WO2009084216A1 - 経口粉粒状抗腫瘍剤 - Google Patents
経口粉粒状抗腫瘍剤 Download PDFInfo
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- WO2009084216A1 WO2009084216A1 PCT/JP2008/003991 JP2008003991W WO2009084216A1 WO 2009084216 A1 WO2009084216 A1 WO 2009084216A1 JP 2008003991 W JP2008003991 W JP 2008003991W WO 2009084216 A1 WO2009084216 A1 WO 2009084216A1
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- WIPO (PCT)
- Prior art keywords
- antitumor agent
- granular
- oral
- agent according
- tegafur
- Prior art date
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- PZDOWFGHCNHPQD-VNNZMYODSA-N sophorose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PZDOWFGHCNHPQD-VNNZMYODSA-N 0.000 description 1
- 229960000487 sorafenib tosylate Drugs 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002812 sunitinib malate Drugs 0.000 description 1
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 1
- 229950010130 tamibarotene Drugs 0.000 description 1
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- 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
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- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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Definitions
- the present invention relates to an oral powder granular antitumor agent coated with a saccharide coating film.
- treatments for cancers affecting many people include surgical treatment, chemotherapy, radiation therapy, gene therapy, immunotherapy, and the like.
- chemotherapy is drug therapy performed using an antitumor agent
- antitumor agents include dosage forms such as injections, tablets, capsules, dry syrups and granules.
- Treatment methods using injections are often administered gradually by instillation, which imposes long-term restraints on patients.
- oral preparations such as capsules and tablets can be taken by patients outside of hospitals such as homes and workplaces, they have a great advantage that they do not cause significant trouble in daily life. Therefore, it is often used as adjuvant therapy after discharge for patients who cannot be treated by long-term hospitalization after surgery.
- Patent Document 1 As a granular antitumor agent that has been surface-treated so as not to expose the drug, only an enteric-coated granule is known so far (Patent Document 1), and the purpose of the coating is mainly Because of the reduction of side effects, there was no powdered antitumor agent that was coated mainly for safe use. This is thought to be due to the lack of consideration for the treatment of antitumor agents with high pharmacological activity by patients, caregivers, and healthcare professionals. JP-A-4-36237
- An object of the present invention is to provide an oral powdered antitumor agent that can safely be taken with an antitumor agent that is often dangerous to handle due to its high pharmacological activity and has the same stability as a capsule or tablet. is there.
- the phrase “can be safely taken” means that the drug is not exposed and does not contaminate the drug during dispensing and taking.
- the present inventors have attempted to produce a granular antitumor agent that can be administered orally using various coating bases that dissolve rapidly.
- various coating bases that dissolve rapidly.
- the risk of drug contamination has been eliminated by coating the drug
- the amount of total related substances including new related substances that have not been recognized in conventional dosage forms has been increased, resulting in a significant decrease in stability.
- the following findings were obtained.
- the present invention provides an oral granular antitumor agent characterized by coating a granular composition containing an antitumor agent with a saccharide excluding a cellulose derivative.
- the “powder and granular material” refers to a preparation in which a pharmaceutical product is made into powder or granules. Powders, granules, granules, etc. are classified according to the particle size distribution of these powders or granules.
- the antitumor agent in the present invention is not particularly limited as long as it contains a medicinal component showing an antitumor effect.
- an alkylating agent an antimetabolite, an antitumor antibiotic, an antitumor plant component preparation, etc.
- the alkylating agent include chloroethylamine antitumor agents, ethyleneimine antitumor agents, and sulfonate ester antitumor agents.
- the antimetabolite include mercaptopurine antitumor agents, methotrexate antitumor agents, fluorouracil antitumor agents, and cytosine antitumor agents.
- antitumor antibiotics include mitomycin C, actinomycin D, bleomycin-based antitumor agents, anthracycline-based antibiotics, neocartinostatin antitumor agents, and the like.
- an antitumor agent that can be administered orally is preferable from the viewpoint of drug efficacy and safety.
- the “orally administrable antitumor agent” is not particularly limited as long as it contains a medicinal component that exhibits an antitumor effect by being taken from the mouth, but is currently being marketed as an oral agent. Those containing components are preferred.
