JPH01113322A - Acrylic emulsion and ph-independent slowly releasing drug - Google Patents
Acrylic emulsion and ph-independent slowly releasing drugInfo
- Publication number
- JPH01113322A JPH01113322A JP62268804A JP26880487A JPH01113322A JP H01113322 A JPH01113322 A JP H01113322A JP 62268804 A JP62268804 A JP 62268804A JP 26880487 A JP26880487 A JP 26880487A JP H01113322 A JPH01113322 A JP H01113322A
- Authority
- JP
- Japan
- Prior art keywords
- copolymer
- methacrylate
- emulsion
- drug
- coating
- 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
- 239000000839 emulsion Substances 0.000 title claims abstract description 26
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 title claims description 11
- 239000003814 drug Substances 0.000 title abstract description 25
- 229940079593 drug Drugs 0.000 title abstract description 25
- 230000003578 releasing effect Effects 0.000 title abstract 2
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 27
- 229920001577 copolymer Polymers 0.000 claims abstract description 19
- -1 hydroxyalkyl methacrylate Chemical compound 0.000 claims abstract description 13
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims abstract description 11
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims abstract description 7
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 15
- 230000003111 delayed effect Effects 0.000 claims description 11
- 229920006243 acrylic copolymer Polymers 0.000 abstract description 9
- 239000000178 monomer Substances 0.000 abstract description 9
- 238000007720 emulsion polymerization reaction Methods 0.000 abstract description 6
- 230000004927 fusion Effects 0.000 abstract description 3
- 125000005250 alkyl acrylate group Chemical group 0.000 abstract 1
- 230000000979 retarding effect Effects 0.000 abstract 1
- 238000010828 elution Methods 0.000 description 16
- 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 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000008101 lactose Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 8
- 239000011162 core material Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000004014 plasticizer Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000003999 initiator Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 238000012360 testing method Methods 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
- 229920003134 Eudragit® polymer Polymers 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 210000002429 large intestine Anatomy 0.000 description 3
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 102220289725 rs778831047 Human genes 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- 102100026735 Coagulation factor VIII Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 206010053649 Vascular rupture Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- KCAMXZBMXVIIQN-UHFFFAOYSA-N octan-3-yl 2-methylprop-2-enoate Chemical compound CCCCCC(CC)OC(=O)C(C)=C KCAMXZBMXVIIQN-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- OQUKIQWCVTZJAF-UHFFFAOYSA-N phenol;sulfuric acid Chemical compound OS(O)(=O)=O.OC1=CC=CC=C1 OQUKIQWCVTZJAF-UHFFFAOYSA-N 0.000 description 1
- 229920005597 polymer membrane Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、アクリル系共重合体の水系エマルジョン、ア
クリル系共重合体の被膜、およびかかる被膜を有するｐ
Ｈ非依存性の遅延放出型製剤に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to an aqueous emulsion of an acrylic copolymer, a coating of an acrylic copolymer, and a polymer having such a coating.
This invention relates to H-independent delayed release formulations.
従来の技術
近年、薬物を体内の目的部位に作用させる方法としてＤ
Ｄ Ｓ （Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ Ｓｙｓｔｅ
ｍ）と呼ばれるシステムが注目されている。ＤＤＳは、
薬物を病的部位や組織に、より選択的、効率的に作用さ
せることを目的とするもので、目標部位に、有効な最小
限の薬剤を投与し、有効濃度を長期間持続させるもので
ある。このため、薬剤による副作用が減少し、また投与
回数が減るため弘者の苦痛が低減し、治療の省力化も可
能となる。このためには薬剤中の有効成分の放出の開始
時間と放出速度を調節する技術、すなわち遅延放出性（
徐放性）が必要となる。Conventional technology In recent years, D
DS (Drug Delivery System)
A system called m) is attracting attention. DDS is
The aim is to make drugs act more selectively and efficiently on diseased areas and tissues, by administering the minimum amount of effective drug to the target area and maintaining the effective concentration for a long period of time. . Therefore, the side effects of the drug are reduced, and the number of administrations is also reduced, which reduces the patient's pain and saves labor in treatment. To this end, techniques for adjusting the onset time and rate of release of the active ingredient in the drug, i.e. delayed release (
sustained release) is required.
このようなりＤＳ製剤の１つとして、腸溶性製剤がある
。これはカルボキシル基を有する高分子のエマルジョン
を製剤にコーティングしたものであり、高分子膜溶解の
ｐＨ依存性を利用するものである。したがって、該製剤
は、胃の酸性条件下では溶出せず、腸へ製剤が移行し環
境ｐＨが上昇することによってはじめて溶解し、活性成
分の大腸への溶解溶出を行う。One such DS preparation is an enteric-coated preparation. This is a preparation coated with an emulsion of a polymer having carboxyl groups, and utilizes the pH dependence of polymer membrane dissolution. Therefore, the preparation does not dissolve under the acidic conditions of the stomach, but dissolves only when the preparation moves into the intestine and the environmental pH increases, and the active ingredient dissolves and elutes into the large intestine.
