WO2004054602A1 - Orally administerable protein preparation and method of orally administering the same - Google Patents

Orally administerable protein preparation and method of orally administering the same Download PDF

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Publication number
WO2004054602A1
WO2004054602A1 PCT/JP2003/014602 JP0314602W WO2004054602A1 WO 2004054602 A1 WO2004054602 A1 WO 2004054602A1 JP 0314602 W JP0314602 W JP 0314602W WO 2004054602 A1 WO2004054602 A1 WO 2004054602A1
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Prior art keywords
protein preparation
enteric
protein
capsule
drug
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PCT/JP2003/014602
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French (fr)
Japanese (ja)
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Seishi Takahashi
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Seishi Takahashi
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the present invention relates to an orally administrable protein preparation and an oral administration method thereof.
  • the protein preparation according to the present invention contains a protease inhibitor in the gastric acid-resistant outer layer.
  • the present invention relates to an encapsulation technology for dissolving a protein preparation to exert a drug effect.
  • stomach acid ⁇ 1 ⁇ 3
  • intestinal proteolytic enzymes inactivating their activities. Therefore, when a conventional protein preparation is orally administered, it is degraded by stomach acid ( ⁇ 1-3) and intestinal proteolytic enzymes, and its activity is inactivated. It is usually administered intravenously, intramuscularly or subcutaneously.
  • these protein preparations can prevent degradation in the stomach, they can be absorbed from the intestinal surface by a simple method of oral administration, and their effects can be exhibited.
  • these protein preparations can be administered orally, the pain at the time of intravenous injection, intramuscular injection or subcutaneous injection, and frequent visits to the hospital will be eliminated, and inconvenience in use can be eliminated.
  • oral administration of these protein preparations is simpler than conventional administration methods by injection, can eliminate pain at the time of administration, and does not require frequent hospital visits. It can make a great contribution to improving the quality of life for patients. Disclosure of the invention
  • the present inventor has found that it is possible to orally administer a protein preparation by combining encapsulation technology and enzymatic chemistry and combining its excellent properties, and has completed the present invention.
  • the strongly acidic state of the stomach ( ⁇ 1 ⁇ 3) is passed through preparations such as acid-resistant forcepsels, etc.
  • preparations such as acid-resistant forcepsels, etc.
  • the acid-resistant pH-dependent dissolving capsule used in the present invention can be produced using, for example, vectin, glycerin, and gelatin (1: 4: 5).
  • a protease inhibitor inside the capsule and further placing the target protein preparation inside the capsule, enterolysis while maintaining the activity becomes possible.
  • the released protein preparation is resorbed from the intestinal surface and the intestinal tract and can exert its drug effect.
  • FIG. 1 is a schematic diagram illustrating an example of a protein preparation according to the present invention.
  • FIG. 2 shows a graph showing the anti-inflammatory effect of the protein preparation according to the invention.
  • the protein preparation according to the present invention is composed of, for example, as shown in FIG. 1, a plurality of layers, for example, two to four or more layers.
  • the outer layer of the protein preparation is preferably prepared in a capsule form, but the form of the preparation is not particularly limited, and may be any form suitable for administration.
  • the protein preparation of the present invention has a form in which a proteinase inhibitor B such as a protease inhibitor and a protein preparation D are contained in a mixture in the outer layer having a shape such as a capsule. Is also good.
  • the outer capsule may be composed of a double capsule with an inner capsule therein.In a protein preparation comprising a double capsule in this form, the protein is contained inside the outer capsule.
  • Degradase inhibitor B can also be formulated so that protein drug D is contained inside inner layer capsule C.
  • a plurality of inner layer forceps or ultra-small nanoforce forcers may be mixed in the protease B filled in the outer layer capsule.
  • the preparation can be prepared so that the protease is contained in the outer layer and the protein drug D is contained in the inner capsule.
  • the protein preparation is composed of an enteric outer capsule A and an inner layer.
  • the inner layer of the capsule having this structure contains a protease inhibitor B and other protease inhibitors B and a protein preparation in a mixed state.
  • this protein M agent moves to the intestinal tract, and as the pH increases, the outer layer capsule A dissolves and releases the protease inhibitor B, which is the contents of the inner layer, It is formulated so that protein preparation D mixed in it is also released.
  • Fig. 1 (b) shows a capsule-shaped tamper composed of an outer layer and an inner layer consisting of three layers. 1 shows a dendritic formulation.
  • a protease inhibitor B or another protease inhibitor B is encapsulated in the inner layer adjacent to the outer layer capsule A.
  • the inside of the inner layer B is formed of an inner capsule C, and another inner layer D is provided inside the inner layer capsule C, in which the protein drug D is sealed.
  • a protein preparation having this configuration can be prepared by a method in which each component solution is dropped into a coagulation liquid from four nozzles having a common center.
  • the outer capsule A first begins to dissolve at the intestinal entrance, releasing proteolytic enzyme inhibitors B such as protease inhibitors.
  • proteolytic enzyme inhibitors B such as protease inhibitors.
  • the inner surface of the intestinal tract becomes saturated with the proteolytic enzyme inhibitor, and then the inner capsule C dissolves in the intestine to release the target protein drug D.
  • protein drugs such as low-molecular-weight insulin can be absorbed from the intestinal tract and effectively transferred into the blood.
  • FIG. 1 (c) shows a protein preparation having a configuration in which a plurality of inner capsules C are contained in an outer capsule A.
  • the outer layer capsule A is filled with the protease inhibitor B inside.
  • the proteolytic enzyme inhibitor encapsulated in the inner layer contains a plurality of intestinal absorbable inner layer capsules C, each of which is filled with the protein drug D.