- an antimetabolite is preferable from the viewpoint of improving drug stability, and a combination thereof is particularly preferable.
- antimetabolites include mercaptopurine, methotrexate, capecitabine, carmofur, tegafur, doxyfluridine, fluorouracil, cytarabine ocphosphate, hydroxycarbamide, tegafur uracil, tegafur, gimeracil and oteracil potassium, particularly preferably tegafur and More preferred is a gimeracil / oteracil potassium compounding agent having a molar ratio of 1: 0.4: 1.
- the oral granular antitumor agent of the present invention is obtained by coating a granular composition containing the antitumor agent with a saccharide excluding a cellulose derivative.
- the saccharide in the present invention is not particularly limited as long as it is generally used as an additive for pharmaceuticals excluding cellulose derivatives, and examples thereof include monosaccharides, oligosaccharides and polysaccharides.
- Monosaccharides include tricarbon sugars (glyceroaldehyde, dihydroxyacetone, etc.), tetracarbon sugars (erythrose, threose, etc.), pentose sugars (xylose, arabinose, ribose, deoxyribose, etc.), hexose sugars (glucose, fructose, etc.) , Galactose, mannose, etc.), deoxy sugar (fucose, rhamnose, thioglucose, etc.), amino sugar (glucosamine, galactosamine, etc.), sugar alcohol (mannitol, inositol, etc.), uronic acid (glucuronic acid, galacturonic acid, etc.), aldonic acid (Such as gluconic acid).
- oligosaccharides examples include disaccharides (trehalose, cordobiose, nigerose, maltose, isomaltose, melibiose, sophorose, laminaribiose, gentiobiose, cellobiose, lactose, tulanose, sucrose, leucorose, palatinose, etc.), trisaccharide (6-kestose) , 1-kestose, neokestose, meretitol, raffinose, panose, isopanose, lactosucrose, etc., tetrasaccharides (stachyose, scorodose, etc.), pentasaccharides (belvacose, etc.) and others (cyclodextrin, cyclofructan, cyclodextran, etc.) Can be mentioned.
- disaccharides trehalose, cordobiose, nigerose, maltose
- polysaccharide examples include starch, agarose, carrageenan, chitin and the like. In addition, you may use these saccharides individually or in combination of 2 or more types.
- saccharides in the present invention monosaccharides or oligosaccharides are preferable, sugar alcohols or disaccharides are particularly preferable, and mannitol or sucrose is more preferable, from the viewpoint of improving drug stability and physical wear of the coating film.
- cellulose and cellulose derivatives are removed from saccharides, and examples of cellulose derivatives to be removed include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose and the like.
- Examples of the granular composition to be coated with these saccharides include those granulated by an ordinary granulation means using an antitumor agent and a known formulation additive.
- Examples of the granulation means include, for example, means for granulating core particles using a fluidized bed granulation method, an agitation granulation method, a rolling fluidized bed granulation method, an extrusion granulation method, a spray drying granulation method, or the like. It is done.
- a typical method for producing the granular composition used in the present invention includes, for example, a method of granulating core particles containing an antitumor agent that can be administered orally by using an additive granulation device by an extrusion granulator. .
- formulation additives As long as they are various formulation additives generally used in the production of granular formulations.
- excipients include saccharides, light anhydrous silicic acid and calcium silicate.
- disintegrant include low-substituted hydroxypropylcellulose, carmellose, crospovidone, carmellose calcium, and croscarmellose sodium.
- binder examples include hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, polyvinyl pyrrolidone and the like.
- lubricant examples include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester.
- colorant examples include edible yellow No. 5 dye, edible red No. 2 dye, edible blue No. 2 dye, edible lake dye, yellow ferric oxide and titanium oxide.
- flavoring agents include oranges and lemons.
- corrigent examples include L-menthol, camphor, and mint.
- Examples of a coating means for the obtained granulated product include a means using a fluidized bed, a coating pan and the like. More preferably, a method in which an aqueous solution in which saccharides are dissolved is sprayed onto the core particles using a fluidized bed granulation coating apparatus.