発明が解決しようとする問題点
しかしながら、人の胃酸の分泌には個人差があり、また
満腹時であるか、空腹時であるかによってもｐＨ値は変
化し、投与後の薬剤が放出されるに至る時間は大きく変
動する。このため、各種条件により血中への薬物の移行
量が変動し、人体に対し副作用などの重大な障害をもた
らす恐れがある。Problems to be Solved by the Invention However, there are individual differences in the secretion of gastric acid, and the pH value changes depending on whether the patient is full or fasting, and the drug is released after administration. The time it takes to reach this point varies widely. Therefore, the amount of drug transferred into the blood varies depending on various conditions, which may cause serious problems such as side effects to the human body.
また、例えば薬剤の腸内放出などもともとｐＨ変化のな
い場所において遅延放出特性が必要とされる場合もあり
、このような要望に応えるｐＨ非依存性の遅延放出性製
剤の出現も望まれる。Further, there are cases where delayed release characteristics are required in places where pH does not change, such as when a drug is released into the intestine, and it is desired that a pH-independent delayed-release preparation be developed to meet such needs.
かかるｐＨ非依存性の製剤としては、従来、有機溶媒系
の溶媒を用いた溶液により被膜を形成したものがあるが
、製剤中に残留有機溶媒が含まれる恐れがあり、また製
造時の環境衛生面からも問題がある。Conventionally, such pH-independent preparations have been made by forming a film with a solution using an organic solvent, but there is a risk that the preparation may contain residual organic solvent, and there is also a risk of environmental sanitation during manufacturing. There are also problems from this perspective.
一方、ｐＨ非依存性の被膜を形成する水系のエマルジョ
ンコーティング剤としてＥ ｕｄｒａｇｉｔＥ３０Ｄ（
ＥＡ−ＥＭＡ−ＭＡ−ＭＭＡ共重合体）、Ｅｕｄｒａｇ
ｉｔ Ｒ５３０Ｄ（２−トリメチルアンモニウムエチル
メタクリレート等からなる共重合体）などがある。しか
しながら、Ｅｕｃｌｒａｇｉｔ Ｅ３０Ｄにより得られ
た被膜は軟化点が低くすぎ、これを被膜とする製剤は常
温で付着、凝集、融着を生じる。これに対し、Ｅｕｄｒ
ａｇｉｔ Ｒ３３０Ｄは軟化点が高すぎ可塑剤の添加を
行うか、あるいは製剤時の加熱操作を行わないと被膜が
形成されず、製剤時のコーティング操作が極めて困難と
なる。また、得られた製剤は付着、凝集も生じやすい。On the other hand, Eudragit E30D (
EA-EMA-MA-MMA copolymer), Eudrag
it R530D (a copolymer consisting of 2-trimethylammonium ethyl methacrylate, etc.). However, the softening point of the film obtained with Euclragit E30D is too low, and preparations using this film as a film tend to adhere, aggregate, and fuse at room temperature. On the other hand, Eudr
agit R330D has a too high softening point and will not form a film unless a plasticizer is added or a heating operation is performed during formulation, making coating operations during formulation extremely difficult. Furthermore, the obtained preparation is likely to cause adhesion and aggregation.
本発明は、消化器官内などにおける薬物放出に至るまで
の滞留時間を長く設定しえ、かつその制御の容易な水系
エマルジョン由来の被膜を有するｒ＋ Ｈ非依存型の遅
延放出性製剤を提供することを目的とする。An object of the present invention is to provide an r+H-independent delayed-release preparation having a coating derived from an aqueous emulsion, which allows a long residence time until drug release in the digestive tract and the like, and which can be easily controlled. With the goal.
また、本発明の他の目的はかかる遅延放出性製剤の被膜
形成に用いられる水系エマルジョン、および該製剤の外
部被膜として好ましい共重合体被膜を提供することを目
的とする。Another object of the present invention is to provide an aqueous emulsion for use in forming a coating for such delayed-release preparations, and a copolymer coating that is preferable as an outer coating for such preparations.