  • the efficacy can be adjusted over time by changing the number or size (particle size and capsule thickness) of the inner layer capsule (such as ultra-small minicapsules). .
  • the protein drug applicable to the protein preparation according to the present invention is preferably a peptide compound having a peptide structure derived from animals, plants or microorganisms or a synthetic peptide compound.
  • Representative examples of such protein drugs include, for example, insulin, growth hormone, interferon, perokinase, TPA, SOD, and the like. It is to be noted that the present invention can be effectively applied not only to the above-mentioned peptide compounds, but also to any drug that is preferably absorbed in the intestine.
  • the dose of the protein drug contained in the protein preparation of the present invention varies depending on the drug, but it is preferable to formulate the protein drug so that an effective drug effect is recognized by enteric coating.
  • the enteric capsule (A) constituting the outer layer of the protein preparation according to the present invention is made of any component that is resistant to gastric acid and pharmacologically harmless.
  • Such substances include gastric acid-resistant substances such as pectin.
  • the enteric force capsule should be filled with a protease inhibitor.
  • a protease inhibitor B include, for example, protease 'inhibitor, and such inhibitor may be a natural product or a synthetic product.
  • synthetic products include AEBSF and E-64, and natural products include, for example, Bestatin, Leupeptin, Aprotinin and the like.
  • natural products include, for example, Bestatin, Leupeptin, Aprotinin and the like.
  • Antipan, Benzamindine-HCI, Cathepsin inhibitors, Chymostatin, Ecotin, EDTA, Epsilon-aminocaproic acid, N-Ethylmaleimide, Pepstatin A, 1,10-Phenanthroline, Phosphoramidon, Trypsin inhibitors and the like can also be used.
  • the protease inhibitor can be selected depending on the type of the protein preparation to be administered.
  • the polypeptide constituting a protein has its unique amino acid sequence determined by the gene sequence, and the site of action of the digestive enzyme is also determined by the specific amino acid sequence. Therefore, a protein preparation having the site is cleaved by a specific digestive enzyme and decomposed and inactivated, so that an anti-digestive enzyme inhibitor is selected.
  • the anti-digestive enzyme inhibitor becomes unnecessary.
  • another digestive enzyme acts on the cleavage site for the other digestive enzyme, so that another anti-digestive enzyme inhibitor is selected.
  • the protein preparation according to the present invention is preferably made into a preparation such as a capsule in a state in which the protein drug is mixed as a content inside the protease inhibitor encapsulated in the outer layer of the preparation.
  • the drug may be mixed with the inhibitor as it is, or another capsule may be provided inside the outer layer to form a two-layer preparation, and the inner layer may be mixed with the inhibitor.
  • the drug may be encapsulated in a capsule, or the drug may be formulated into an ultra-small nanoforce cell and mixed with the inhibitor.
  • the inner capsule in the protein preparation according to the present invention is preferably formed of an intestinal absorbable material. As such a material, for example, polylactic acid or glycolic acid is preferably used.
  • the protein preparation according to the present invention is in the form of a capsule or the like whose outer layer is an acid-resistant capsule, when orally administered, it begins to dissolve with an increase in pH, so that various protein degradation occurs when it reaches the duodenum. It releases proteolytic enzyme inhibitors such as protease II inhibitors that inhibit enzymes.
  • the protein preparation according to the present invention can be applied to any peptide compound. That is, an artificial peptide consisting of several to several tens of amino acids, a protein molecule drug such as a naturally-occurring nutrient kinase, hirudin, various lymphokines, interferins, and various growth hormones. Almost any protein can be used, including thrombolytic agents and thrombolytic agents. These protein preparations can be used after being freeze-dried and stabilized together with a saccharide (dextrin, trehalose, etc.) which is a kind of stabilizer. Further, glycosaminoglycans that aid absorption into the intestinal tract can also be used.
  • a saccharide dextrin, trehalose, etc.
  • glycosaminoglycans that aid absorption into the intestinal tract can also be used.
  • glycosaminoglycans that promote absorption into the intestinal tract, basic amino, and the like can be added to the peptide compound to enhance the absorption polarity into the intestinal tract.
  • the above-mentioned peptide compound may be encapsulated in intestinal-absorbable nanocapsules based on polylactic acid or glycolic acid to enhance the absorption polarity into the intestinal tract.
  • Insulin with a molecular weight of about 6000 is a small molecule consisting of an A chain consisting of only 30 amino acids and a B chain consisting of 21 amino acids. For this reason, it is presumed that absorption from the intestinal tract is easier than high molecular weight proteins.
  • Purified insulin was encapsulated by this method and orally administered to mice. Blood was collected 4, 8, 12, 16, 20, 24 hours later, and the blood insulin concentration was measured. The blood concentration of insulin increased with time, indicating that insulin administered orally by the encapsulation method of the present invention was transferred from the intestinal tract to the bloodstream after passing through the stomach (Table 2). ).
  • Example 3 Acid-resistant enteric-coated capsule containing human growth hormone
  • Human growth hormone (hGH) containing an amino acid labeled with radiocarbon C-14 was purified from a microorganism cloned by recombinant DNA technology. This growth hormone, the capsule of the present invention Encapsulated by technique and orally administered to mice. Blood was collected over time, and the radiation dose of the fraction having the molecular weight of hGH was measured by gel filtration. At 0, 2, 4, 8, and 12 hours after oral administration, the amount of isotope was significantly increased, confirming that hGH was transferred from the intestinal tract to blood.
