JP2000309588A - Solid dispersing element - Google Patents
Solid dispersing elementInfo
- Publication number
- JP2000309588A JP2000309588A JP11121193A JP12119399A JP2000309588A JP 2000309588 A JP2000309588 A JP 2000309588A JP 11121193 A JP11121193 A JP 11121193A JP 12119399 A JP12119399 A JP 12119399A JP 2000309588 A JP2000309588 A JP 2000309588A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- water
- medicament
- formula
- soluble polymer
- 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
- 239000007787 solid Substances 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 19
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims description 27
- 239000007962 solid dispersion Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 15
- 239000002904 solvent Substances 0.000 abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 4
- 239000000654 additive Substances 0.000 abstract description 3
- 230000000996 additive effect Effects 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000018300 basal ganglia disease Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 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
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、体内吸収性及び安
定性が向上することによるバイオアベイラビリティーが
改善された医薬製剤に関する。[0001] The present invention relates to a pharmaceutical preparation having improved bioavailability due to improved absorbability and stability in the body.
【０００２】[0002]
【０００３】[0003]
【化３】 Embedded image
【０００４】上記式（１）の薬物は、ドーパミンＤ4受
容体が関与する種々の病態、例えば精神***病及び脳血
管障害や老年期痴呆に伴う問題行動等の疾患の予防及び
治療剤として有用であり、かつ副作用である錐体外路障
害を伴わない薬物として有用であることが知られている
（ＷＯ９８／１２１９５）。しかしながら、この薬物
は、その溶解性が低いため吸収性が悪く、経口投与した
場合のバイオアベイラビリティー（ＢＡ）が低い欠点を
有している。The drug of the above formula (1) is useful as an agent for preventing and treating various conditions associated with the dopamine D 4 receptor, for example, schizophrenia and diseases such as cerebrovascular disorders and senile dementia. And it is known to be useful as a drug without extrapyramidal disorders as a side effect (WO98 / 12195). However, this drug has the drawback of poor absorption due to its low solubility and low bioavailability (BA) when administered orally.
【０００５】通常、難水溶性薬物の溶解性を改善する手
法としては、塩、包接体、固体分散体にすることなどが
知られている。しかしながら、式（１）の薬物は、単に
塩により溶解性を改善しても胃内で速やかに難水溶性の
塩酸塩に変換してしまい、吸収性の向上は見られない。
また、式（１）の薬物は、通常包接体のホストとして用
いられるシクロデキストリンによる包接能は小さく、包
接体としての開発も困難であった。固体分散体による場
合であっても、式（１）の薬物は水だけでなくアルコー
ルにも溶け難いことから調製に多量の溶媒を必要とし実
際的ではなく、更に原因は不明であるが式（１）の薬物
の化学的安定性が低下してしまうことが明らかになっ
た。[0005] Usually, as a technique for improving the solubility of a poorly water-soluble drug, it is known to use a salt, an inclusion body, or a solid dispersion. However, even when the solubility of the drug of the formula (1) is simply improved by a salt, the drug is rapidly converted into a poorly water-soluble hydrochloride in the stomach, and no improvement in absorption is observed.
Further, the drug of formula (1) has a low inclusion ability with cyclodextrin, which is usually used as a host of an inclusion complex, and it has been difficult to develop an inclusion complex. Even in the case of a solid dispersion, the drug of formula (1) is not practically soluble in alcohol as well as water, and thus requires a large amount of solvent for preparation. It has been revealed that the chemical stability of the drug 1) is reduced.
【０００６】[0006]
【発明が解決しようとする課題】本発明の目的は、式
（１）の薬物の化学的安定性を保ちつつ体内吸収性を高
め、経口投与であってもＢＡが高い固形製剤を提供する
ことにある。SUMMARY OF THE INVENTION An object of the present invention is to provide a solid preparation having a high BA even when administered orally by increasing the absorbability in the body while maintaining the chemical stability of the compound of formula (1). It is in.
【０００７】[0007]
【課題を解決するための手段】本発明者らは、上記目的
を解決するために検討を重ねた結果、酸を添加して固体
分散体とすることによって体内吸収性のみならず、化学
的安定性が保持された固形製剤が得られることを見出
し、本発明を完成するに至った。すなわち本発明は、式
（１）の薬物、水溶性高分子及び酸からなる固体分散体
である。Means for Solving the Problems As a result of repeated studies to solve the above-mentioned problems, the present inventors have found that adding an acid to a solid dispersion not only allows absorption into the body but also enhances chemical stability. The present inventors have found that a solid preparation having good properties can be obtained, and have completed the present invention. That is, the present invention is a solid dispersion comprising the drug of the formula (1), a water-soluble polymer, and an acid.