問題点を解決するための手段
本発明者らは、前記問題点を解決すべく鋭意研究を行っ
た結果、ハイドロキシアルキルメタクリレートをコモノ
マーとするアクリル系共重合体の外部被膜を製剤に施す
ことにより良好な薬剤の遅延放出性が得られることを知
り本発明を完成するに至った。Means for Solving the Problems The inventors of the present invention have conducted intensive research to solve the above problems, and as a result, it has been found that by applying an outer coating of an acrylic copolymer containing hydroxyalkyl methacrylate as a comonomer to the formulation, a better solution can be obtained. They found that delayed release of drugs can be obtained and completed the present invention.
すなわち、本発明はアクリル酸アルキルエステル、メタ
クリル酸アルキルエステル、およびハイドロキシアルキ
ルメタクリレートからなる共重合体の外部被膜を有する
ことを特徴とするｐＨ非依存性遅延放出型製剤を提供す
るものである。That is, the present invention provides a pH-independent delayed-release preparation characterized by having an outer coating of a copolymer consisting of an acrylic acid alkyl ester, a methacrylic acid alkyl ester, and a hydroxyalkyl methacrylate.
さらに本発明は、アクリル酸アルキルエステル、メタク
リル酸アルキルエステル、およびハイドロキシアルキル
メタクリレートの共重合体からなることを特徴とする水
系エマルジョンおよび被膜を提供するものである。Furthermore, the present invention provides an aqueous emulsion and a film characterized by comprising a copolymer of an acrylic acid alkyl ester, a methacrylic acid alkyl ester, and a hydroxyalkyl methacrylate.
本発明製剤の共重合体からなる被膜はコモノマーとして
ハイドロキシアルキルメタクリレートを用いたため膜の
軟化点より低い温度でコーティングが可能となり、また
保存中に融着、溶出特性の変化がない。また、体内にお
いて一定時間溶出せずに所定時間後に薬剤を放出する。Since the coating made of the copolymer of the formulation of the present invention uses hydroxyalkyl methacrylate as a comonomer, it can be coated at a temperature lower than the softening point of the coating, and there is no change in fusion or elution characteristics during storage. Moreover, the drug is released after a predetermined time without dissolving in the body for a predetermined time.
本発明製剤の被膜を形成するアクリル系共重合体のモノ
マーであるアクリル酸アルキルエステルとしては、メチ
ルアクリレート、エチルアクリレート、ブヂルアクリレ
ート、２−エチルヘキシルアクリレートなどの公知のア
クリル酸エステルが挙げられ、特にエチルアクリレート
が好ましい。Examples of the acrylic acid alkyl ester, which is a monomer of the acrylic copolymer forming the coating of the present invention, include known acrylic esters such as methyl acrylate, ethyl acrylate, butyl acrylate, and 2-ethylhexyl acrylate. Ethyl acrylate is preferred.
また、メタクリル酸アルキルエステルとしてはメチルメ
タクリレート、エチルメタクリレート、ブチルメタクリ
レート、エチルへキシルメタクリレートなどが挙げられ
、特にエチルメタクリレートが好ましい。Examples of the methacrylic acid alkyl ester include methyl methacrylate, ethyl methacrylate, butyl methacrylate, and ethylhexyl methacrylate, with ethyl methacrylate being particularly preferred.
さらに、ハイドロキシアルキルメタクリレートとしては
、特に２−ハイドロキンメチルメタクリレートか好まし
い。Further, as the hydroxyalkyl methacrylate, 2-hydroquine methyl methacrylate is particularly preferred.
上記モノマーの共重合比は、アクリル酸アルキルエステ
ル／メタクリル酸アルキルエステル−３／１〜１／３で
あるのが好ましい。アクリル酸アルキルエステルがこれ
より多いと被膜がやわらか過ぎ得られた製剤がベタつく
。またメタクリル酸アルキルエステルの割合がこの範囲
を上回ると被膜が硬く脆くなり良好な被膜が形成されな
い。The copolymerization ratio of the monomers is preferably acrylic acid alkyl ester/methacrylic acid alkyl ester - 3/1 to 1/3. If the amount of acrylic acid alkyl ester is more than this, the coating will be too soft and the resulting preparation will be sticky. Furthermore, if the proportion of the methacrylic acid alkyl ester exceeds this range, the film becomes hard and brittle, and a good film cannot be formed.
また、ハイドロキシアルキルメタクリレートの配合量は
、前記２種類のモノマーの和に対してモル比で１７２〜
１／１０であるのが好ましい。ハイドロキシアルキルエ
ステルの量が、この範囲より少ないと薬剤の溶出が遅く
なりすぎ、一方、この範囲を越えると溶出が早くなりす
ぎるため実用に供しえなくなる。In addition, the amount of hydroxyalkyl methacrylate blended is 172 to 172 molar ratio to the sum of the two types of monomers.