  • Example 4 Capsule containing human Mn-SOD
  • the capsule of the present invention was made to contain human Mn-SOD, and the anti-inflammatory effect in rats was examined. As shown in FIG. 2, a great effect was observed in the force capsule containing Mn-SOD.
  • the anti-inflammatory effects were compared by the method described in Morris et al. (Gastroenterology, 90: 799-803) using the degree of injury as a control. As a result, encapsulated Mn-SOD showed a significant inhibitory effect, whereas non-encapsulated powdered Mn-SOD showed almost no medicinal effect.
  • the protein preparation prepared by the gabselization technology according to the present invention can be orally administered, so that various burdens on the patient can be reduced, and the progress of the treatment technology can be reduced. There is a great advantage that it is effective.
  • the present invention is applicable not only to peptide preparations but also to any drug whose intestinal absorption is desired, and it is to be understood that this embodiment is also included in the present invention. It is.

Abstract

An enteric protein preparation composed of an enteric outer layer tolerant to gastric acid and a protein drug and a protease inhibitor provided inside. When the enteric outer layer tolerant to gastric acid of the enteric protein preparation is dissolved in the intestines, the active ingredient is released into the intestines and thus the drug effect thereof can be effectively and continuously exerted.

Description

明細書 経口投与可能なタンパク質製剤およびその経口投与法 技術分野  Technical Field Orally administrable protein preparation and its oral administration method
この発明は、経口投与可能なタンパク質製剤およびその経口投与法に関するものであ る。 この発明にかかるタンパク質製剤は、経口投与可能にするため、 胃酸耐性の外層に タンパク質分解酵素阻害剤を含有せしめて、胃を通過後腸溶化し腸管内にタンパク質分 解酵素阻害剤を放出した後に、タンパク質製剤を溶出して薬効を発揮させるカプセル化 技術に関するものである。 背景技術  The present invention relates to an orally administrable protein preparation and an oral administration method thereof. In order to enable oral administration, the protein preparation according to the present invention contains a protease inhibitor in the gastric acid-resistant outer layer. The present invention relates to an encapsulation technology for dissolving a protein preparation to exert a drug effect. Background art
近年の遺伝子工学の進歩によって、 多くのヒト由来のタンパク質 (バイオ医薬)が開発 されてきている。  Recent advances in genetic engineering have led to the development of many human-derived proteins (biopharmaceuticals).
これらのタンパク質は、ぺプチド構造のため、胃酸 (ρΗ1~3)や腸内のタンパク質分解 酵素で分解し、 その活性を失活してしまう。 したがって、従来のタンパク質製剤を経口 投与すると、胃酸 (ρΗ1〜3)ならびに腸内のタンパク質分解酵素で分解され、その活性が 失活してしまって、薬効を発揮することは不可能であるので、通常は、静注、筋注投与 あるいは皮下投与されている。  Due to their peptide structure, these proteins are degraded by stomach acid (ρΗ1 ~ 3) and intestinal proteolytic enzymes, inactivating their activities. Therefore, when a conventional protein preparation is orally administered, it is degraded by stomach acid (ρΗ1-3) and intestinal proteolytic enzymes, and its activity is inactivated. It is usually administered intravenously, intramuscularly or subcutaneously.
しかし、 これらのタンパク質製剤は、 胃での分解を防止できれば、経口投与という簡 単な方法で腸表面より吸収させることができ、 その効果を発揮することが可能となる。 また、 これらのタンパク質製剤が経口投与できれば、静注、筋注投与や皮下注射時に おける疼痛や、頻繁に通院する必要がなくなり、使用に際しての不便を解消することが できることになる。  However, if these protein preparations can prevent degradation in the stomach, they can be absorbed from the intestinal surface by a simple method of oral administration, and their effects can be exhibited. In addition, if these protein preparations can be administered orally, the pain at the time of intravenous injection, intramuscular injection or subcutaneous injection, and frequent visits to the hospital will be eliminated, and inconvenience in use can be eliminated.
したがって、 これらのタンパク質製剤を経口投与することは、従来の注射による投与 法に比べて、簡便で、投与時の痛みを解消することができると共に、頻繁に通院する必 要性もなくなリ、患者にとって生活の質を向上させるのに大きく貢献できることになる。 発明の開示  Therefore, oral administration of these protein preparations is simpler than conventional administration methods by injection, can eliminate pain at the time of administration, and does not require frequent hospital visits. It can make a great contribution to improving the quality of life for patients. Disclosure of the invention
そこで、本発明者は、 カプセル化技術と酵素化学とを応用して、その優れた特性を組 み合わせることによってタンパク質製剤の経口投与を可能にすることを見出して、この 発明を完成した。  Thus, the present inventor has found that it is possible to orally administer a protein preparation by combining encapsulation technology and enzymatic chemistry and combining its excellent properties, and has completed the present invention.
