し本発明はこれらの側稜に限定されるものではな
い。
本発明の塩酸フラボキサート徐放性積層製剤を得るため
には、まず徐放部分を調魁する。
徐放部分の調魁方法は特に限定されたものではなく、従
来の押出し造粒、破砕造粒、転勤造粒等の方法を用いる
ことができるが、最も簡便な例としては、遠心流動型コ
ーティング造粒装置を用い、市販球形類粒上に塩酸フラ
ボキサートを順次被覆していく方法がある。
具体的には球形顆粒を遠心流動型コーティング造粒装置
に投入し、遠心力（ローターの回転による）により回転
せしめつつ、同時に造粒機の側壁と回転体との間（スリ
ット）から吹出す空気流により制御された高さまで吹き
上げ、その上方に位置するスプレーガンからショ糖、ヒ
ドロキシプロピルセルロース、ヒドロキシプロピルメチ
ルセルロース、ポリビニルアルコール、ポリビニルピロ
リドン、メチルセルロース等の水溶液あるいは有機溶媒
溶液を噴霧し、同時に造粒機の上方に位置する粉末導入
口より塩酸フラボキサートを含むコーンスターチ、乳糖
、低置換度ヒドロキシプロピルセルロース、結晶セルロ
ース、タルク等の混合粉末を導入して造粒を行う。
続いてこの上に薬物の放出を制御するための腸溶性皮膜
物質を被覆する。
腸溶性皮膜物質としてはセルロースアセテートフタレー
ト、ヒドロキシプロピルメチルセルロースフタレート、
ヒドロキシプロピルメチルセルロースアセテートサクシ
ネート、カルボキシメチルエチルセルロース、メタアク
リル酸アクリル酸エチルコポリマー、メタアクリル酸メ
タアクリル酸メチルコポリマー等が用いられるが、本発
明者らはこれらの腸溶性皮膜物質を被覆した顆粒につい
て日局第２液による溶出試験、又は経時的ｐＨ変化溶出
試験（上野和行、最近の製剤技術とその応用Ｐ、 １２
４、医薬ジャーナル社）等を実施した場合に、はとんど
の腸溶性皮膜物質に皮膜の溶解遅延及びそれに伴う薬物
の放出遅延が生じ、不溶化物が長時間に渡って残存する
現象を見い出した。
原因は不明であるが、いずれにせよ放出調節機構の問題
は徐放性製剤としての有用性を著しく阻害するものであ
る。
本発明者らはかかる欠陥を改善する方法として、両者の
間に一種のバリヤーとしての中間層を形成し、徐放部分
の放出制御機構を保護することを企図した。
この目的の為に、ヒドロキシプロピルセルロース、ヒド
ロキシプロピルメチルセルロース、ポリビニルアルコー
ル、ポリビニルピロリドン、メチルセルロース等の水溶
性高分子物質、乳糖、マンニトール、ショ糖等の水溶性
物質、澱粉、リン酸水素カルシウム等の親水性物質、結
晶セルロース、低置換度ヒドロキシプロピルセルロース
等の膨潤性物質、タルク、ステアリン酸マグネシウム、
高級脂肪酸、高級アルコール等の滑沢効果及び付着防止
目的物質、炭酸ナトリウム、炭酸水素す） ＩＪウム、
炭酸カルシウム等のアルカリ性物質等のそれぞれ性質の
異なる添加物と各々の腸溶性皮膜物質との組合せを逐−
行い、相互作用について詳細に検討を行った。
その結果、これらの大半に不溶化物の残存及び薬物の放
出遅延が認められ、充分な成果が得られなかった中にあ
って、ヒドロキシプロピルメチルセルロースアセテート
サクシネートと中間層形成成分としての澱粉との組合せ
のみが唯一相互作用に対して有効であることを見い出し
、本発明を完成させることができた。
中間層を設ける方法は特に限定されるものではないが、
遠心流動型コーティング造粒装置中で徐放部造粒顆粒１
００重量部に対して１−１００重量部、好ましくは５〜
５０重量部を被覆する方法が良い。
これ以下では均一な中間層を得ることが難しく従って放
出性にバラツキを生じやすく、一方これ以上では中間層
形成成分自身の崩壊性の影響が生じるため好ましくない
。
中間層に用いる澱粉は特別な目的のない限り単独使用が
好ましいが、他の添加物と少量を併用することは可能で
ある。
このようにして中間層を設けた顆粒に対して腸溶性皮膜
物質のヒドロキシプロピルメチルセルロースアセテート
サクシネートを被覆する。その被覆量は徐放部造粒顆粒
１００重量部に対して１〜５０重量部、好ましくは５〜
２０重量部である。これ以下では胃内における対酸性が
不十分となり、またこれ以上では小腸上部以降のｐＨで
の溶解が遅くなりバイオアベイラビリティに問題を生じ
ることになる。
なお、腸溶性皮膜物質中には必要に応じてポリエチレン
グリコール、プロピレングリコール、クエン酸トリエチ
ル、トリアセチン、グリセリン、グリセリン脂肪酸エス
テル等の可塑剤を添加することができる。
以上までの工程で得られた部分が徐放部分である。
次いでその上に、徐放部分の造粒と同じ要領で塩酸フラ
ボキサートを含むコーンスターチ、乳糖、低置換度ヒド
ロキシプロピルセルロース、結晶セルロース、タルク等
の混合粉末を被覆し徐放部分を形成させる。
最終的に塩酸フラボキサートの苦味をマスクするために
、酸可溶性皮膜物質であるポリビニルアセタルジエチル
アミノアセテートを被覆する。その被覆量は徐放部造粒
顆粒１００重量部に対して１〜３０重量部、好ましくは
１〜１５重量部である。これ以下では十分なマスキング
とはならず口中で苦味を生じ、またこれ以上では酸性下
において速やかな溶解を示しにくく従って初期の薬効が
期待できない可能性がある。
更に塩酸フラボキサート製剤を服用する対象に老人が多
いことを考慮するならば、無酸症状というものを軽視す
ることはできない。その場合、上記のコーテイング量で
あれば、ｐＨ６近辺においても日局第１液の酸性条件下
と大きく変らない速放部分の薬物の放出性を示すことが
明らかとなった。
ポリビニルアセタルジエチルアミノアセテートの被覆に
関しては、必要に応じてポリエチレングリコール、プロ
ピレングリコール、クエン酸トリエチル、トリアセチン
、グリセリン、グリセリン脂肪酸エステル等の可塑剤を
添加することができる。
本発明において、速放部分と徐放部分における塩酸フラ
ボキサートの配合比率は、重量比で１＝０．５〜４好ま
しくはｌ：１〜４、特に好ましくは１：２，３である。
配合比が１：０．５より少ない徐放部配合量では、従来
の製品と殆ど同じ血中濃度パターンを示すため、本発明
の持続性目的の達成が困難であり、１：５より大きい徐
放部配合量では投与初期の血中濃度が上がらず、持続時
間を延ばすことができプεIn the present invention, the immediate release portion is the portion that quickly releases the drug in the stomach after administration and exhibits initial drug efficacy, and the sustained release portion is the portion that does not release the drug in the stomach but releases the drug after the pH reaches the upper part of the small intestine. This is the part that exhibits medicinal effects. The present invention will be described in detail below, mainly focusing on the granule type side edges. However, the present invention is not limited to these side edges. In order to obtain the flavoxate hydrochloride sustained release laminated preparation of the present invention, the sustained release portion is first prepared. The method for adjusting the sustained release portion is not particularly limited, and conventional methods such as extrusion granulation, crushing granulation, transfer granulation, etc. can be used, but the simplest example is centrifugal flow coating. There is a method in which flavoxate hydrochloride is sequentially coated onto commercially available spherical particles using a granulation device. Specifically, spherical granules are put into a centrifugal fluid coating granulator and rotated