Preferably it is 1/10. If the amount of hydroxyalkyl ester is less than this range, the elution of the drug will be too slow, while if it exceeds this range, the elution will be too fast, making it impractical.
前記アクリル系共重合体を製造するには乳化重合を行い
水系の共重合エマルジョンを得る。乳化重合の方法とし
ては、例えばＭｏ１ｄａｙら（Ｊ、ＣｅｌｌＢｉｏｌｏ
ｇｙ、 ６４．７５（１９７５）の方法に準じて行うの
が好ましい。すなわち、乳化剤を溶かした蒸留水中に所
定の割合で混合したモノマーを加え乳化する。To produce the acrylic copolymer, emulsion polymerization is performed to obtain an aqueous copolymer emulsion. As a method of emulsion polymerization, for example, Mo1day et al. (J, Cell Biolo
It is preferable to carry out the method according to the method of J. gy, 64.75 (1975). That is, monomers mixed at a predetermined ratio are added to distilled water in which an emulsifier is dissolved and emulsified.
これを反応容器中、窒素流通下で撹拌し、ついでこれに
反応開始剤を加える。一定時間反応を続け、反応中、適
宜反応開始剤を添加する。反応終了後、反応液をフルイ
に通し、粗大固体（非乳化固体）を取り除く。This is stirred in a reaction vessel under nitrogen flow, and then a reaction initiator is added thereto. The reaction is continued for a certain period of time, and a reaction initiator is appropriately added during the reaction. After the reaction is complete, the reaction solution is passed through a sieve to remove coarse solids (non-emulsified solids).
なお、乳化重合に用いられる乳化剤としてはドデシル硫
酸ナトリウム（ＳＤＳ） 、また反応開始剤として過硫
酸アンモニウム（ＡＰ Ｓ ）などアクリル系モノマー
の乳化重合に用いられる従来公知の乳化剤、開始剤がい
ずれも用い得る。Note that any of the conventionally known emulsifiers and initiators used in the emulsion polymerization of acrylic monomers can be used, such as sodium dodecyl sulfate (SDS) as the emulsifier used in the emulsion polymerization, and ammonium persulfate (APS) as the reaction initiator. .
本発明の徐放性製剤を製造するには、このようにして得
られた共重合体エマルジョンを用いて所定の活性成分を
含む薬剤をコーティング（マイクロカプセル化）する。To produce the sustained-release preparation of the present invention, the copolymer emulsion thus obtained is used to coat (microencapsulate) a drug containing a predetermined active ingredient.
マイクロカプセル化はゐ動造粒装置などの造粒装置を用
い、例えばＷｕｒｓｔｅｒ法にて製剤のコーティングを
行う。すなわち、所定の活性成分を含有する薬剤を造粒
装置に仕込みスプレーノズルより前記エマルジョンを添
加しコーティングを行う。For microencapsulation, a granulation device such as a moving granulation device is used, and the preparation is coated by, for example, the Wurster method. That is, a drug containing a predetermined active ingredient is charged into a granulating device, and the emulsion is added through a spray nozzle to perform coating.
寒檄鯉
つぎに本発明を実施例にもとづき更に具体的に説明する
。実施例にて得られた製剤の溶出試験はつぎの方法によ
り行った。Next, the present invention will be explained in more detail based on examples. The dissolution test of the preparations obtained in the examples was conducted by the following method.
富山産業製ＮＴＲ５Ｓ３型溶出試験機を用い、日周ＸＩ
バドル法にて行った。回転速度は２００ｒｐｍ、試験液
は日局第２液を用いた。試験に供する試料は、乳糖の場
合は１００ Ｈ、ツェナセチンの場合は５０ｍｇを含む
債とした。試料は溶出試験の直前１２時間、減圧デシケ
ータ中室温で乾燥した。溶出開始後、１時間毎（実施例
１０では２時間毎）に１ｍＱのサンプル液を濾過して抜
き取り、乳糖はフェノール硫酸法にて呈色させ波長４８
５ｎｍで、またツェナセチンは波長２４５ｎｍでＵＶ
１９０（（株）島津製作所製）を用い比色定量した。１
０時間（実施例１０では２４時間）の溶出後、試験液中
に高分子の虫に応じて、４〜ｌｏｍ１２のクロロホルム
を加え、ホモミキサーでマイクロカプセルを破壊し、１
００％溶出量を同様に測定した。Diurnal cycle XI using Toyama Sangyo NTR5S3 type dissolution tester
I did it using the badr method. The rotation speed was 200 rpm, and the test liquid used was Japanese Pharmacopoeia No. 2 liquid. The samples used for the test were bonds containing 100 H in the case of lactose and 50 mg in the case of zenacetin. Samples were dried at room temperature in a vacuum desiccator for 12 hours immediately prior to dissolution testing. After the start of elution, 1 mQ of sample liquid was filtered and extracted every hour (every 2 hours in Example 10), and the lactose was colored using the phenol-sulfuric acid method and treated at a wavelength of 48.