【０００８】本発明で使用することのできる水溶性高分
子とはヒドロキシプロピルメチルセルロース、ヒドロキ
シプロピルセルロース、ポリビニルピロリドン又はメチ
ルセルロースであり、これらは１種又は２種以上配合す
ることができる。酸とは無機酸又は有機酸のいずれであ
ってもよく、例えば塩酸、硫酸、燐酸、酢酸、クエン
酸、酒石酸、コハク酸、フマール酸、マレイン酸等が挙
げられる。好ましくは有機酸であり、中でもクエン酸が
最も好ましい。The water-soluble polymer that can be used in the present invention is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or methylcellulose, and one or more of these can be blended. The acid may be any of an inorganic acid and an organic acid, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, succinic acid, fumaric acid, and maleic acid. Organic acids are preferred, and citric acid is most preferred.
【０００９】式（１）の薬物に対する水溶性高分子及び
酸の配合量は重要で、水溶性高分子又は酸の種類により
異なるが、水溶性高分子の重量比が１〜１０、かつ酸の
重量比が０．１〜１０、好ましくは水溶性高分子の重量
比が１〜１０、かつ酸の重量比が０．１〜１とすること
により本発明の効果が最も発揮される。The amounts of the water-soluble polymer and the acid relative to the drug of the formula (1) are important and differ depending on the type of the water-soluble polymer or the acid. When the weight ratio is 0.1 to 10, preferably the weight ratio of the water-soluble polymer is 1 to 10, and the weight ratio of the acid is 0.1 to 1, the effect of the present invention is most exhibited.
【００１０】[0010]
【発明の実施の形態】本発明の固体分散体は、常法の溶
媒法（共沈法）により製造される。すなわち、式（１）
の薬物、水溶性高分子及び酸を溶媒に溶解後、溶媒を留
去することにより製造される。溶媒は水、その他の有機
溶媒及びその混合溶媒のいずれであってもよい。一般に
毒性に対する配慮からエタノールが用いられるが、本発
明に係る式（１）の薬物は水だけでなくエタノールにも
溶けにくいことから、通常の方法では溶解に多量の溶媒
を必要とする。しかしながら、酸を更に添加することに
より少量の水とエタノールの混合溶媒でも式（１）の薬
物を溶解することができる。BEST MODE FOR CARRYING OUT THE INVENTION The solid dispersion of the present invention is produced by a conventional solvent method (coprecipitation method). That is, equation (1)
It is produced by dissolving the drug, water-soluble polymer and acid in a solvent and distilling off the solvent. The solvent may be any of water, other organic solvents, and a mixed solvent thereof. In general, ethanol is used in consideration of toxicity. However, since the drug of the formula (1) according to the present invention is hardly soluble in not only water but also ethanol, an ordinary method requires a large amount of solvent for dissolution. However, by further adding an acid, the drug of formula (1) can be dissolved even in a small amount of a mixed solvent of water and ethanol.
【００１１】本発明の固体分散体には、発明の効果に支
障のない限り、一般的に用いられている添加剤を配合し
ても良い。一般的に用いられている添加剤としては、例
えば嬌味剤、着色剤、香料、崩壊剤、滑沢剤、賦形剤、
結合剤などがある。The solid dispersion of the present invention may contain commonly used additives as long as the effects of the present invention are not hindered. Commonly used additives include, for example, flavoring agents, coloring agents, flavors, disintegrants, lubricants, excipients,
Binders and the like.
【００１２】[0012]
【実施例】以下、実施例及び試験例を挙げて本発明をさ
らに詳しく説明する。 実施例１ 式（１）の薬物１００ｍｇ、ヒドロキシプロピルメチル
セルロース（ＨＰＭＣ）５００ｍｇ及びクエン酸５０ｍ
ｇを水とエタノール混液８ｍｌに溶解後、溶媒を留去
し、固体分散体を得た。The present invention will be described below in more detail with reference to examples and test examples. Example 1 100 mg of the drug of formula (1), 500 mg of hydroxypropylmethylcellulose (HPMC) and 50 m of citric acid
g was dissolved in 8 ml of a mixture of water and ethanol, and the solvent was distilled off to obtain a solid dispersion.