- the ratio of coating with saccharides is not particularly limited as long as it does not interfere with the effect of the present invention, but is preferably 70 to 100% by mass of the total coating amount, and more preferably 90 to 100% by mass. It is particularly preferable to coat only with sugars.
- the coating amount in coating is not particularly limited as long as the effect of the present invention is not hindered, but is preferably 1 to 20% by mass, more preferably 2 to 15% by mass with respect to the total amount of the granular antitumor agent. Particularly preferred is 3 to 10% by mass.
- the dosage form of the granular antitumor agent of the present invention is not particularly limited, and examples thereof include granules, powders and fine granules.
- Granules, powders, and fine granules include dry syrups that are dissolved at the time of use, and powders and granules that dissolve rapidly in the oral cavity and can be taken without water.
- the particle size of the powdery granular material referred to in the present invention is preferably 75 to 1400 ⁇ m, and more preferably 250 to 1000 ⁇ m in the case of a granule.
- the minimum dose of tegafur per dose is expected to be about 20 mg.
- 4 g for taking tegafur equivalent dose is 4 g.
- the equivalent amount of tegafur 20 mg is less than 133 mg. Since it becomes an extremely difficult amount to fill with a packaging device, it is preferable to contain 0.5 to 15% by mass, particularly 5 to 10% by mass, of tegafur in a granular material coated with a coating film. Is preferred.
- the oral granular antitumor agent of the present invention contains an antitumor agent and, if necessary, the above-mentioned preparation additive, and the drug may adhere because it is surface-treated so that the drug is not exposed on the surface. It is an oral preparation that can be safely taken.
- Example 1 150 g of tegafur, 43.5 g of gimeracil, 147 g of oteracil potassium, 2659.5 g of lactose and 60 g of hydroxypropylcellulose (trade name “HPC-M” manufactured by Nippon Soda Co., Ltd.) are kneaded (device name “Dalton Universal Mixing Stirrer 25AM” -02-rr "(manufactured by Dalton Co., Ltd.), 300 g of purified water was added, and kneaded at a rotational speed of 75 min -1 for 5 minutes.
- HPC-M hydroxypropylcellulose
- This kneaded product was granulated using an extrusion granulator equipped with a screen having a diameter of 0.5 mm (apparatus name “Peletter Double EXD-60”, manufactured by Fuji Powder Co., Ltd.).
- the granulated product was sieved with a sieve having an aperture of 1.5 mm, and then dried using a fluidized bed granulation coating apparatus (apparatus name “Multiplex MP-01”, manufactured by POWREC Co., Ltd.). After drying, the resulting granulated product was sized to 355 to 1000 ⁇ m to obtain granules.
- Hypromellose (substitution degree type 2910, trade name TC-5R) 23.5 g and talc 5.9 g were added to 441 g of purified water to obtain a coating solution.
- 800 g of the granules of Example 1 were charged into a fluidized bed granulation coating apparatus (Multiplex MP-01), and the coating liquid was sprayed at a spray rate of 3.2 g / min to obtain coated granules.
- Comparative Examples 2-4 According to the same method as in Comparative Example 1, coated granules were obtained using the water-soluble polymers shown in Table 1 in the amounts shown in Table 1.
- Test example 1 After the granules obtained in Example 1 and Comparative Examples 1 to 4 were stored at 60 ° C. for 10 days, the amount of total related substances produced was measured by the liquid chromatography method listed in the Japanese Pharmacopoeia General Test Method Physical Test Method. .
- Example 2 300 g of tegafur, 87 g of gimeracil, 294 g of oteracil potassium, 2319 g of lactose and 60 g of hydroxypropylcellulose (trade name “HPC-L” manufactured by Nippon Soda Co., Ltd.) (equipment name “Dalton Universal Mixing Agitator 25 AM-02-rr”) )), 300 g of purified water was added, and kneaded for 10 minutes at a rotational speed of 75 min ⁇ 1 . This kneaded product was granulated by using an extrusion granulator (equipment name “Peletter Double EXD-60”) equipped with a screen of ⁇ 0.5 mm.
- HPC-L manufactured by Nippon Soda Co., Ltd.