by centrifugal force (due to the rotation of the rotor), while at the same time air is blown out from between the side wall of the granulator and the rotating body (slit). Aqueous or organic solvent solutions of sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, etc. are sprayed from a spray gun located above the flow to a controlled height, and at the same time a granulator is A mixed powder of corn starch containing hydrochloric acid flavoxate, lactose, low-substituted hydroxypropyl cellulose, crystalline cellulose, talc, etc. is introduced from the powder inlet located above to perform granulation. This is then coated with an enteric coating material to control drug release. Enteric coating materials include cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,
Hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, methacrylic acid ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, etc. are used, but the present inventors have developed granules coated with these enteric coating materials. Dissolution test using second liquid or pH change dissolution test over time (Kazuyuki Ueno, Recent Formulation Technology and Its Applications P, 12
4. When conducting tests such as Iyaku Journal Co., Ltd., we found that most enteric coated coating materials experience delayed film dissolution and associated drug release delays, and that insolubilized substances remained for a long period of time. . The cause is unknown, but in any case, the problem with the release control mechanism significantly impedes its usefulness as a sustained release preparation. As a method to improve this defect, the present inventors attempted to form an intermediate layer between the two as a kind of barrier to protect the release control mechanism of the sustained release portion. For this purpose, water-soluble polymer substances such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and methylcellulose, water-soluble substances such as lactose, mannitol, and sucrose, and hydrophilic substances such as starch and calcium hydrogen phosphate are used. Swelling substances such as crystalline cellulose and low-substituted hydroxypropyl cellulose, talc, magnesium stearate,
Substances with lubricant effect and adhesion prevention such as higher fatty acids and higher alcohols, sodium carbonate, hydrogen carbonate)
Combinations of additives with different properties, such as alkaline substances such as calcium carbonate, and each enteric coating substance are sequentially carried out.
We conducted a detailed study of the interactions. As a result, in most of these, residual insolubilized substances and delayed drug release were observed, and satisfactory results were not obtained.However, the combination of hydroxypropyl methyl cellulose acetate succinate and starch as an intermediate layer forming component was found. The present invention was completed by discovering that only one method is effective for interaction. The method of providing the intermediate layer is not particularly limited, but
Sustained release part granules 1 in centrifugal flow type coating granulator
1-100 parts by weight, preferably 5-100 parts by weight
A method of coating 50 parts by weight is preferred. If the amount is less than this, it is difficult to obtain a uniform intermediate layer, and therefore the release properties tend to vary, while if it is more than this, the disintegration of the intermediate layer forming component itself is affected, which is not preferable. Starch used in the intermediate layer is preferably used alone unless there is a special purpose, but it is possible to use small amounts in combination with other additives. The granules thus provided with the intermediate layer are coated with the enteric coating material hydroxypropyl methylcellulose acetate succinate. The coating amount is 1 to 50 parts by weight, preferably 5 to 50 parts by weight, based on 100 parts by weight of the sustained release part granules.