胃の強酸性状態 (ρΗ1~3)を酸耐性の力プセルなどの製剤で通過せしめ腸管内での pH の上昇によって製剤の腸溶化を計り、まずタンパク質分解酵素阻害剤を放出し消化酵素 の活性を失活した後に目的のタンパク質製剤を放出せしめることによつて活性を保持 したままの状態で薬効を発揮することが可能となる。 この発明で用いる酸耐性 pH依存性溶解カプセルは、例えばべクチンとグリセリンと ゼラチン (1 : 4： 5)を用いて作製することが可能である。 このカプセルの内部にプロテ ァーゼ阻害剤を含み、さらにその内部に目的のタンパク質製剤を酉己置することによって 活性を保持した状態での腸溶化が可能となる。放出されたタンパク質製剤は腸管内表層 および腸管よリ吸収されて薬効を発揮することが可能となる。 図面の簡単な説明 The strongly acidic state of the stomach (ρΗ1 ~ 3) is passed through preparations such as acid-resistant forcepsels, etc. By releasing the target protein preparation after deactivating the protein, it becomes possible to exert a drug effect while maintaining the activity. The acid-resistant pH-dependent dissolving capsule used in the present invention can be produced using, for example, vectin, glycerin, and gelatin (1: 4: 5). By containing a protease inhibitor inside the capsule and further placing the target protein preparation inside the capsule, enterolysis while maintaining the activity becomes possible. The released protein preparation is resorbed from the intestinal surface and the intestinal tract and can exert its drug effect. BRIEF DESCRIPTION OF THE FIGURES
図 1はこの発明に係るタンパク質製剤の実施例を説明する概略図を示す。  FIG. 1 is a schematic diagram illustrating an example of a protein preparation according to the present invention.
図 2はこの発明に係るタンパク質製剤の抗炎症効果を表すグラフを示す。 発明を実施するための最良の態様  FIG. 2 shows a graph showing the anti-inflammatory effect of the protein preparation according to the invention. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 この発明を実施例によって詳細に説明するが、 この発明はこれらの実施例に一 切限定されるものではない。  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
この発明に係るタンパク質製剤は、例えば、 図 1に示すように、 複数層、例えば、 2 ないし 4層もしくはそれ以上の層から構成されている。 また、 このタンパク質製剤は、 外層がカプセル状に調剤されているのがよいが、調剤の形状は特に限定されるものでは なく、 投与に適した形状であればいかなる形状であってもよい。  The protein preparation according to the present invention is composed of, for example, as shown in FIG. 1, a plurality of layers, for example, two to four or more layers. The outer layer of the protein preparation is preferably prepared in a capsule form, but the form of the preparation is not particularly limited, and may be any form suitable for administration.
この発明のタンパク質製剤には、 カプセル状などの形状を有するその外層の内部に、 プロテアーゼ阻害剤などのタンパク質分解酵素阻害剤 Bとタンパク質製剤 Dとが混在 した状態で含まれている形態であってもよい。また、別の形態として、かかる外層カブ セルと、その内部に内層カプセルとの 2重カプセルから構成されていてもよく、 この形 態の 2重カプセルからなるタンパク質製剤においては、外層カプセル内部にタンパク質 分解酵素阻害剤 Bを、また内層カプセル Cの内部にタンパク質薬剤 Dを含ませるように 調剤することもできる。更に、別の形態として、かかる外層カプセルに充填したタンパ ク質分解酵素阻害剤 B内に、複数個の内層力プセルもしくは超小粒のナノ力プセルなど を混在させた状態で構成されていてもよい。 この形態のタンパク質製剤においては、外 層内部にタンパク質分解酵素阻害剤 Bを、また内層カプセル内部にそれぞれタンパク質 薬剤 Dを含ませるように製剤することができる。  The protein preparation of the present invention has a form in which a proteinase inhibitor B such as a protease inhibitor and a protein preparation D are contained in a mixture in the outer layer having a shape such as a capsule. Is also good. In another form, the outer capsule may be composed of a double capsule with an inner capsule therein.In a protein preparation comprising a double capsule in this form, the protein is contained inside the outer capsule. Degradase inhibitor B can also be formulated so that protein drug D is contained inside inner layer capsule C. Further, as another form, a plurality of inner layer forceps or ultra-small nanoforce forcers may be mixed in the protease B filled in the outer layer capsule. . In this form of the protein preparation, the preparation can be prepared so that the protease is contained in the outer layer and the protein drug D is contained in the inner capsule.
更に具体的には、 図 1 ( a ) に示すように、 タンパク質製剤は腸溶性の外層カプセル Aと内層からなる構成からなっている。 この構成からなるカプセルの内層には、プロテ ァーゼ阻害剤などのタンパク質分解酵素阻害剤 Bとタンパク質製剤とが混在した状態 で含まれている。 このタンパク質 M剤は、 胃を通過した後腸管へ移行して、 p Hの向上 に伴って、外層カプセル Aが溶解して、内層の内容物であるタンパク質分解酵素阻害剤 Bを放出すると共に、その中に混在しているタンパク質製剤 Dも放出されるように製剤 化されている。 More specifically, as shown in Fig. 1 ( a ), the protein preparation is composed of an enteric outer capsule A and an inner layer. The inner layer of the capsule having this structure contains a protease inhibitor B and other protease inhibitors B and a protein preparation in a mixed state. After passing through the stomach, this protein M agent moves to the intestinal tract, and as the pH increases, the outer layer capsule A dissolves and releases the protease inhibitor B, which is the contents of the inner layer, It is formulated so that protein preparation D mixed in it is also released.
図 1 ( b ) は、外層と、 3層からなる内層とから構成されているカプセル状のタンパ ク質製剤を示す。この構成からなるカプセル状のタンパク質製剤においては、外層カブ セル Aに隣接する内層には、プロテアーゼ阻害剤などのタンパク質分解酵素阻害剤 Bが 封入されている。 また、該内層 Bの内部は、 内側カプセル Cからなリ、該内層カプセル Cの内部には更に別の内層 Dが設けられていて、その内部にタンパク質薬剤 Dが封入さ れている。 Fig. 1 (b) shows a capsule-shaped tamper composed of an outer layer and an inner layer consisting of three layers. 1 shows a dendritic formulation. In the capsule-shaped protein preparation having this configuration, a protease inhibitor B or another protease inhibitor B is encapsulated in the inner layer adjacent to the outer layer capsule A. Further, the inside of the inner layer B is formed of an inner capsule C, and another inner layer D is provided inside the inner layer capsule C, in which the protein drug D is sealed.
