JPH0635394B2 - Method for improving drug solubility and absorption - Google Patents
Method for improving drug solubility and absorptionInfo
- Publication number
- JPH0635394B2 JPH0635394B2 JP1045107A JP4510789A JPH0635394B2 JP H0635394 B2 JPH0635394 B2 JP H0635394B2 JP 1045107 A JP1045107 A JP 1045107A JP 4510789 A JP4510789 A JP 4510789A JP H0635394 B2 JPH0635394 B2 JP H0635394B2
- Authority
- JP
- Japan
- Prior art keywords
- drug
- casein
- casein hydrolyzate
- prednisolone
- absorption
- 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.)
- Expired - Lifetime
Links
- 229940079593 drug Drugs 0.000 title claims description 55
- 239000003814 drug Substances 0.000 title claims description 55
- 238000010521 absorption reaction Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 10
- 239000005018 casein Substances 0.000 claims description 51
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims description 48
- 235000021240 caseins Nutrition 0.000 claims description 48
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 102000011632 Caseins Human genes 0.000 description 46
- 108010076119 Caseins Proteins 0.000 description 46
- 229960005205 prednisolone Drugs 0.000 description 15
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 15
- 210000002966 serum Anatomy 0.000 description 13
- 239000007962 solid dispersion Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- 229960003529 diazepam Drugs 0.000 description 8
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 8
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 8
- 229960001259 diclofenac Drugs 0.000 description 8
- 238000010828 elution Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229960002537 betamethasone Drugs 0.000 description 5
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 4
- 229960002036 phenytoin Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 229960005156 digoxin Drugs 0.000 description 3
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 3
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- OAABHEHWRQAHEJ-UHFFFAOYSA-N butan-1-ol;chloroform Chemical compound ClC(Cl)Cl.CCCCO OAABHEHWRQAHEJ-UHFFFAOYSA-N 0.000 description 1
- 229940021722 caseins Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 229920003170 water-soluble synthetic polymer Polymers 0.000 description 1
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は、薬物、特に難溶性薬物の溶解性および吸収性
の改善方法に関するものである。TECHNICAL FIELD The present invention relates to a method for improving the solubility and absorbability of drugs, particularly poorly soluble drugs.
（従来の技術と発明が解決しようとする課題） 経口的に投与された医薬品は、消化管内において破壊→
分散→溶解の過程を経て、溶液状態になった薬物のみが
吸収される。みかけの吸収速度はこれらの全過程を含む
ため、薬物が溶解されるまでの過程が律速となる場合が
多い。(Problems to be solved by conventional techniques and inventions) Orally administered drugs are destroyed in the digestive tract →
Only the drug in the solution state is absorbed through the process of dispersion → dissolution. Since the apparent absorption rate includes all these processes, the process until the drug is dissolved is often the rate-determining process.
特に、難溶性薬物の場合には薬物の溶出が薬効発現時
間、バイオアベイラビリティを予測するための重要なパ
ラメータとなっている。そのため、難溶性薬物の溶解性
改善の研究は多く、複合体形成、粒子の微細化、水溶性
担体への薬物の分散などが行われている。中でも、水溶
性担体への薬物の分散は操作が簡便で、広範囲の薬物に
利用できるため、ポリビニルピロリドンやポリエチレン
グリコールなどの水溶性合成高分子を用いた多くの検討
がなされている。In particular, in the case of poorly soluble drugs, drug elution is an important parameter for predicting the drug onset time and bioavailability. Therefore, much research has been conducted on improving the solubility of poorly soluble drugs, and complex formation, particle miniaturization, and dispersion of the drug in a water-soluble carrier have been conducted. Among them, since the operation of dispersing a drug in a water-soluble carrier is simple and can be used for a wide range of drugs, many studies using water-soluble synthetic polymers such as polyvinylpyrrolidone and polyethylene glycol have been made.
しかしながら、水溶性担体としては安全性が高く、経済
的で広範囲の薬物に応用できるものが望ましく、この観
点から合成高分子よりも天然高分子、例えば蛋白質ある
いは多糖類が適しているものと考えられる。However, it is desirable that the water-soluble carrier be highly safe, economical and applicable to a wide range of drugs, and from this viewpoint, natural polymers such as proteins or polysaccharides are considered to be more suitable than synthetic polymers. .
そこで、本発明ではカゼイン加水分解物を用い、水溶性
担体としての有用性を検討し、安全性が高く、経済的で
広範囲の薬物に応用できる薬物の溶解性および吸収性の
改善方法を提供することを目的とする。Therefore, in the present invention, a casein hydrolyzate is used to examine its usefulness as a water-soluble carrier, and a method of improving solubility and absorbability of a drug, which is highly safe, economical and applicable to a wide range of drugs, is provided. The purpose is to
（課題を解決するための手段） 本発明は、カゼインを加水分解し、得られたカゼイン加
水分解物を水溶性担体として、この担体に難溶性薬物を
分散させることを特徴とする。(Means for Solving the Problems) The present invention is characterized in that casein is hydrolyzed, and the obtained casein hydrolyzate is used as a water-soluble carrier to disperse a poorly soluble drug in the carrier.