It is 20 parts by weight. If it is less than this, the acid resistance in the stomach will be insufficient, and if it is more than this, the dissolution at the pH in the upper part of the small intestine will be delayed, causing a problem in bioavailability. In addition, a plasticizer such as polyethylene glycol, propylene glycol, triethyl citrate, triacetin, glycerin, glycerin fatty acid ester, etc. can be added to the enteric coating material as necessary. The portion obtained through the steps above is the sustained release portion. Next, a mixed powder of cornstarch containing flavoxate hydrochloride, lactose, low-substituted hydroxypropylcellulose, crystalline cellulose, talc, etc. is coated thereon in the same manner as in the granulation of the sustained-release portion to form the sustained-release portion. Finally, in order to mask the bitter taste of flavoxate hydrochloride, polyvinyl acetal diethylamino acetate, which is an acid-soluble coating material, is coated. The coating amount is 1 to 30 parts by weight, preferably 1 to 15 parts by weight, per 100 parts by weight of the sustained release part granules. If it is less than this, sufficient masking will not be achieved and a bitter taste will occur in the mouth, and if it is more than this, it will be difficult to dissolve quickly under acidic conditions, and therefore initial medicinal efficacy may not be expected. Furthermore, considering that many of the subjects who take flavoxate hydrochloride preparations are elderly, acid-free symptoms cannot be underestimated. In that case, it was revealed that with the above-mentioned coating amount, the drug release properties of the immediate release portion were not significantly different from those of the JP No. 1 solution under acidic conditions even at around pH 6. Regarding the coating of polyvinyl acetal diethylamino acetate, a plasticizer such as polyethylene glycol, propylene glycol, triethyl citrate, triacetin, glycerin, glycerin fatty acid ester can be added as necessary. In the present invention, the blending ratio of flavoxate hydrochloride in the immediate release part and the sustained release part is 1=0.5 to 4, preferably 1:1 to 4, particularly preferably 1:2,3 in terms of weight ratio. If the blending ratio is less than 1:0.5, the blood concentration pattern will be almost the same as that of conventional products, so it will be difficult to achieve the sustainability objective of the present invention. With the release dose, the blood concentration does not increase at the initial stage of administration, and the duration can be extended.
【い。
本発明の塩酸フラボキサート徐放性積層製剤における特
徴の１つとして、速放部分と徐放部分を一体化したこと
が挙げられる。
速放部顆粒と徐放部顆粒の各々を混合して戊るタイプの
側稜では、両顆粒の投与単位における組成割合が一定し
にくくバラツキが大きいことが公知の事実となっている
。この原因は両顆粒の比重、大きさ、表面状態、帯電性
等の要因からくる混合操作にあるものと考えられるが、
いずれにしても組成割合のバラツキは徐放性製剤として
の信頼性、有用性を損なう重大な欠陥である。
本発明者らは塩酸フラボキサートに関して詳細に検討を
行い、その結果これらの欠陥を改善した本発明の積層タ
イプの徐放性製剤を発明したものである。
【実施例】
以下に実施例、比較例、及び試験例をあげて更に詳しく