この構成を有するタンパク質製剤は、 4本の中心を共通としたノズルから、それぞれ の成分溶液を凝固液中へ滴下する方法によつて製剤することができる。このタンパク質 製剤は、 胃を通過した後、外層カプセル Aがまず腸入口で溶解し始め、 プロテアーゼ阻 害剤などのタンパク質分解酵素阻害剤 Bを放出する。これによつて、腸管内面はタンパ ク質分解酵素阻害剤で飽和された状態になり、その後、その腸中で内層カプセル Cが溶 解して、 目的のタンパク質薬剤 Dを放出する。 これによつて、低分子のインスリンなど のタンパク質薬剤は、 腸管より吸収され、 血中へと効果的に移行することができる。 図 1 ( c )は、外層カプセル A中に、複数個の内層カプセル Cが含まれている構成から なるタンパク質製剤を示している。この形態のタンパク質製剤においては、外層カプセ ル Aの内部はタンパク質分解酵素阻害剤 Bが充填されている。この内層に封入されてい るタンパク質分解酵素阻害剤内には、複数個の腸吸収性の内層カプセル Cが含まれてい て、 この内層カプセルのそれぞれにタンパク質薬剤 Dがそれぞれ充填されている。 この タンパク質製剤においては、 この内層カプセル（超小粒のミニカプセルなど） の数もし くはサイズ (粒子の大きさとカプセルの厚み)を変化させることによって、薬効を経時的 に調節できるようになつている。  A protein preparation having this configuration can be prepared by a method in which each component solution is dropped into a coagulation liquid from four nozzles having a common center. In this protein preparation, after passing through the stomach, the outer capsule A first begins to dissolve at the intestinal entrance, releasing proteolytic enzyme inhibitors B such as protease inhibitors. As a result, the inner surface of the intestinal tract becomes saturated with the proteolytic enzyme inhibitor, and then the inner capsule C dissolves in the intestine to release the target protein drug D. As a result, protein drugs such as low-molecular-weight insulin can be absorbed from the intestinal tract and effectively transferred into the blood. FIG. 1 (c) shows a protein preparation having a configuration in which a plurality of inner capsules C are contained in an outer capsule A. In this type of protein preparation, the outer layer capsule A is filled with the protease inhibitor B inside. The proteolytic enzyme inhibitor encapsulated in the inner layer contains a plurality of intestinal absorbable inner layer capsules C, each of which is filled with the protein drug D. In this protein formulation, the efficacy can be adjusted over time by changing the number or size (particle size and capsule thickness) of the inner layer capsule (such as ultra-small minicapsules). .
この発明に係るタンパク質製剤に適用できるタンパク質薬剤は、動植物または微生物 由来のぺプチド構造を有するぺプチド化合物または合成べプチド化合物であることが 好ましい。かかるタンパク質薬剤の代表例としては、例えば、 インスリン、成長ホルモ ン、 インターフェロン、 ゥロキナーゼ、 TPA、 SODなどが挙げられる。 なお、 この発明 は、上記ペプチド化合物ばかりではなく、腸での吸収が好ましい薬剤であれば、 いずれ の薬剤に対しても有効に適用することができることは当然である。また、 この発明のタ ンパク質製剤に含有されるタンパク質薬剤の用量は、薬剤によって異なるが、腸溶によ つて有効な薬効が認められる用量になるように製剤化するのがよい。  The protein drug applicable to the protein preparation according to the present invention is preferably a peptide compound having a peptide structure derived from animals, plants or microorganisms or a synthetic peptide compound. Representative examples of such protein drugs include, for example, insulin, growth hormone, interferon, perokinase, TPA, SOD, and the like. It is to be noted that the present invention can be effectively applied not only to the above-mentioned peptide compounds, but also to any drug that is preferably absorbed in the intestine. The dose of the protein drug contained in the protein preparation of the present invention varies depending on the drug, but it is preferable to formulate the protein drug so that an effective drug effect is recognized by enteric coating.
この発明に係るタンパク質製剤の外層を構成する腸溶性カプセル（A) は、 胃酸に対 して耐性を有すると共に、薬理的に無害の物質であればいずれの成分より構成されてい る。 かかる物質としては、 ぺクチンなどの胃酸耐性の物質が挙げられる。  The enteric capsule (A) constituting the outer layer of the protein preparation according to the present invention is made of any component that is resistant to gastric acid and pharmacologically harmless. Such substances include gastric acid-resistant substances such as pectin.
この腸溶性力プセルの内部には、タンパク質分解酵素阻害剤が充填されているのがよ い。かかるタンパク質分解酵素阻害剤 Bとしては、例えば、 プロテア一ゼ'インヒビタ 一などが挙げられ、かかるィンヒビタ一は、天然物であっても、合成品であってもよい。 かかる合成品としては、 AEBSFや E-64などが、 また天然物としては、 例えば Bestatin, Leupeptin, Aprotinin などが挙げられる。 更に、 例えば、 Antipan, Benzamindine-HCI, Cathepsin inhibitors, Chymostatin, Ecotin, EDTA, Epsilon-aminocaproic acid, N-Ethylmaleimide, Pepstatin A, 1,10-Phenanthroline, Phosphoramidon, Trypsin inhibitors なども使用することができる。 The enteric force capsule should be filled with a protease inhibitor. Examples of such a protease inhibitor B include, for example, protease 'inhibitor, and such inhibitor may be a natural product or a synthetic product. Such synthetic products include AEBSF and E-64, and natural products include, for example, Bestatin, Leupeptin, Aprotinin and the like. Further, for example, Antipan, Benzamindine-HCI, Cathepsin inhibitors, Chymostatin, Ecotin, EDTA, Epsilon-aminocaproic acid, N-Ethylmaleimide, Pepstatin A, 1,10-Phenanthroline, Phosphoramidon, Trypsin inhibitors and the like can also be used.