【００１３】実施例２ 式（１）の薬物１００ｍｇ、ポリビニルピロリドン（Ｐ
ＶＰ）５００ｍｇ及びクエン酸５０ｍｇを水とエタノー
ル混液８ｍｌに溶解後、溶媒を留去し、固体分散体を得
た。Example 2 100 mg of a drug of the formula (1) and polyvinylpyrrolidone (P
After dissolving 500 mg of (VP) and 50 mg of citric acid in 8 ml of a mixture of water and ethanol, the solvent was distilled off to obtain a solid dispersion.
【００１４】比較例１ 式（１）の薬物１００ｍｇ及びヒドロキシプロピルメチ
ルセルロース５００ｍｇをエタノール２００ｍｌに溶解
後、溶媒を留去し、固体分散体を得た。Comparative Example 1 After dissolving 100 mg of the drug of the formula (1) and 500 mg of hydroxypropylmethylcellulose in 200 ml of ethanol, the solvent was distilled off to obtain a solid dispersion.
【００１５】試験例１ ［結晶性の確認］ 実施例１、２及び比較例１の固体分散体の結晶性を粉末
Ｘ線回折装置で確認した。この時、式（１）の薬物原薬
も対照として測定した。その結果、式（１）の薬物原薬
は良好な結晶性粉末であったが、調製した固体分散体は
いずれも非晶質体であった。Test Example 1 [Confirmation of Crystallinity] The crystallinity of the solid dispersions of Examples 1 and 2 and Comparative Example 1 was confirmed with a powder X-ray diffractometer. At this time, the drug substance of formula (1) was also measured as a control. As a result, the drug substance of formula (1) was a good crystalline powder, but all the prepared solid dispersions were amorphous.
【００１６】試験例２［安定性試験］ 実施例１及び比較例１の固体分散体を８０℃に保存し経
時的な式（１）の薬物の残存率をＨＰＬＣにより定量し
た。その結果、表１に示すように、クエン酸の添加され
ていない比較例１の固体分散体では経時的な分解による
式（１）の薬物の残存率の低下が確認されたが、実施例
１の固体分散体の残存率は良好であった。Test Example 2 [Stability Test] The solid dispersions of Example 1 and Comparative Example 1 were stored at 80 ° C., and the residual ratio of the drug of the formula (1) over time was quantified by HPLC. As a result, as shown in Table 1, in the solid dispersion of Comparative Example 1 to which citric acid was not added, a decrease in the residual ratio of the drug of Formula (1) due to decomposition over time was confirmed. Of the solid dispersion was good.
【００１７】[0017]
【表１】 [Table 1]
【００１８】試験例３ ［イヌＢＡ試験］ 実施例１、２及び比較例１の固体分散体を崩壊剤（低置
換度ヒドロキシプロピルセルロース）と混合し、カプセ
ルに充填後［式（１）の薬物１０ｍｇ相当量］、水２０
ｍｌとともにビーグル犬（１０ｋｇ）に経口投与した。
対照として式（１）の薬物原薬１０ｍｇを５％アラビア
ゴム液１５ｍｌに懸濁したものを同様に経口投与した
（対照群）。経時的に採血し、血漿中の式（１）の薬物
濃度をＨＰＬＣにより定量した。また、式（１）の薬物
１０ｍｇのポリエチレングリコール溶液２ｍｌを静脈内
投与したものの血漿中濃度推移も同様に測定し標準値と
した。その結果、表２及び図１に示すように、対照群の
ＢＡは約１１％と低かったが、実施例１、２及び比較例
１の固体分散体のＢＡはそれぞれ７４％、５８％、３０
％と向上していた。特にクエン酸を添加した実施例１と
２のＢＡは高かった。Test Example 3 [Canine BA test] The solid dispersions of Examples 1 and 2 and Comparative Example 1 were mixed with a disintegrant (low-substituted hydroxypropylcellulose), filled into capsules, and then filled with the drug of formula (1) 10 mg equivalent], water 20
The dose was orally administered to a beagle dog (10 kg) together with the ml.
As a control, a suspension of 10 mg of the drug substance of formula (1) in 15 ml of a 5% gum arabic solution was orally administered similarly (control group). Blood was collected over time, and the concentration of the drug of formula (1) in the plasma was quantified by HPLC. In addition, 2 ml of a polyethylene glycol solution of 10 mg of the drug of the formula (1) was intravenously administered, and the change in plasma concentration was measured in the same manner and used as a standard value. As a result, as shown in Table 2 and FIG. 1, the BA of the control group was as low as about 11%, but the BAs of the solid dispersions of Examples 1, 2 and Comparative Example 1 were 74%, 58%, and 30%, respectively.