説明する。
実施例１
市販球形顆粒 （フロイント社製、 商品名 ： ノン
バレル、１４−２０１４−２Ｏ６００ｇを遠心流動型コ
ーティング造粒装置（７０インド社製、商品名： ＣＦ
−３６０）に投入し、ヒドロキシプロピルセルロース（
以下、ＲＰＣという）の５％溶液を噴霧しながら、塩酸
フラボキサート５６０ｇ、コーンスターチ３００ｇ、低
置換度ヒドロキシプロピルセルロース７０ｇ１タルク４
０ｇの混合物を徐々に添加して造粒した後、引き続きコ
ーンスターチ３２（Ｉｇを中間層として被覆した。乾燥
後、５００ｇを流動層コーティング装置（富士産業製、
商品名： ５ＴＲＢ八）に投入し、腸溶性皮膜物質ヒド
ロキシプロピルメチルセルロースアセテートサクシネー
ト（以下、ＡＱＯ＾Ｔ−Ｍという） ５０ｇ、クエン
酸トリエチルｌｏｇ、タルク１５ｇを含むエタノール／
水混合溶液１４００−を噴霧し徐放部顆粒を得た。
次いで徐放ａＢ顧粒５５５ｇを遠心流動型コーティング
造粒装置に投入し、ＮＰＣの５％溶液を噴霧しながら塩
酸フラボキサ−トロ０ｇ１コーンスターチ４５ｇ１タル
ク３ｇの混合物を徐々に添加して速放部分を被覆した。
乾燥後、速放部被覆顆粒５００ｇを流動層コーティング
装置に投入しポリビニルアセタルジエチルアミノアセテ
ート（以下、へＢへという） １５ｇ 、マクロゴール
−６０００３，５ｇ、タルク １．５ｇを含むエタノー
ル溶液３００ｒｎ１を噴霧して本発明の塩酸フラボキサ
ート徐放性積層製剤を得た。
比較例１
実施例１と同様の方法で徐放部分の造粒をした後、中間
層を被覆することなく乾燥を行った。
乾燥後、顆粒５００ｇについて同操作を行い、八〇〇Ａ
Ｔ−Ｍを被覆した徐放部顆粒を得た。
次いで徐放部顆粒５００ｇを遠心流動型コーティング造
粒装置に投入し、）ＩＰＣの５％溶液を噴霧しながら塩
酸フラボキサ−）６５ｇ、コーンスターチ４７ｇ、タル
ク３ｇの混合物を徐々に添加して速放部分を被覆した。
乾燥後、速放部被覆類粒５００ｇを流動層コーティング
装置に投入し、Ａ［ｉＡ １５ｇ 、マクロゴール−６
０００３，５ｇ 、タルク １．５ｇを含むエタノール
溶液３００−を噴霧して塩酸フラボキサート徐放性積層
製剤を得た。
比較例２
比較例１における腸溶性皮膜物質ＡＱＯＡＴ−Ｍの代わ
りに、ヒドロキシプロピルメチルセルロースフタレート
（以下ＨＰ−５５という）を用いて同様の操作を行い、
塩酸フラボキサート徐放性積層製剤を得た。
比較例３
比較例１における腸溶性皮膜物質ＡＱＯＡＴ−Ｍの代わ
りに、メタアクリル酸アクリル酸エチルコポリマー（以
下オイドラギヲ）Ｌ３０ロー５５という）を用いて同様
の操作を行い、塩酸フラボキサート徐放性積層製剤を得
た。
比較例４
比較例１における腸溶性皮膜物質ＡＱＯＡＴ−Ｍの代わ
りに、メタアクリル酸メタアクリル酸メチルコポリマー
（以下オイドラギフ）Ｌ−１００という）を用いて同様
の操作を行い、塩酸フラボキサート徐放性積層製剤を得
た。
比較例５
比較例１における腸溶性皮膜物質ＡＱＯ＾Ｔ−Ｍの代わ
りに、カルボキシメチルエチルセルロース（以下ＣＭＢ
Ｃという）を用いて同様の操作を行い、塩酸フラボキサ
ート徐放性積層製剤を得た。
比較例６
中間層の成分の比較試験として、実施例１における中間
層の成分であるコーンスターチの代りに、ヒドロキシプ
ロピルメチルセルロースを徐放部造粒顆粒に対して重量
比で■０％量被覆して塩酸フラボキサート徐放性積層製
剤を得た。
比較例？
中間層の成分の比較試験として、実施例１における中間
層の成分であるコーンスターチの代りに低置換度ヒドロ
キシプロピルセルロースを、徐放部造粒顆粒に対して重
量比で２０％量被覆して塩酸フラボキサート徐放性積層
製剤を得た。
比較例８
中間層の成分の比較試験として、実施例１における中間
層の成分であるコーンスターチの代りに乳糖を、徐放部
造粒頚粒に対して重量比で２０％量被覆して塩酸フラボ
キサート徐放性積層製剤を得た。
比較例９
実施例１における腸溶性皮膜物質＾ＱＯ＾Ｔ−Ｍの代わ
りに、）ＩＰ−５５を用いて同様の操作を行い、塩酸フ
ラボキサート徐放性積層製剤を得た。
比較例１０
中間層の成分の比較試験として、比較例９における中間
層の成分であるコーンスターチの代りにヒドロキシプロ
ピルメチルセルロースを徐放部造ｒＬＭ粒に対して重量
比でｌＯ％量被覆して塩酸フラボキサート徐放性積層製
剤を得た。
比較例１１
中間層の成分の比較試験として、比較例９における中間
層の成分であるコーンスターチの代りに低置換度ヒドロ
キシプロピルセルロースを、徐放部造粒顆粒に対して重
量比で２０％量被覆して塩酸フラボキサート徐放性積層
製剤を得た。
比較例１２
中間層の成分の比較試験として、比較例９における中間
層の成分であるコーンスターチの代りに乳糖を、徐放部
造粒顆粒に対して重量比で２０％量被覆して塩酸フラボ
キサート徐放性積層製剤を得た。
試験例１
実施例１及び比較例１〜５で得られた顆粒について日局
第１液及び第２液による溶出試験を行った。試験方法は
塩酸フラボキサート ４００ｍｇ相当量の顆粒を第１液
で２時間行った後、試料を第２液に移し、引続き３時間
の試験を行った。各時間でサンプリングを行い、吸光度
法によって溶出量を求めた。液量は９ＱＱｄとし、パド
ル法（１０（ｌｒｐｍ）を用いた。
図１に示したように何れの顆粒も第１液においては速や
かな放出が認められ、速放部分の薬物量３０％を２時間
に渡って維持している。しかしながら第２液においては
かなり様子が異なっており、徐放部上に直接腸溶性皮膜
物質を被覆したＭｒＬが緩慢な放出を示すのに対して、
中間層形ｔＬ酸成分あるコーンスターチを被覆した顆粒
では明らかに速やかな放出が認められる。
表１には溶出試験中の顆粒の状況を示した。
徐放部上に直接腸溶性皮膜物質を被覆した顆粒では皮膜
によって第２液における状況がそれぞれ異なり、ＡＱＯ
ＡＴ−Ｍ、 ＣＭＩｌｉＣ，ｔイドラギフトＬ−１００
が顆粒のまま、又は一部の顆粒が破壊されたカケラ状で
長時間に渡って残存するタイプであるのに対して、ＩＩ
Ｐ−５５１オイドラギフトし３００−５５では、第２液
に移して数分後より顆粒同士の付着！！集が起こり、こ
の付着凝集体が長時間浮遊状態で残存する状況が見受け
られた。
また表２に各々の腸溶性皮膜物質について３例づつの溶
出試験結果を示した。
付着凝集を起こすタイプのものは当然のことながら放出
性に大きなバラツキが見られる。
以上の溶出試験の結果より、塩酸フラボキサートと腸溶
性皮膜物質間の不溶化現象に係わる問題を解消するため
には中間層を設けることが有効であることが判明した。
表２
試験例２
実施例１、比較例６．７．８．９．１（１，１１，１２
で得られた顆粒について試験例１と同様の方法で溶出試
験を実施し、中間層形成成分及び腸溶性皮膜物質の効果
の比較を行った。