- the granulated product was dried using a fluidized bed granulation coating apparatus (apparatus name “multiplex MP-01”). After drying, the obtained granulated product was sized to 250 to 1000 ⁇ m to obtain granules. On the other hand, 15 g of sucrose was dissolved in 135 g of purified water to obtain a coating solution. 500 g of the above granules were charged into a fluidized bed granulation coating apparatus (Multiplex MP-01), and the coating liquid was sprayed at a spray speed of 9 g / min to obtain coated granules.
- a fluidized bed granulation coating apparatus Appatus name “multiplex MP-01”.
- Example 3 According to the same method as in Example 2, 25 g of D-mannitol was dissolved in 225 g of purified water to obtain a coating solution. 500 g of the above granules were charged into a fluidized bed granulation coating apparatus (Multiplex MP-01), and the coating liquid was sprayed at a spray speed of 12 g / min to obtain coated granules.
- a fluidized bed granulation coating apparatus Multiplex MP-01
- Comparative Example 5 Granules were obtained in the same manner as in Example 2 except that coating with sucrose was not performed.
- Test example 2 The granules obtained in Examples 2 and 3 and Comparative Example 5 were subjected to moisture-proof packaging (HDPE bottle + silica gel), and 40 ° C. 75% R.D. H. After being stored for 6 months, the amount of the related substances produced was measured by the liquid chromatography method listed in the Japanese Pharmacopoeia General Test Method Physical Test Method.
- Test example 3 The friability of the coated granules obtained in Examples 2 and 3 was evaluated according to the following evaluation method. Evaluation method: About 30 g of the coated granules with a particle size adjusted to 355 to 710 ⁇ m are placed in a planetary ball mill equipped with an alumina pot (Pulverisette 5, manufactured by FRITSCH) together with four alumina balls, and run for 10 minutes at a rotation speed scale of 6. The granule is taken out from the pot and sieved with a sieve having an opening of 250 ⁇ m. The friability is calculated from the following formula.
- Abrasion degree A (%) (preparation amount ⁇ mass on sieve having an opening of 250 ⁇ m) / preparation amount ⁇ 100
Abstract
Description