5 nm, and zenacetin has a UV wavelength of 245 nm.
190 (manufactured by Shimadzu Corporation) for colorimetric determination. 1
After elution for 0 hours (24 hours in Example 10), 4 to 12 mL of chloroform was added to the test solution depending on the polymeric insects, and the microcapsules were destroyed with a homomixer.
00% elution amount was measured in the same manner.
製造例１〜９（エマルジョンの調製） 乳化重合は、Ｍｏ１ｄａｙらの方法を修正して行った。Production Examples 1 to 9 (Preparation of emulsion) Emulsion polymerization was carried out by modifying the method of Mo1day et al.
後記第１表に示す所定の割合のモノマー〔エチルアクリ
レート（ＥＡ）、メチルメタアクリレート（ＭＭＡ）お
よび２−ハイドロキシエチルメタアクリレ−） （ＨＥ
ＭＡ）、いずれも牛丼化学（株）製〕を含む混合物４３
３９を調製した。５ＤＳ（牛丼化学（株）製）４９を溶
かした蒸留水１３００ｇに前記モノマー混合物を加え、
ホモミキサー（４Ｃ１特殊機化工業）を用いて乳化した
。これを口頚フラスコ中、窒素流通下、８０°Ｃで撹拌
した。反応開始剤ＡＰＳ（牛丼化学（株）製）２ｇを蒸
留水３０９に溶解、水冷し、このＩｍＱをさきの８０℃
に加温した乳液中に添加した。３時間の反応中、３０分
置きにＡＰＳ水溶液］ｎＪを添加した。反応終了後、反
応液をフルイ（８０メツシユ）に通し、粗大固体を取り
除いた。高分子としての収率はほぼ１００％であった。Monomers [ethyl acrylate (EA), methyl methacrylate (MMA) and 2-hydroxyethyl methacrylate] (HE) in the predetermined proportions shown in Table 1 below.
MA), both manufactured by Gyudon Kagaku Co., Ltd.] Mixture 43
No. 39 was prepared. Add the monomer mixture to 1300 g of distilled water in which 5DS (manufactured by Gyudon Kagaku Co., Ltd.) 49 was dissolved,
It was emulsified using a homomixer (4C1 Tokushu Kika Kogyo). This was stirred in a neck flask at 80°C under nitrogen flow. 2 g of the reaction initiator APS (manufactured by Gyudon Kagaku Co., Ltd.) was dissolved in distilled water 309, cooled with water, and the ImQ was heated to 80°C.
It was added to the emulsion heated to . During the 3 hour reaction, nJ of APS aqueous solution was added every 30 minutes. After the reaction was completed, the reaction solution was passed through a sieve (80 mesh) to remove coarse solids. The yield as a polymer was almost 100%.
結果をつぎの第１表に示す。The results are shown in Table 1 below.
第 １ 表
（モノマー比）
ＥＡ １２ １２ １２ ９ ９ ９
６ ６ ６ＭＭＡ ６ ６ ６
９ ９ ９ １２ １２ １２（エマルジョン）
固形分（％） ２２．８２２．９２０．８２２．２２
２，７２１．４２３，１２１．１２２．６実施例１〜９
（乳糖のマイクロカプセル化）流動造粒装置（ＣＰＣＧ
−１、Ｇ １ａｔｔ社製）を使用しＷｕｒｓｔｅｒ法に
よりマイクロカプセル化を行った。芯物質として各々乳
糖（ＤＭＶ、５０メツンユ）５００ｇを仕込み、製造例
１〜９にて得られた各アクリル系共重合体エマルジョン
をコーティングした。Table 1 (monomer ratio) EA 12 12 12 9 9 9
6 6 6MMA 6 6 6
9 9 9 12 12 12 (emulsion) Solid content (%) 22.822.920.822.22
2,721.423,121.122.6 Examples 1-9
(Microencapsulation of lactose) Fluid granulation equipment (CPCG)
Microencapsulation was performed using the Wurster method using G-1, manufactured by G 1att Co., Ltd.). 500 g of lactose (DMV, 50 mt) was added to each sample as a core material, and coated with each acrylic copolymer emulsion obtained in Production Examples 1 to 9.