% Had improved. In particular, BA of Examples 1 and 2 to which citric acid was added was high.
【００１９】[0019]
【表２】 [Table 2]
【００２０】[0020]
【発明の効果】本発明により、通常の固体分散体とする
方法では分解が起こってしまう式（１）の薬物について
化学的安定性を保ちつつ、体内吸収性を高めることが可
能となった。本発明によれば、経口投与でＢＡが高い固
形製剤を提供することができる。Industrial Applicability According to the present invention, it has become possible to increase the absorbability in the body while maintaining the chemical stability of the drug of the formula (1), which is decomposed by the usual method of forming a solid dispersion. According to the present invention, a solid preparation having a high BA by oral administration can be provided.
【図１】 試験例３における式（１）の薬物の血漿中濃
度推移を示す。FIG. 1 shows the change in plasma concentration of the drug of formula (1) in Test Example 3.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 山田 憲司 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 Ｆターム(参考） 4C063 AA03 BB03 CC62 DD10 EE01 4C086 AA01 AA02 BC82 GA07 GA10 GA12 MA03 MA05 MA23 MA52 NA03 NA10 NA11 ZA15 ZA18 ZA36 ZC52 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Kenji Yamada 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C063 AA03 BB03 CC62 DD10 EE01 4C086 AA01 AA02 BC82 GA07 GA10 GA12 MA03 MA05 MA23 MA52 NA03 NA10 NA11 ZA15 ZA18 ZA36 ZC52
Claims (5)
酸からなる固体分散体。 【化１】 1. A solid dispersion comprising a drug represented by the following formula, a water-soluble polymer and an acid. Embedded image
１０、及び酸の重量比が０．１〜１０である請求項１記
載の固体分散体。2. The weight ratio of the water-soluble polymer to the drug is from 1 to 1.
The solid dispersion according to claim 1, wherein the weight ratio of the acid dispersion to the acid is 10 to 10.
セルロース、ヒドロキシプロピルセルロース、ポリビニ
ルピロリドン及びメチルセルロースから選ばれる少なく
とも１種である請求項１又は２記載の固体分散体。3. The solid dispersion according to claim 1, wherein the water-soluble polymer is at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and methylcellulose.
体分散体。4. The solid dispersion according to claim 1, wherein the acid is an organic acid.
らなる固体分散体に酸を添加することを特徴とする固体
分散体の安定化方法。 【化２】 5. A method for stabilizing a solid dispersion, comprising adding an acid to a solid dispersion comprising a drug represented by the following formula and a water-soluble polymer. Embedded image
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11121193A JP2000309588A (en) | 1999-04-28 | 1999-04-28 | Solid dispersing element |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11121193A JP2000309588A (en) | 1999-04-28 | 1999-04-28 | Solid dispersing element |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2000309588A true JP2000309588A (en) | 2000-11-07 |
Family
ID=14805178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11121193A Pending JP2000309588A (en) | 1999-04-28 | 1999-04-28 | Solid dispersing element |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2000309588A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016507489A (en) * | 2012-12-13 | 2016-03-10 | ハンミ ファーム． シーオー．， エルティーディー． | Solid dispersion with improved solubility, containing tetrazole derivative as active ingredient |
| US10231929B2 (en) | 2014-03-18 | 2019-03-19 | Takeda Pharmaceutical Company Limited | Solid dispersion |
| US10813937B2 (en) | 2016-03-29 | 2020-10-27 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| JP2021046410A (en) * | 2016-03-29 | 2021-03-25 | シェンチェン ファーマシン シーオー．，エルティーディー． | Pharmaceutical preparation of palbociclib and preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
-
1999
- 1999-04-28 JP JP11121193A patent/JP2000309588A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016507489A (en) * | 2012-12-13 | 2016-03-10 | ハンミ ファーム． シーオー．， エルティーディー． | Solid dispersion with improved solubility, containing tetrazole derivative as active ingredient |
| US10231929B2 (en) | 2014-03-18 | 2019-03-19 | Takeda Pharmaceutical Company Limited | Solid dispersion |
| US10813937B2 (en) | 2016-03-29 | 2020-10-27 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US10894049B2 (en) | 2016-03-29 | 2021-01-19 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| JP2021046410A (en) * | 2016-03-29 | 2021-03-25 | シェンチェン ファーマシン シーオー．，エルティーディー． | Pharmaceutical preparation of palbociclib and preparation method thereof |
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
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