この発明において、タンパク質分解酵素阻害剤は、投与するタンパク質製剤の種類に よって選択することが可能である。例えば、 タンパク質を構成するポリペプチドは、遺 伝子配列によってそのユニークなアミノ酸配列が決まっているので、消化酵素の作用部 位も特異的アミノ酸配列によって決まった部位となっている。 したがって、その部位を 有しているタンパク質製剤は、特定の消化酵素によって切断され分解失活するため、抗 消化酵素阻害剤を選択することになる。一方、かかる切断部位がない場合には、抗消化 酵素阻害剤は不要となる。また、別の消化酵素は、その別の消化酵素用の切断部位に作 用するので、別の抗消化酵素阻害剤を選択することになる。このように投与タンパク質 製剤が決定すれば、 阻害剤は自ずから選択可能となる。  In the present invention, the protease inhibitor can be selected depending on the type of the protein preparation to be administered. For example, the polypeptide constituting a protein has its unique amino acid sequence determined by the gene sequence, and the site of action of the digestive enzyme is also determined by the specific amino acid sequence. Therefore, a protein preparation having the site is cleaved by a specific digestive enzyme and decomposed and inactivated, so that an anti-digestive enzyme inhibitor is selected. On the other hand, if there is no such cleavage site, the anti-digestive enzyme inhibitor becomes unnecessary. In addition, another digestive enzyme acts on the cleavage site for the other digestive enzyme, so that another anti-digestive enzyme inhibitor is selected. Once the administered protein formulation is determined, the inhibitor can be selected on its own.
この発明に係るタンパク質製剤は、その製剤外層の内部に封入されたこのタンパク質 分解酵素阻害剤の内部に、タンパク質薬剤を内容物として混在させた状態でカプセルな どの製剤にするのがよい。そのタンパク質薬剤をタンパク質分解酵素阻害剤と混在させ るには、該薬剤をそのまま阻害剤と混在されてもよいし、該外層の内部に別のカプセル を設けて 2層の製剤にして、内層のカプセルに該薬剤を封入してもよいし、または、該 薬剤を超小粒のナノ力プセル状に製剤化して、 該阻害剤中に混在させることもできる。 この発明に係るタンパク質製剤における内層カプセルは、腸管吸収性の素材で形成す るのがよい。かかる素材としては、たとえば、ポリ乳酸またはグリコール酸などが使用 されるのがよい。  The protein preparation according to the present invention is preferably made into a preparation such as a capsule in a state in which the protein drug is mixed as a content inside the protease inhibitor encapsulated in the outer layer of the preparation. In order to mix the protein drug with the protease inhibitor, the drug may be mixed with the inhibitor as it is, or another capsule may be provided inside the outer layer to form a two-layer preparation, and the inner layer may be mixed with the inhibitor. The drug may be encapsulated in a capsule, or the drug may be formulated into an ultra-small nanoforce cell and mixed with the inhibitor. The inner capsule in the protein preparation according to the present invention is preferably formed of an intestinal absorbable material. As such a material, for example, polylactic acid or glycolic acid is preferably used.
この発明に係るタンパク質製剤は、その外層が酸耐性であるカプセルなどの製剤にな つているので、 経口投与されると、 pHの上昇とともに溶解し始めるため、 十二指腸へ 到達する時期で、各種タンパク質分解酵素を阻害するプロテアーゼ■インヒビターなど のタンパク質分解酵素阻害剤を放出するようになっている。  Since the protein preparation according to the present invention is in the form of a capsule or the like whose outer layer is an acid-resistant capsule, when orally administered, it begins to dissolve with an increase in pH, so that various protein degradation occurs when it reaches the duodenum. It releases proteolytic enzyme inhibitors such as protease II inhibitors that inhibit enzymes.
この発明に係るタ I《ク質製剤は、あらゆるぺプチド化合物に応用することができる。 すなわち、数個ないし数十個のァミノ酸よりなる人工的べプチドゃ天然に発見されてい るナツトウキナーゼゃヒルジン等のタンパク質分子薬物、各種リンホカインやインタ一 フエ口ン類、また各種生長ホルモン類や血栓溶解剤などほとんどのタンパク質を用いる ことができる。 これらのタンパク質製剤は、 安定化剤の一種である糖類 (デキストリン やトレハロースなど)と共に凍結乾燥し安定化したものを使用することができる。また、 グリコサミノグリカンの中から腸管への吸収を補助するものを使用することもできる。 つまり、 この発明の腸溶性タンパク質製剤では、上記ペプチド化合物に、腸管への吸収 を促すグリコサミノグリカン類ゃ塩基性ァミノなどを付加して腸管内への吸収極性を 高めることができる。更に、上記べプチド化合物をポリ乳酸またはグリコール酸を基材 とした腸吸収性のナノカプセルに封入して腸管内への吸収極性を高めるのもよい。 実施例 1 ： タンパク質製剤を含有する酸耐性腸溶化力プセルの製造 下表 1に示したように、各々の成分を配合した図 1のカプセルをシームレスカプセル 充填機で作製した。 The protein preparation according to the present invention can be applied to any peptide compound. That is, an artificial peptide consisting of several to several tens of amino acids, a protein molecule drug such as a naturally-occurring nutrient kinase, hirudin, various lymphokines, interferins, and various growth hormones. Almost any protein can be used, including thrombolytic agents and thrombolytic agents. These protein preparations can be used after being freeze-dried and stabilized together with a saccharide (dextrin, trehalose, etc.) which is a kind of stabilizer. Further, glycosaminoglycans that aid absorption into the intestinal tract can also be used. That is, in the enteric protein preparation of the present invention, glycosaminoglycans that promote absorption into the intestinal tract, basic amino, and the like can be added to the peptide compound to enhance the absorption polarity into the intestinal tract. Further, the above-mentioned peptide compound may be encapsulated in intestinal-absorbable nanocapsules based on polylactic acid or glycolic acid to enhance the absorption polarity into the intestinal tract. Example 1 Production of Acid-Resistant Enteric-Isolating Capsule Containing a Protein Formulation As shown in Table 1 below, a capsule of FIG. 1 containing each component was produced by a seamless capsule filling machine.