芯物質に対するコーテイング量は、１０．２０．３０．
４０．５０．６０％の６種類とした。コーティング条件
は、パーティションと底盤との間隔２５關、バグフィル
タ−の目あい２５μ肩、スプレーノズル径０ 、８ ｍ
ｍとした。コーティング中の造粒装置の運転条件は吸気
温度４０〜６０°Ｃ１排気温度２７〜３２℃、フラップ
目盛４８〜５２％、送風速度１゜１ ＝ １ 、７ ｍ
３／ｍｉｎ、送液速度３．５〜８．５ｍ１２／ｍｉｎ
、スプレー圧２．１〜２ 、４ ａｔｍの範囲で適宜調
整した。なお、スプレー液は合成したエマルジョンを希
釈せず原則として添加剤も加えず使用した。The amount of coating relative to the core material is 10.20.30.
There were 6 types of 40.50.60%. The coating conditions were: the distance between the partition and the bottom plate was 25 mm, the gap between the bag filters was 25 μ, and the spray nozzle diameter was 0, 8 m.
It was set as m. The operating conditions of the granulator during coating are: intake air temperature 40-60°C, exhaust temperature 27-32°C, flap scale 48-52%, air blowing speed 1°1 = 1,7 m.
3/min, liquid feeding speed 3.5-8.5m12/min
The spray pressure was appropriately adjusted within the range of 2.1 to 2.4 atm. In addition, the spray liquid was used without diluting the synthesized emulsion and without adding any additives in principle.
エマルジョン中の固形分は２０〜２３％であった。The solids content in the emulsion was 20-23%.
得られた製剤の被膜はＥＡの多いものほど柔らかく、Ｅ
Ａ ：ＭＭＡ ： ＨＥＭＡのモル比が６：１２：（４
〜６）のエマルジョンの場合、生成する膜の硬度が高く
、膜形成に困難を生じたため、可塑剤として高分子に対
して１０％のトリアセチンを加えた。The film of the obtained preparation is softer as the amount of EA increases;
A: MMA: HEMA molar ratio is 6:12:(4
In the case of emulsions 6) to 6), the hardness of the produced film was high and it was difficult to form the film, so 10% triacetin was added to the polymer as a plasticizer.
得られた製剤を前記溶出試験に供した。製造例１．５．
８のエマルジョンを用いた製剤の乳糖溶出曲線を第１〜
３図に示す。なお、溶出曲線は各々図中左より芯物質に
対するコーテイング量が１０．２０．３０．４０．５０
．６０％のものを示す。The obtained formulation was subjected to the dissolution test described above. Production example 1.5.
The lactose elution curves of formulations using emulsions No. 8 to 1
Shown in Figure 3. In addition, the elution curves are shown from the left in the figure, with the coating amount relative to the core material being 10, 20, 30, 40, and 50.
．． 60% is shown.
また、製造例７にて得られたエマルジョンにより乳糖を
コーティング（芯物質に対し６０％）した製剤の溶出試
験結果を第４図に示す。図中〇−〇はコーティング時可
塑剤を添加しなかった場合（被膜の軟化点７２°Ｃ）、
・−・は可塑剤トリアセチンを１０％添加した場合（被
膜の軟化点５０’Ｃ）を示す。なお、△−△はＥｕｄｒ
ａｇｉｔ Ｒ５３０Ｄを、 用いて被膜（軟化点５０°
Ｃ・クエン酸トリエチル１０％添加）を形成した製剤の
溶出曲線を示す。従来の水系エマルジョンＥ ｕｄｒａ
ｇｉｔでは可塑剤がないと被膜が形成されず、遅延放出
性を付与するに ・は、さらに可塑剤を加え軟化点を
下げなければならない。その結果、製品の付着、融着が
生じやすくなる。Further, the results of the dissolution test of the formulation coated with lactose (60% based on the core substance) using the emulsion obtained in Production Example 7 are shown in FIG. 〇-〇 in the figure indicates the case where no plasticizer was added during coating (softening point of the coating was 72°C).
. . . indicates the case where 10% of the plasticizer triacetin was added (the softening point of the film was 50'C). In addition, △−△ is Eudr
agit R530D was used to coat (softening point 50°
1 shows the dissolution curve of a formulation formed with C.triethyl citrate (10% addition). Conventional water-based emulsion E udra
With git, a film cannot be formed without a plasticizer, and in order to provide delayed release properties, a plasticizer must be added to lower the softening point. As a result, adhesion and fusion of products are likely to occur.