図２及び図３に示したように第２液に移行した後の薬物
の放出性においては、コーンスターチを用いた顆粒が最
も速やかな放出を示したのに対してヒドロキシプロピル
メチルセルロース、低ｉｍ度ヒドロキシプロピルセルロ
ース、乳糖を用いた顆粒では、中間層を被覆しない顆粒
に比べれば若干の改善は見られたが（図１参照）、依然
として塩酸フラボキサートと腸溶性皮膜物質との間の相
互作用による不溶化物が認められ、それに伴って緩慢な
薬物の放出性を示すものであった。
また、同図から明らかなように腸溶性皮膜物質としては
ヒドロキシプロピルメチルセルロースアセテートサクシ
ネートがｔｙｋれていることが判明した。
これらの結果より、塩酸フラボキサートと腸溶性皮膜物
質との間の相互作用による皮膜物質の不溶化及び薬物の
放出性に関する問題を改善するためには、徐放部上に澱
粉を必須成分とした中間層を被覆し、これに腸溶性皮膜
物質であるヒドロキシプロピルメチルセルロースアセテ
ートサクシネートを被覆する方法が最も有効であること
が判った。
試験例３
実施例１で得られた本発明の塩酸フラボキサート徐放性
積層製剤を、健康成人に下記の試験条件に従って服用せ
しめ、塩酸フラポキサートの主代謝物である３−メチル
フラボン−８−カルボン酸の尿中***量を測定し、徐放
性製剤の評価を行った。
〔試験条件〕
５名の男子健康成人を被験者とし、絶食時（試験開始１
２時間前より試験当日の朝食）及び軽食後の２条件下に
水１００−と共に服用し、予め設定した採尿スケジュー
ルに従って２４時間まで採取した。
両試験は１週間以上の体薬期間をおいて実施した。
服用量は、それぞれ塩酸フラボキサート徐放性積層製剤
約１．３ｇ（塩酸フラボキサートとして４００ｍｇ含有
）を１日１回、対照としてブラダロン錠１錠（日本新薬
社製、塩酸フラボキサートとして１錠に２０Ｏｎ＋ｇ含
有）を１日１回とした。
〔試験結果〕
試験結果を表３及び図４にそれぞれ示した。
（以下次頁）
表３ヒト投与時における尿中***量に係わるパラメータ
ＲＴ
二体内滞留時間の分散
本発明の塩酸フラポキサート徐放性積層製剤は対照であ
る錠剤と比較してバイオアベイラビリティの低下を伴う
ことなく、徐放性製剤の指標となるべき最高尿中***速
度到達時間の明らかなる遅延、及び平均滞留時間におけ
る大幅な延長（絶食時においては約１．６倍、非絶食時
においては約２倍）が認められており、徐放性製剤とし
て充分なる有用性を備えているものと言える。
加えて最高尿中***速度が通常用量（２００ｍｇ）と同
程度を示すことから、本発明の塩酸フラポキサート徐放
性積層製剤は体内における安全性についても優れている
ものである。【stomach. One of the features of the flavoxate hydrochloride sustained release laminated preparation of the present invention is that the immediate release portion and sustained release portion are integrated. It is a well-known fact that in a type of side ridge in which immediate release part granules and sustained release part granules are mixed and formed, the composition ratio of both granules in a dosage unit is difficult to be constant and varies widely. The reason for this is thought to be the mixing operation, which is caused by factors such as the specific gravity, size, surface condition, and chargeability of both granules.
In any case, variations in the composition ratio are a serious defect that impairs the reliability and usefulness of sustained-release preparations. The present inventors conducted a detailed study on flavoxate hydrochloride, and as a result, invented the layered sustained-release preparation of the present invention, which improves these defects. [Example] A more detailed explanation will be given below with reference to Examples, Comparative Examples, and Test Examples. Example 1 600 g of commercially available spherical granules (manufactured by Freund, trade name: Non-barrel, 14-2014-2O) were added to a centrifugal fluid coating granulator (70 made by India Ltd., trade name: CF).
-360) and hydroxypropyl cellulose (
While spraying a 5% solution of (hereinafter referred to as RPC), 560 g of flavoxate hydrochloride, 300 g of corn starch, 70 g of low-substituted hydroxypropyl cellulose, 1 talc 4
After gradually adding 0 g of the mixture and granulating it, corn starch 32 (Ig) was subsequently coated as an intermediate layer. After drying, 500 g was coated with a fluidized bed coating device (manufactured by Fuji Sangyo Co., Ltd.).