表 1 ： カプセルの組成  Table 1: Capsule composition
Figure imgf000007_0001
実施例 2 : インスリン含有酸耐性腸溶化力プセル
Figure imgf000007_0001
Example 2 : Insulin-containing acid-resistant enterolytic force peptide
分子量約 6000のインスリンはわずか 30個のアミノ酸よりなる A鎖と、 2 1個のァ ミノ酸からなる B鎖とからなる小さな分子である。このため腸管よりの吸収は高分子の タンパク質より容易と推定される。  Insulin with a molecular weight of about 6000 is a small molecule consisting of an A chain consisting of only 30 amino acids and a B chain consisting of 21 amino acids. For this reason, it is presumed that absorption from the intestinal tract is easier than high molecular weight proteins.
精製インスリンを本法でカプセル化しマウスに経口投与し、 4、 8、 1 2、 1 6、 2 0、 2 4時間後に採血後、血中のインスリン濃度を測定した。経時的にインスリンの血中濃 度は、上昇していて、 この発明のカプセル化法によって経口投与したインスリンが胃を 通過後、 腸管よリ血中へ移行吸収されたことが判明した (表 2)。  Purified insulin was encapsulated by this method and orally administered to mice. Blood was collected 4, 8, 12, 16, 20, 24 hours later, and the blood insulin concentration was measured. The blood concentration of insulin increased with time, indicating that insulin administered orally by the encapsulation method of the present invention was transferred from the intestinal tract to the bloodstream after passing through the stomach (Table 2). ).
表 2 ：血中インスリン濃度  Table 2: Blood insulin levels
Figure imgf000007_0002
実施例 3 ： ヒト成長ホルモン含有耐酸性腸溶化カプセル
Figure imgf000007_0002
Example 3: Acid-resistant enteric-coated capsule containing human growth hormone
放射性炭素 C-14でラベルしたアミノ酸を含むヒト成長ホルモン (hGH)を組換え DNA 技術でクローン化した微生物より精製した。 この成長ホルモンを、 この発明のカプセル 技術によりカプセル化し、マウスに経口投与した。経時的に採血し、ゲルろ過法により hGHの分子量を持つ分画の放射線量を計測した。経口投与後、 0 , 2， 4， 8， 1 2時 間後のアイソト一プ量は有意に増加していて、 hGHが腸管よリ血中へと移行したことが 確認された。 実施例 4： ヒト Mn-SOD含有カプセル Human growth hormone (hGH) containing an amino acid labeled with radiocarbon C-14 was purified from a microorganism cloned by recombinant DNA technology. This growth hormone, the capsule of the present invention Encapsulated by technique and orally administered to mice. Blood was collected over time, and the radiation dose of the fraction having the molecular weight of hGH was measured by gel filtration. At 0, 2, 4, 8, and 12 hours after oral administration, the amount of isotope was significantly increased, confirming that hGH was transferred from the intestinal tract to blood. Example 4: Capsule containing human Mn-SOD
大腸炎の原因の一因として腸絨毛毛細管血流中で発生する活性酸素が疑われている。 この可能性をこの発明のカプセルにヒト Mn-SOD を含有せしめラッ卜での抗炎症効果 を調べたところ、図 2に示すように、 Mn-SODを含む力プセルに大きな効果がみられた。 本実施例では、 抗炎症効果を、 Morrisら（Gastroenterology, 90: 795-803)に記載され ている方法によって障害度をコントロールとし比較した。 その結果、 カプセル化 Mn-SODは、大幅な抑制効果を示したのに対して、非カプセル化の粉末状 Mn-SODはほ とんど薬効を示さなかった。 産業上の利用可能性  Active oxygen generated in the intestinal villous capillary bloodstream is suspected to be a cause of colitis. To investigate this possibility, the capsule of the present invention was made to contain human Mn-SOD, and the anti-inflammatory effect in rats was examined. As shown in FIG. 2, a great effect was observed in the force capsule containing Mn-SOD. In this example, the anti-inflammatory effects were compared by the method described in Morris et al. (Gastroenterology, 90: 799-803) using the degree of injury as a control. As a result, encapsulated Mn-SOD showed a significant inhibitory effect, whereas non-encapsulated powdered Mn-SOD showed almost no medicinal effect. Industrial applicability
従来のタンパク質製剤は、胃酸によリ失活し、また腸管では消化酵素により分解され るため、経口投与は不可能とされ、静注、皮下注射または筋注投与などが一般的な投与 方法であったので、 投与時に疼痛があり、 また頻繁な通院を必要があった。  Conventional protein preparations are inactivated by stomach acid and degraded in the intestinal tract by digestive enzymes, making oral administration impossible.Intravenous, subcutaneous or intramuscular administration is a common administration method. She had pain at the time of administration and required frequent outpatient visits.