実施例１Ｏ
微粉砕したツェナセチン３０ｇを懸濁した３％ＰＶＰ水
溶液を調製した。これを乳糖３００ｇに対して用いて、
あらかじめ芯物質のアンダーコーティングを行った。つ
いで前記製造例６にて得られたアクリル系共重合体エマ
ルジョンを用い、前記実施例と同様にしてマイクロカプ
セル化した。ただし芯物質に対するコーテイング量は２
０．４０．６０．８０．１００．１２０％の６種類とし
た。Example 1O A 3% aqueous PVP solution in which 30 g of finely ground zenacetin was suspended was prepared. Use this for 300g of lactose,
The core material was undercoated in advance. Next, using the acrylic copolymer emulsion obtained in Production Example 6, microcapsules were formed in the same manner as in the Example. However, the amount of coating on the core material is 2
There were six types: 0.40.60.80.100.120%.
溶出試験の結果を第５図（乳糖の溶出）および第６図（
ツェナセチンの溶出）に示す。なお、図中、溶出曲線は
左より芯物質に対するコーテイング量が２０．４０．６
０．８０．１００．１２０％のものを示す。The results of the elution test are shown in Figure 5 (lactose elution) and Figure 6 (
Elution of zenacetin). In addition, in the figure, the elution curve is from the left when the coating amount relative to the core material is 20.40.6.
0.80.100.120% is shown.
発明の効果
本発明の徐放性製剤はｐ）（非依存性であり、ま、た薬
剤溶出の遅延時間の延長が実現したため、ｐＨ変化の少
ない小腸から大腸にかけての広範囲の領域に薬物を配送
することが可能となった。このため胃の酸性条件下で分
解されやすい薬物の保護が可能となり、また消化酵素か
ら内容物を保護し酵素活性の低くなった下部小腸以降で
はじめて薬物を放出することも可能となった。また、胃
酸分泌の個人差による薬物血中濃度の変動を少なくする
ことも可能となった。Effects of the Invention The sustained-release preparation of the present invention is (p) (independent) and has an extended delay time for drug elution, so it can deliver the drug to a wide area from the small intestine to the large intestine, where there is little pH change. This makes it possible to protect drugs that are easily degraded under the acidic conditions of the stomach, and also protects the contents from digestive enzymes and releases drugs only after the lower small intestine, where enzyme activity is low. It has also become possible to reduce fluctuations in blood drug concentrations due to individual differences in gastric acid secretion.
したがって、ペプチド系医薬品に適用して腸への薬剤配
送を行い大腸を吸収部位とする新しい網形が得られる。Therefore, a new network structure can be obtained that can be applied to peptide-based drugs to deliver drugs to the intestines, with the large intestine as the absorption site.
また、マイクロカプセルによる微小動脈の閉塞、血管破
裂、出血、出血性壊死という過程を経てカプセルが組織
に取り込まれた後、急速に薬物を放出させることにより
、副作用の少ない癌の化学治療が可能となる。In addition, after the capsules are incorporated into tissues through the process of microarterial occlusion, vascular rupture, bleeding, and hemorrhagic necrosis, the drug is rapidly released, making it possible to perform chemotherapy for cancer with fewer side effects. Become.
さらに本発明のエマルジョンを用いると被膜の軟化点以
下でのコーティングが可能となり製剤時の操作条件が緩
和される。Furthermore, when the emulsion of the present invention is used, coating can be performed at a temperature below the softening point of the film, which eases the operating conditions during formulation.
なお、本発明のアクリル系共重合体からなる水系エマル
ジョンは遅延放出型製剤の被膜の形成だけではなく、食
品の防湿用被膜の形成、あるいは遅効性の香味料や肥料
の被膜形成にも使用し得ろ。The aqueous emulsion made of the acrylic copolymer of the present invention can be used not only to form a film for delayed-release preparations, but also to form a moisture-proof film for foods, or a film for slow-release flavorings and fertilizers. Get it.
第１〜３図は実施例１．５．８の製剤の乳糖溶出曲線を
示すグラフ、第４図は実施例７の製剤の乳糖溶出曲線を
示すグラフ、第５および６図は各々実施例６の製剤にお
ける乳糖溶出曲線およびツェナセチン溶出曲線を示すグ
ラフである。
第１図
第２図
時間（ｈ）
第３図
第４図
瞬間（ｈ）Figures 1 to 3 are graphs showing the lactose dissolution curve of the formulation of Example 1.5.8, Figure 4 is a graph showing the lactose dissolution curve of the formulation of Example 7, and Figures 5 and 6 are graphs showing the lactose dissolution curve of the formulation of Example 6, respectively. 2 is a graph showing a lactose elution curve and a zenacetin elution curve in a formulation of Figure 1 Figure 2 Time (h) Figure 3 Figure 4 Moment (h)
Claims (6)
キルエステル、およびハイドロキシアルキルメタクリレ
ートの共重合体からなることを特徴とする水系エマルジ
ョン。(1) An aqueous emulsion comprising a copolymer of an acrylic acid alkyl ester, a methacrylic acid alkyl ester, and a hydroxyalkyl methacrylate.