Product name: 5TRB8) and ethanol/containing 50 g of enteric coating material hydroxypropyl methyl cellulose acetate succinate (hereinafter referred to as AQO^T-M), log triethyl citrate, and 15 g of talc.
Aqueous mixed solution 1400- was sprayed to obtain sustained release part granules. Next, 555 g of sustained-release aB pellets were put into a centrifugal flow type coating granulator, and while spraying a 5% solution of NPC, a mixture of 0 g of Flavoxatoro hydrochloride, 45 g of corn starch, and 3 g of talc was gradually added to coat the immediate release portion. did. After drying, 500 g of the immediate release part coated granules were put into a fluidized bed coating device and 300 rn1 of an ethanol solution containing 15 g of polyvinyl acetal diethylaminoacetate (hereinafter referred to as "HeB"), 5 g of macrogol-60003, and 1.5 g of talc was sprayed. The flavoxate hydrochloride sustained release laminated preparation of the present invention was obtained. Comparative Example 1 After granulating the sustained release portion in the same manner as in Example 1, drying was performed without covering the intermediate layer. After drying, perform the same operation on 500g of granules to obtain 800A
Sustained release part granules coated with TM were obtained. Next, 500 g of the sustained release part granules were put into a centrifugal fluid coating granulator, and while spraying a 5% solution of IPC, a mixture of 65 g of flavoxer hydrochloride, 47 g of cornstarch, and 3 g of talc was gradually added to form the immediate release part. coated. After drying, 500 g of immediate-release part-coated granules were put into a fluidized bed coating device, and A [iA 15 g, macrogol-6
An ethanol solution containing 300 g of flavoxate hydrochloride and 1.5 g of talc was sprayed to obtain a sustained-release laminated preparation of flavoxate hydrochloride. Comparative Example 2 The same operation was carried out using hydroxypropyl methyl cellulose phthalate (hereinafter referred to as HP-55) in place of the enteric coating material AQOAT-M in Comparative Example 1.
A sustained-release laminated preparation of flavoxate hydrochloride was obtained. Comparative Example 3 In place of the enteric coating material AQOAT-M in Comparative Example 1, the same operation was carried out using methacrylic acid ethyl acrylate copolymer (hereinafter referred to as Eudragio L30 Rho 55), and a sustained release laminated preparation of flavoxate hydrochloride was prepared. I got it. Comparative Example 4 The same operation was carried out using methacrylic acid methyl methacrylate copolymer (hereinafter referred to as Eudragift L-100) instead of the enteric coating material AQOAT-M in Comparative Example 1, and a flavoxate hydrochloride sustained release laminate was obtained. A formulation was obtained. Comparative Example 5 Carboxymethylethyl cellulose (hereinafter referred to as CMB) was substituted for the enteric coating material AQO^T-M in Comparative Example 1.
A similar operation was performed using (referred to as C) to obtain a sustained-release laminated preparation of flavoxate hydrochloride. Comparative Example 6 As a comparative test of the components of the intermediate layer, instead of cornstarch, which is a component of the intermediate layer in Example 1, hydroxypropyl methyl cellulose was coated on the sustained release part granules in an amount of 0% by weight. A sustained-release laminated preparation of flavoxate hydrochloride was obtained. Comparative example? As a comparative test of the components of the intermediate layer, low-substituted hydroxypropyl cellulose was coated in an amount of 20% by weight on the sustained release part granules instead of cornstarch, which was a component of the intermediate layer in Example 1, and hydrochloric acid was added. A flavoxate sustained release laminated preparation was obtained. Comparative Example 8 As a comparative test of the components of the intermediate layer, lactose was coated in an amount of 20% by weight on the sustained release part granulated neck granules instead of cornstarch, which was a component of the intermediate layer in Example 1, and flavoxate hydrochloride was coated. A sustained release laminated preparation was obtained. Comparative Example 9 The same operation was carried out using IP-55 instead of the enteric coated material ^QO^TM in Example 1 to obtain a sustained-release laminate preparation of flavoxate hydrochloride. Comparative Example 10 As a comparative test of the components of the intermediate layer, instead of cornstarch, which is a component of the intermediate layer in Comparative Example 9, hydroxypropyl methylcellulose was coated on the sustained release part-formed rLM grains in an amount of 10% by weight, and flavoxate hydrochloride was coated. A sustained release laminated preparation was obtained. Comparative Example 11 As a comparative test of the components of the intermediate layer, low-substituted hydroxypropylcellulose was coated in an amount of 20% by weight on the sustained release part granules instead of cornstarch, which is a component of the intermediate layer in Comparative Example 9. A sustained-release laminated preparation of flavoxate hydrochloride was obtained. Comparative Example 12 As a comparative test of the components of the intermediate layer, lactose was coated in an amount of 20% by weight on the sustained release part granules instead of cornstarch, which was a component of the intermediate layer in Comparative Example 9. A release laminated formulation was obtained. Test Example 1 The granules obtained in Example 1 and Comparative Examples 1 to 5 were subjected to a dissolution test using the Japanese Pharmacopoeia No. 1 and No. 2 liquids. The test method was to test granules equivalent to 400 mg of hydrochloric acid flavoxate in the first liquid for 2 hours, then transfer the sample to the second liquid, and then conduct the test for 3 hours. Sampling was performed at each time, and the elution amount was determined by absorbance method. The liquid volume was 9QQd, and the paddle method (10 lrpm) was used.As shown in Figure 1, rapid release of all granules was observed in the first liquid, and 30% of the drug amount in the immediate release portion was However, the behavior of the second solution is quite different, and whereas MrL, which is coated with enteric coating material directly on the sustained release part, shows slow release.