この内、化学療法は抗腫瘍剤を用いて行う薬物療法であり、抗腫瘍剤には注射剤、錠剤、カプセル剤、ドライシロップ剤、顆粒剤などの剤形がある。
注射剤を用いた治療法は点滴を用いて徐々に投与することが多く、患者に長時間の拘束を強いている。一方、カプセル剤、錠剤などの経口剤は患者が自宅や職場など病院以外でも服用出来る事から、日常生活に著しい支障をきたさないといった大きな利点がある。そのため、術後の長期入院による治療が出来ない患者に対し、退院後のアジュバント療法として用いられることも多い。
一方、これまでに粉粒状製剤として散剤、ドライシロップ剤、細粒剤、顆粒剤等が上市されている。しかしながら、薬物が剥き出さないよう表面処理された粉粒状抗腫瘍剤としては現在までに腸溶性コーティングを施した顆粒剤が知られているのみであり(特許文献1)、コーティングの目的が主に副作用軽減であることから、安全に服用することを主眼にコーティングを施した粉粒状抗腫瘍剤は存在しなかった。これは薬理活性の高い抗腫瘍剤を患者、介助者及び医療従事者が取り扱うことに対して、配慮が不足していた為ではないかと考えられる。
なお、本明細書において、「安全に服用できる」とは、薬物が剥き出しになっておらず、調剤及び服用時に薬物汚染することがないことをいう。
その結果、薬物をコーティングすることで薬物汚染の危険性はなくなったものの、従来の剤形では認められなかった新規類縁物質を含む総類縁物質量の増加が認められ、安定性が著しく低下する問題点が明らかとなった。
そのため、速やかに溶解するコーティング基剤を用いて、表面をコーティングしつつ従来の剤形と同等の安定性を有する、粉粒状物を得ることは不可能かと思われたが、本発明者らは、引き続き種々の検討を行ったところ、次の知見を得た。
(a)コーティング基剤に水溶性高分子ではなく、糖類を用いると従来の剤形と同等の安定性が確保できる。
(b)こうして得られる粉粒状物は、コーティング膜の物理的摩損が少ない為、調剤及び服用時に薬物が付着するおそれがなく、安全に服用できる。また、コーティング膜は速やかに溶解するためにバイオアベイラビリティーの低下を招かない。
本発明は、かかる知見に基づき、完成されたものである。
本明細書において、「粉粒状物」とは、医薬品を粉又は粒状に製した製剤を指す。これら粉又は粒状に製した医薬品の粒度分布によって、散剤、細粒剤、顆粒剤等の分類がなされる。
(a)コーティング基剤に水溶性高分子ではなく、糖類を用いると従来の剤形と同等の安定性が確保できる。
(b)こうして得られる粉粒状物は、コーティング膜の物理的摩損が少ない為、調剤及び服用時に薬物が付着するおそれがない。また、コーティング膜は速やかに溶解するためにバイオアベイラビリティーの低下を招かない。
(c)したがって、本発明により、高い薬理活性により、取り扱いが危険であることが多い抗腫瘍剤を安全に服用でき、カプセル剤や錠剤と同等の安定性を有する経口粉粒状抗腫瘍剤が得られる。
アルキル化剤としては、具体的にはクロルエチルアミン系抗腫瘍剤、エチレンイミン系抗腫瘍剤、スルホン酸エステル系抗腫瘍剤等を挙げることができる。
代謝拮抗剤としては、具体的にはメルカプトプリン系抗腫瘍剤、メトトレキサート抗腫瘍剤、フルオロウラシル系抗腫瘍剤、シトシン系抗腫瘍剤等を挙げることができる。
抗腫瘍性抗生物質としては、具体的にはマイトマイシンC、アクチノマイシンD、ブレオマイシン系抗腫瘍剤、アントラサイクリン系抗生物質、ネオカルチノスタチン抗腫瘍剤等を挙げることができる。
経口投与可能な抗腫瘍剤のうちでも、薬剤安定性を改善するという観点から、代謝拮抗剤が好ましく、特に好ましくはその配合剤である。代謝拮抗剤としてはメルカプトプリン、メトトレキサート、カペシタビン、カルモフール、テガフール、ドキシフルリジン、フルオロウラシル、シタラビンオクホスファート、ヒドロキシカルバミド、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム配合剤を挙げられ、特に好ましくはテガフール・ギメラシル・オテラシルカリウム配合剤であり、それらのモル比が1:0.4:1である配合剤が更に好ましい。
本発明における糖類としては、セルロース誘導体を除く医薬品の添加剤として一般に用いられるものであれば特に制限はなく、例えば単糖類、オリゴ糖、多糖類等を挙げることができる。
なお、これらの糖類は単独で又は2種以上組み合わせて使用してもよい。
より好ましくは、流動層造粒コーティング装置を用いて、糖類を溶解した水溶液を、核粒子に噴霧してコーティングする方法を挙げることができる。
また、コーティングの際のコーティング量は本発明の効果を妨げない範囲であれば特に制限はないが、粉粒状抗腫瘍剤全量に対して1~20質量%が好ましく、更に2~15質量%が好ましく、特に3~10質量%が好ましい。
テガフール150g、ギメラシル43.5g、オテラシルカリウム147g、乳糖2659.5g、ヒドロキシプロピルセルロース(商品名「HPC-M」日本曹達株式会社製)60gを練合機(装置名「ダルトン万能混合撹拌機 25AM-02-rr」、株式会社ダルトン製)に仕込み、精製水300gを加え回転速度75min-1で5分間練合した。