レートおよび２−ハイドロキシエチルメタクリレートの
共重合体である前記第１項のエマルジョン。(2) The emulsion according to item 1 above, wherein the copolymer is a copolymer of ethyl acrylate, methyl methacrylate and 2-hydroxyethyl methacrylate.
キルエステル、およびハイドロキシアルキルメタクリレ
ートの共重合体からなることを特徴とする被膜。(3) A coating comprising a copolymer of an acrylic acid alkyl ester, a methacrylic acid alkyl ester, and a hydroxyalkyl methacrylate.
レートおよび２−ハイドロキシエチルメタクリレートの
共重合体である前記第３項の被膜。(4) The coating according to item 3 above, wherein the copolymer is a copolymer of ethyl acrylate, methyl methacrylate and 2-hydroxyethyl methacrylate.
キルエステル、およびハイドロキシアルキルメタクリレ
ートからなる共重合体の外部被膜を有することを特徴と
するｐＨ非依存性遅延放出型製剤。(5) A pH-independent delayed-release preparation characterized by having an outer coating of a copolymer consisting of an acrylic acid alkyl ester, a methacrylic acid alkyl ester, and a hydroxyalkyl methacrylate.
レートおよび２−ハイドロキシエチルメタクリレートの
共重合体である前記第５項の製剤。(6) The formulation according to item 5 above, wherein the copolymer is a copolymer of ethyl acrylate, methyl methacrylate and 2-hydroxyethyl methacrylate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62268804A JPH01113322A (en) | 1987-10-23 | 1987-10-23 | Acrylic emulsion and ph-independent slowly releasing drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62268804A JPH01113322A (en) | 1987-10-23 | 1987-10-23 | Acrylic emulsion and ph-independent slowly releasing drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01113322A true JPH01113322A (en) | 1989-05-02 |
Family
ID=17463497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62268804A Pending JPH01113322A (en) | 1987-10-23 | 1987-10-23 | Acrylic emulsion and ph-independent slowly releasing drug |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01113322A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000044376A (en) * | 1998-07-30 | 2000-02-15 | Yamagata Three Top:Kk | Fertilizer sensitive to acidification of soil, and its production |
| WO2001068767A1 (en) * | 2000-03-10 | 2001-09-20 | Röhm GmbH & Co. KG | Dispersion comprising a non-ionic emulsifier |
| JP2005522542A (en) * | 2002-04-12 | 2005-07-28 | アストラゼネカ・アクチエボラーグ | New film / coating |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5842608A (en) * | 1981-08-29 | 1983-03-12 | レ−ム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング | Plastic dispersion comprising acryl monomer majorly as plastic component and manufacture |
| JPS6067435A (en) * | 1983-08-15 | 1985-04-17 | アグリパット アクチエンゲゼルシヤフト | Bridged porous polymer for controlling drug release |
| JPS6210023A (en) * | 1985-07-08 | 1987-01-19 | レ−ム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング | Aqueous dispersion for drug coating |
-
1987
- 1987-10-23 JP JP62268804A patent/JPH01113322A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5842608A (en) * | 1981-08-29 | 1983-03-12 | レ−ム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング | Plastic dispersion comprising acryl monomer majorly as plastic component and manufacture |
| JPS6067435A (en) * | 1983-08-15 | 1985-04-17 | アグリパット アクチエンゲゼルシヤフト | Bridged porous polymer for controlling drug release |
| JPS6210023A (en) * | 1985-07-08 | 1987-01-19 | レ−ム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング | Aqueous dispersion for drug coating |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000044376A (en) * | 1998-07-30 | 2000-02-15 | Yamagata Three Top:Kk | Fertilizer sensitive to acidification of soil, and its production |
| WO2001068767A1 (en) * | 2000-03-10 | 2001-09-20 | Röhm GmbH & Co. KG | Dispersion comprising a non-ionic emulsifier |
| US6998140B2 (en) | 2000-03-10 | 2006-02-14 | Roehm Gmbh & Co. Kg | Dispersion comprising a non-ionic emulsifier |
| JP4944334B2 (en) * | 2000-03-10 | 2012-05-30 | エボニック レーム ゲゼルシャフト ミット ベシュレンクテル ハフツング | Dispersion with nonionic emulsifier |
| JP2005522542A (en) * | 2002-04-12 | 2005-07-28 | アストラゼネカ・アクチエボラーグ | New film / coating |
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