A clear rapid release is observed for the corn starch coated granules containing the intermediate tL acid component. Table 1 shows the condition of the granules during the dissolution test. In the case of granules in which the sustained release part is directly coated with an enteric coating material, the situation in the second liquid differs depending on the coating, and the AQO
AT-M, CMIliC, tHydragift L-100
II is a type that remains as granules or fragments with some of the granules destroyed for a long time, whereas II
With P-551 Eudragift 300-55, the granules start to stick to each other a few minutes after being transferred to the second liquid! ! A situation was observed in which these adhered aggregates remained in suspension for a long time. Furthermore, Table 2 shows the elution test results for three cases of each enteric coating material. Naturally, large variations in release properties can be seen in the types that cause adhesion and aggregation. From the results of the above elution test, it was found that providing an intermediate layer is effective in solving the problem related to the insolubilization phenomenon between flavoxate hydrochloride and the enteric coating material. Table 2 Test Example 2 Example 1, Comparative Example 6.7.8.9.1 (1, 11, 12
A dissolution test was conducted on the granules obtained in the same manner as in Test Example 1, and the effects of the intermediate layer forming component and the enteric coating material were compared. As shown in Figures 2 and 3, in terms of drug release after transfer to the second liquid, granules using corn starch showed the fastest release, while granules using hydroxypropyl methylcellulose and low im Granules using propylcellulose and lactose showed a slight improvement compared to granules that did not coat the intermediate layer (see Figure 1), but insolubilized substances still remained due to the interaction between flavoxate hydrochloride and the enteric coating material. was observed, indicating slow drug release. Further, as is clear from the figure, it was found that hydroxypropyl methylcellulose acetate succinate was used as the enteric coating material. Based on these results, in order to improve the problems related to insolubilization of the coating material and drug release properties due to the interaction between flavoxate hydrochloride and the enteric coating material, it is necessary to create an intermediate layer containing starch as an essential component on the sustained release part. It has been found that the most effective method is to coat the film with hydroxypropyl methyl cellulose acetate succinate, which is an enteric coating material. Test Example 3 The flavoxate hydrochloride sustained release laminated preparation of the present invention obtained in Example 1 was administered to healthy adults according to the test conditions below, and 3-methylflavone-8-carboxylic acid, the main metabolite of flavoxate hydrochloride, was The urinary excretion amount of the drug was measured and the sustained-release formulation was evaluated. [Test conditions] Five healthy adult male subjects were tested during fasting (test start 1).
The urine was taken with 100ml of water under two conditions: 2 hours before (breakfast on the day of the test) and after a light meal, and urine was collected for up to 24 hours according to a preset urine collection schedule. Both tests were conducted after a one week or more period of physical therapy. The dosage was approximately 1.3 g of flavoxate hydrochloride sustained-release laminated preparation (containing 400 mg of flavoxate hydrochloride) once a day, and 1 tablet of Bradalon (manufactured by Nippon Shinyaku Co., Ltd., containing 20 On+g of flavoxate hydrochloride per tablet) as a control. was once a day. [Test Results] The test results are shown in Table 3 and FIG. 4, respectively. (See next page) Table 3 Parameters related to urinary excretion amount during human administration RT Dispersion of residence time in the body The sustained release laminated formulation of frapoxate hydrochloride of the present invention is accompanied by a decrease in bioavailability compared to the control tablet. However, there was a clear delay in the time to reach the maximum urinary excretion rate, which is an indicator for sustained-release preparations, and a significant prolongation of the average retention time (approximately 1.6 times in the fasting state and approximately 2 times in the non-fasting state). 2 times), and it can be said that it has sufficient utility as a sustained-release preparation. In addition, since the maximum urinary excretion rate is comparable to that of the normal dose (200 mg), the sustained-release laminated preparation of frapoxate hydrochloride of the present invention is also excellent in terms of safety in the body.
本発明の塩酸フラボキサート徐放性積層製剤は、塩酸フ
ラボキサートと腸溶性皮膜物質との相互作用による皮膜
物質の不溶化及び薬物の放出性に関する問題を改善する
ために中間層の成分である澱粉と腸溶性皮膜物質である
ヒドロキシプロピルメチルセルロースアセテートサクシ
ネートとを必須成分として用いることにより、安定した
薬物の放出を保証せしめ、徐放性製剤としての有用性を
有意に高めた。
また徐放部分と徐放部分を積層型として一体化すること
によって、従来の混合タイプに較べて安定した徐放部分
と徐放部分の薬物組成割合を持つ製剤を提供することを
可能とし、更に苦味を改善するために酸可溶性皮膜物質
によるマスキング層を設けたことの結果、当薬物が所持
している服用時のコンプライアンスに関する問題をも改
善することができた。
なお、本発明の塩酸フ、ラボキサート徐放性積層製剤は
成人１人あたり１回０．５〜３ｇ（塩酸フラボキサート
として４００ｍｇ）を朝、晩１日２回服用するものであ
る。The flavoxate hydrochloride sustained-release laminated preparation of the present invention is designed to improve the problems associated with insolubilization of the coating material and drug release properties due to the interaction between flavoxate hydrochloride and the enteric coating material. By using hydroxypropyl methylcellulose acetate succinate, which is a coating material, as an essential component, stable drug release was ensured and the usefulness as a sustained release preparation was significantly increased. In addition, by integrating the sustained-release portion and sustained-release portion into a laminated type, it is possible to provide a preparation with a more stable drug composition ratio between the sustained-release portion and sustained-release portion than in the conventional mixed type. As a result of providing a masking layer made of an acid-soluble film material to improve the bitter taste, it was also possible to improve the compliance problem that this drug had when taking it. The sustained-release laminated preparation of flavoxate hydrochloride of the present invention is to be taken per adult at a dose of 0.5 to 3 g (400 mg as flavoxate hydrochloride) twice a day, in the morning and in the evening.