この練合物をφ0.5mmのスクリーンを装着した押出し造粒機(装置名「ペレッターダブル EXD-60」、不二パウダル株式会社製)を用いて造粒した。この造粒物を目開き1.5mmの篩で篩過後、流動層造粒コーティング装置(装置名「マルチプレックス MP-01」、株式会社パウレック製)を用いて乾燥した。乾燥後、得られた造粒物を355~1000μmに整粒し、顆粒剤を得た。
精製水441gにヒプロメロース(置換度タイプ2910、商品名TC-5R)23.5g、タルク5.9gを加えコーティング液とした。実施例1の顆粒800gを流動層造粒コーティング装置(マルチプレックス MP-01)に仕込み、上記コーティング液をスプレー速度3.2g/分で噴霧してコーティング顆粒を得た。
比較例1と同様の方法に従って、表1に示す水溶性高分子を表1に記載の量で用いてコーティング顆粒を得た。
実施例1及び比較例1~4で得られた顆粒を60℃で10日間保存した後、生成する総類縁物質量を日本薬局方一般試験法物理学的試験法収載液体クロマトグラフィー法により測定した。
テガフール300g、ギメラシル87g、オテラシルカリウム294g、乳糖2319g、ヒドロキシプロピルセルロース(商品名「HPC-L」日本曹達株式会社製)60gを練合機(装置名「ダルトン万能混合撹拌機 25AM-02-rr」)に仕込み、精製水300gを加え回転速度75min-1で10分間練合した。この練合物をφ0.5mmのスクリーンを装着した押出し造粒機(装置名「ペレッターダブル EXD-60」)を用いて造粒した。この造粒物を、流動層造粒コーティング装置(装置名「マルチプレックス MP-01」)を用いて乾燥した。乾燥後、得られた造粒物を250~1000μmに整粒し、顆粒剤を得た。
一方、ショ糖15gを精製水135gで溶解してコーティング液とした。上記の顆粒500gを流動層造粒コーティング装置(マルチプレックス MP-01)に仕込み、上記コーティング液をスプレー速度9g/分で噴霧してコーティング顆粒を得た。
実施例2と同様の方法に従って、D-マンニトール25gを精製水225gで溶解してコーティング液とした。上記の顆粒500gを流動層造粒コーティング装置(マルチプレックス MP-01)に仕込み、上記コーティング液をスプレー速度12g/分で噴霧してコーティング顆粒を得た。
ショ糖を用いたコーティングを行わなかった以外は実施例2と同様にして顆粒を得た。
実施例2、3及び比較例5で得られた顆粒に防湿包装(HDPEボトル+シリカゲル)を施し、40℃ 75%R.H.で6箇月間保存した後、生成する類縁物質量を日本薬局方一般試験法物理学的試験法収載液体クロマトグラフィー法により測定した。
実施例2、3で得られたコーティング顆粒の摩損度を下記評価法に従って評価した。
評価法:
粒子径を355~710μmに整粒したコーティング顆粒約30gをアルミナ製ボール4個と共に、アルミナ製ポットを装着した遊星ボールミル(Pulverisette5、FRITSCH製)に入れ、回転数目盛6で10分間運転する。ポットから顆粒を取り出し、目開き250μmの篩で篩過する。なお、摩損度は下記式から算出する。
摩損度A(%)=(仕込み量―目開き250μm篩上質量)/仕込み量×100
摩損度Aが小さいほど顆粒表面からの摩損が小さく、コーティング顆粒の場合薬物による汚染が防げることを意味している。
実施例2、3で得られた顆粒を日本薬局方一般試験法 製剤試験法収載溶出試験法に従い実施した。
<測定条件>
溶出試験法:第2法(50min-1)
試験液:水(900mL)
測定波長:λ=262nm
サンプリング:開始5分後
Claims (12)
- 抗腫瘍剤を含有する粉粒状組成物を、セルロース誘導体を除く糖類によりコーティングしたことを特徴とする経口粉粒状抗腫瘍剤。
- 糖類が単糖類又はオリゴ糖である請求項1に記載の経口粉粒状抗腫瘍剤。
- 糖類が糖アルコール又は二糖類である請求項1又は2に記載の経口粉粒状抗腫瘍剤。
- 糖類がマンニトール又はショ糖である請求項1~3のいずれかに記載の経口粉粒状抗腫瘍剤。
- 剤形が顆粒剤である請求項1~4のいずれかに記載の経口粉粒状抗腫瘍剤。
- 抗腫瘍剤が経口投与可能な抗腫瘍剤である請求項1~5のいずれかに記載の経口粉粒状抗腫瘍剤。
- 抗腫瘍剤が代謝拮抗剤である請求項6に記載の経口粉粒状抗腫瘍剤。
- 抗腫瘍剤がテガフールを含有するものである請求項6又は7に記載の経口粉粒状抗腫瘍剤。
- 抗腫瘍剤が(a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムを含有するものである請求項6~8のいずれかに記載の経口粉粒状抗腫瘍剤。
- (a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムをモル比1:0.4:1で含有する請求項9に記載の経口粉粒状抗腫瘍剤。
- コーティング膜で被覆した粉粒状物中にテガフールを0.5~15質量%含む請求項1~10のいずれかに記載の経口粉粒状抗腫瘍剤。
- コーティング膜で被覆した粉粒状物中にテガフールを5~10質量%含む請求項1~10のいずれかに記載の経口粉粒状抗腫瘍剤。