これに対して、この発明に係るガブセル化技術によって調製されたタンパク質製剤は、 経口投与が可能となったため、患者にとっては、投与に際しての種々の負担が軽減され ることとなり、 治療技術の進歩に効果を発揮するという大きな利点がある。  On the other hand, the protein preparation prepared by the gabselization technology according to the present invention can be orally administered, so that various burdens on the patient can be reduced, and the progress of the treatment technology can be reduced. There is a great advantage that it is effective.
この発明は、 当然のことながら、ペプチド製剤ばかりではなく、腸での吸収が望まし いいずれの薬剤にも適用できることは明らかであり、この態様もこの発明に包含される ものと理解されるべきである。  Obviously, the present invention is applicable not only to peptide preparations but also to any drug whose intestinal absorption is desired, and it is to be understood that this embodiment is also included in the present invention. It is.

Claims

請求の範囲 The scope of the claims
1 胃酸耐性の腸溶性外層と、その内部にタンパク質薬剤と、タンパク質分解酵素阻 害剤とを含有している腸溶性タンパク質製剤。 1 An enteric protein preparation containing a gastric acid-resistant enteric outer layer, a protein drug therein, and a protease inhibitor.
2 請求の範囲 1項に記載の腸溶性タンパク質製剤において、前記胃酸耐性の腸溶性 外層がカプセル状である外層カプセルからなる腸溶性タンパク質製剤。 2. The enteric protein preparation according to claim 1, wherein the gastric acid-resistant enteric outer layer comprises a capsule-shaped outer layer capsule.
3 請求の範囲 1項または 2項に記載の腸溶性タンパク質製剤において、前記内部に 別の力プセルからなる内層カプセルとからなる腸溶性タンパク質製剤。 3. The enteric protein preparation according to claim 1 or 2, wherein the preparation comprises an inner layer capsule made of another force capsule.
4 請求の範囲 1項ないし 3項のいずれか 1項に記載の腸溶性タンパク質製剤にお いて、 前記内層力プセルが複数個含まれていることからなる腸溶性タンパク質製剤。 4. The enteric protein preparation according to any one of claims 1 to 3, wherein the enteric protein preparation comprises a plurality of the inner layer forcepsels.
5 請求の範囲 1項ないし 4項のいずれか 1項に記載の腸溶性タンパク質製剤にお いて、前記外層カプセルの内部にタンパク質分解酵素阻害剤が含まれ、前記内層カプセ ルの内部にはタンパク質薬剤が含まれていることからなる腸溶性タンゾ ク質製剤。 5.The enteric protein preparation according to any one of claims 1 to 4, wherein the outer capsule contains a protease inhibitor, and the inner capsule contains a protein drug. An enteric protein formulation comprising:
6 請求の範囲 1項ないし 5項のいずれか 1項に記載の腸溶性タンパク質製剤にお いて、前記タンパク質薬品が動植物または微生物由来のぺプチド構造を有するぺプチド 化合物または合成べプチド化合物であることからなる腸溶性タンパク質製剤。 6 In the enteric protein preparation according to any one of claims 1 to 5, the protein drug is a peptide compound or a synthetic peptide compound having a peptide structure derived from animals, plants or microorganisms. An enteric protein preparation comprising:
7 請求の範囲 1項ないし 6項のいずれか 1項に記載の腸溶性タンパク質製剤にお いて、前記タンパク質製剤が、前記ペプチド化合物にグリコサミノグリカン類または塩 基性ァミノ酸を付加して腸管内への吸収極性を高めた製剤であることからなる腸溶性 タンパク質製剤。 7.The enteric protein preparation according to any one of claims 1 to 6, wherein the protein preparation is obtained by adding glycosaminoglycans or a basic amino acid to the peptide compound. An enteric protein preparation comprising a preparation with enhanced absorption polarity into the interior.
8 請求の範囲 1項ないし 7項のいずれか 1項に記載の腸溶性タンパク質製剤にお いて、前記タンパク質製剤が、前記べプチド化合物をポリ乳酸またはグリコール酸を基 材としたナノ粒子に封入し腸管内への吸収極性を高めた製剤であることからなる腸溶 性タンパク質製剤。 8 In the enteric protein preparation according to any one of claims 1 to 7, the protein preparation encapsulates the peptide compound in nanoparticles based on polylactic acid or glycolic acid. An enteric protein preparation comprising a preparation having enhanced absorption polarity into the intestinal tract.
9 請求の範囲 1項ないし 8項のいずれか 1項に記載の腸溶性タンパク質製剤を経 口投与することからなる腸溶性タンパク質製剤の経口投与方法。 1 0 請求の範囲 9項に記載の腸溶性タンパク質製剤の経口投与方法において、前記 腸溶性タンパク質製剤の外層が腸中で溶解し、 タンパク質薬剤と、 タンパク質分解酵素 阻害剤とが腸中で放出されることからなる腸溶性タンパク質製剤の経口投与方法。 9. A method for oral administration of an enteric protein preparation, comprising orally administering the enteric protein preparation according to any one of claims 1 to 8. 10.The method for oral administration of an enteric protein preparation according to claim 9, wherein the outer layer of the enteric protein preparation is dissolved in the intestine, and the protein drug and the protease inhibitor are released in the intestine. Oral administration of an enteric protein preparation comprising:
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