図１は、実施例１及び比較例１，２．３．４．５で得ら
れた各々の腸溶性皮膜物質からなる顆粒の中間層の有無
に関する溶出試験結果を示す。
図２、図３は異なる中間層の成分を用いて実施例１１比
較例６．７．８．９．１０．１１．１２で得られた顆粒
の溶出試験結果を示す。
図４は試験例３における本発明の製剤及び従来の製剤で
あるブラダロン錠投与後の３−メチルフラボン−８−カ
ルボン酸尿中***速度曲線を示す。FIG. 1 shows the dissolution test results regarding the presence or absence of an intermediate layer of granules made of enteric coated materials obtained in Example 1 and Comparative Examples 1, 2, 3, 4 and 5. Figures 2 and 3 show the results of the dissolution test of the granules obtained in Example 11 Comparative Example 6.7.8.9.10.11.12 using different intermediate layer components. FIG. 4 shows 3-methylflavone-8-carboxylic acid urinary excretion rate curves after administration of Bradarone tablets, which are the formulation of the present invention and the conventional formulation, in Test Example 3.
Claims (2)
、（ｃ）腸溶性皮膜物質層、の上記（ａ）〜（ｃ）より
なる徐放部分、 （ｄ）塩酸フラボキサート含有層、（ｅ）酸可溶性皮膜
物質層、の上記（ｄ）及び（ｅ）よりなる速放部分、の
二つの部分を積層してなることを特徴とする、塩酸フラ
ボキサート徐放性積層製剤。(1) A sustained release portion consisting of the above (a) to (c) of (a) a flavoxate hydrochloride-containing layer, (b) an intermediate layer, and (c) an enteric coating material layer; (d) a flavoxate hydrochloride-containing layer; A sustained release multilayer preparation of flavoxate hydrochloride, characterized in that it is formed by laminating two parts: e) an acid-soluble film material layer and an immediate release part consisting of the above (d) and (e).
皮膜物質層の成分がヒドロキシプロピルメチルセルロー
スアセテートサクシネートである請求項１の塩酸フラボ
キサート徐放性積層製剤。(2) The flavoxate hydrochloride sustained release multilayer preparation according to claim 1, wherein the component of the intermediate layer (b) is starch, and the component of the enteric coating material layer (c) is hydroxypropyl methyl cellulose acetate succinate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28704889A JPH03148215A (en) | 1989-11-01 | 1989-11-01 | Laminated formulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28704889A JPH03148215A (en) | 1989-11-01 | 1989-11-01 | Laminated formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03148215A true JPH03148215A (en) | 1991-06-25 |
Family
ID=17712378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28704889A Pending JPH03148215A (en) | 1989-11-01 | 1989-11-01 | Laminated formulation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03148215A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007507491A (en) * | 2003-09-29 | 2007-03-29 | シージェー コーポレーション | Sustained release formulation |
| WO2007073702A2 (en) | 2005-12-29 | 2007-07-05 | Osmotica Corp. | Multi-layered tablet with triple release combination |
| USRE41148E1 (en) | 1998-10-21 | 2010-02-23 | Shire Laboratories, Inc. | Oral pulsed dose drug delivery system |
| US8846100B2 (en) | 2006-05-12 | 2014-09-30 | Shire Llc | Controlled dose drug delivery system |
| WO2023089553A1 (en) * | 2021-11-19 | 2023-05-25 | Berlia Sushma Paul | Controlled release formulations of flavoxate and process for preparation thereof |
-
1989
- 1989-11-01 JP JP28704889A patent/JPH03148215A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE41148E1 (en) | 1998-10-21 | 2010-02-23 | Shire Laboratories, Inc. | Oral pulsed dose drug delivery system |
| USRE42096E1 (en) | 1998-10-21 | 2011-02-01 | Shire LLC, USA | Oral pulsed dose drug delivery system |
| JP2007507491A (en) * | 2003-09-29 | 2007-03-29 | シージェー コーポレーション | Sustained release formulation |
| WO2007073702A2 (en) | 2005-12-29 | 2007-07-05 | Osmotica Corp. | Multi-layered tablet with triple release combination |
| US8846100B2 (en) | 2006-05-12 | 2014-09-30 | Shire Llc | Controlled dose drug delivery system |
| US9173857B2 (en) | 2006-05-12 | 2015-11-03 | Shire Llc | Controlled dose drug delivery system |
| WO2023089553A1 (en) * | 2021-11-19 | 2023-05-25 | Berlia Sushma Paul | Controlled release formulations of flavoxate and process for preparation thereof |
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