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EP08866771.2A EP2223683B1 (en) | 2007-12-27 | 2008-12-26 | Oral particulate antitumor preparation |
JP2009547903A JP5356255B2 (ja) | 2007-12-27 | 2008-12-26 | 経口粉粒状抗腫瘍剤 |
US12/810,540 US20100266706A1 (en) | 2007-12-27 | 2008-12-26 | Oral particulate antitumor preparation |
KR1020107013973A KR101503559B1 (ko) | 2007-12-27 | 2008-12-26 | 경구 분립상 항종양제 |
CN2008801233887A CN101909602B (zh) | 2007-12-27 | 2008-12-26 | 口服粉粒状抗肿瘤剂 |
ES08866771.2T ES2476259T3 (es) | 2007-12-27 | 2008-12-26 | Preparación antitumoral de material particulado oral |
HK11102329.5A HK1148206A1 (en) | 2007-12-27 | 2011-03-08 | Oral powder and granular antitumor agent |
US13/680,254 US20130078309A1 (en) | 2007-12-27 | 2012-11-19 | Oral particulate antitumor preparation |
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WO2012161240A1 (ja) | 2011-05-25 | 2012-11-29 | 大鵬薬品工業株式会社 | テガフール、ギメラシル、オテラシルカリウム含有有核錠 |
CN107865871A (zh) * | 2016-09-23 | 2018-04-03 | 江苏恒瑞医药股份有限公司 | 一种替吉奥组合物及其制备方法 |
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ES2476259T3 (es) * | 2007-12-27 | 2014-07-14 | Taiho Pharmaceutical Co., Ltd. | Preparación antitumoral de material particulado oral |
MX2014006201A (es) * | 2011-11-24 | 2014-12-05 | Imuneks Farma Ilaç Sanayi Ve Ticaret A S | Formas de dosificaciones solidas de imatinib reconstituidas justo antes de usarse. |
TWI608849B (zh) * | 2014-06-16 | 2017-12-21 | 國邑藥品科技股份有限公司 | 可調控釋放度之高載藥量之醫藥組合物及其製備方法 |
CN106619689B (zh) * | 2016-12-30 | 2018-05-01 | 陈晓华 | 一种用于治疗癌症的药物组合物、试剂盒及其应用 |
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US20160151295A1 (en) | 2016-06-02 |
EP2223683A1 (en) | 2010-09-01 |
EP2223683A4 (en) | 2011-01-19 |
EP2223683B1 (en) | 2014-06-18 |
KR101503559B1 (ko) | 2015-03-17 |
CN101909602B (zh) | 2012-06-13 |
HK1148206A1 (en) | 2011-09-02 |
KR20100101112A (ko) | 2010-09-16 |
US20130078309A1 (en) | 2013-03-28 |
JP5611403B2 (ja) | 2014-10-22 |
CN101909602A (zh) | 2010-12-08 |
TW200932286A (en) | 2009-08-01 |
US20100266706A1 (en) | 2010-10-21 |
JP2013155184A (ja) | 2013-08-15 |
MY151207A (en) | 2014-04-30 |
TWI455732B (zh) | 2014-10-11 |
ES2476259T3 (es) | 2014-07-14 |
JP5722967B2 (ja) | 2015-05-27 |
JP5356255B2 (ja) | 2013-12-04 |
JPWO2009084216A1 (ja) | 2011-05-12 |
JP2014012705A (ja) | 2014-01-23 |
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