カゼインは乳中の主要な複合蛋白であるが、これを加水
分解して、溶解度を上昇させたものを担体として用い
る。加水分解は、特に制限されないが、酵素による加水
分解が安全性等の面から好ましい。加水分解は、カゼイ
ンの分解率３％以上行うことが、溶解性および吸収性の
面から好ましい。Casein is a major complex protein in milk, and it is used as a carrier by hydrolyzing it to increase its solubility. The hydrolysis is not particularly limited, but enzymatic hydrolysis is preferable from the viewpoint of safety and the like. From the viewpoint of solubility and absorbability, it is preferable that the hydrolysis is carried out with a casein decomposition rate of 3% or more.
（実施例） 以下、実施例につき具体的に本発明を説明する。(Examples) Hereinafter, the present invention will be specifically described with reference to Examples.
実施例 カゼイン加水分解物の調製 酸カゼイン150gと水2,641gを混合し、これに苛性ソーダ
３ｇを添加してカゼイン水溶液を調製し、殺菌処理を行
って冷却した。Example Preparation of Casein Hydrolyzate Acid casein (150 g) and water (2,641 g) were mixed, and caustic soda (3 g) was added thereto to prepare an aqueous casein solution, which was sterilized and cooled.
この酸カゼイン水溶液に市販のプロレザー（天野製薬社
製）を蒸留水に溶解した酵素液を、２U/g(酸カゼイン)
になるように添加しpH６．５、45℃の温度に30分間作用
させて加水分解を行った。2 U / g (acid casein) of an enzyme solution prepared by dissolving commercially available professional leather (manufactured by Amano Pharmaceutical Co., Ltd.) in distilled water in this acid casein aqueous solution
Was added to the reaction mixture at pH 6.5 and 45 ° C. for 30 minutes for hydrolysis.
この加水分解を行った後の反応液を85℃以上の温度で20
分間加熱して酵素失活と殺菌を行った。次いで反応液を
冷却した後、マイクローザで濾過して未反応の蛋白質を
除去し、凍結乾燥を行って、カゼイン加水分解物76.8g
(回収率51.2％)を得た。得られたカゼイン加水分解物の
分解率は12.6％、平均鎖長は17.4であった。The reaction solution after this hydrolysis is performed at a temperature of 85 ° C or higher for 20
After heating for a minute, enzyme deactivation and sterilization were performed. Then, after cooling the reaction mixture, it was filtered with a microsauce to remove unreacted proteins and freeze-dried to give 76.8 g of casein hydrolyzate.
(Recovery rate 51.2%) was obtained. The decomposition rate of the obtained casein hydrolyzate was 12.6%, and the average chain length was 17.4.
反応時間を変え、分解率を変化させて得られた各種のカ
ゼイン加水分解物の分析結果を表１に示す。Table 1 shows the analysis results of various casein hydrolysates obtained by changing the reaction time and changing the decomposition rate.
難溶性のモデル薬物としては、プレドニゾロン、ベタメ
サゾン、ジアゼパム、ジクロフェナック、フェニトイ
ン、ジコキシンを用いた。 Prednisolone, betamethasone, diazepam, diclofenac, phenytoin, and zicoxin were used as poorly soluble model drugs.
以下、図を参照して詳細に説明する。Hereinafter, a detailed description will be given with reference to the drawings.
溶解度相図 一定過剰量の各難溶性薬物を試験管に入れ、１〜５％の
各カゼイン加水分解物溶液を添加して、24時間振盪し
た。溶解平衡に達した薬物を溶媒でジクロフェナックお
よびプレドニゾロンについてはクロロホルムで、ジアゼ
パムについてはヘキサンで抽出して定量した。Solubility Phase Diagram A certain excess amount of each poorly soluble drug was placed in a test tube, 1 to 5% of each casein hydrolyzate solution was added, and the mixture was shaken for 24 hours. Drugs that reached dissolution equilibrium were quantified by extraction with solvent as chloroform for diclofenac and prednisolone and hexane for diazepam.
第１〜３図にカゼイン加水分解物（１、２、３、４）添
加による各薬物（ジクロフェナック、ジアゼパム、プレ
ドニゾロン）の溶解度変化を示す。FIGS. 1 to 3 show changes in the solubility of each drug (diclofenac, diazepam, prednisolone) by the addition of casein hydrolyzate (1, 2, 3, 4).
いずれの薬物においてもカゼイン加水分解物添加によ
り、その溶解度は上昇した。４種のカゼイン加水分解物
の中では、４が最もペプチド鎖長が短いために（平均ペ
プチド鎖３．３）、それ自身の溶解度は非常に高いが、
薬物との相互作用が弱く、薬物を可溶化することは困難
であった。カゼイン１、２および３はほとんど同じペプ
チド鎖長を有するため薬物の可溶化においてもほとんど
同じ効果を示した。The solubility of both drugs was increased by the addition of casein hydrolyzate. Of the four casein hydrolysates, 4 has the shortest peptide chain length (average peptide chain 3.3), so the solubility of itself is very high.
The interaction with the drug was weak and it was difficult to solubilize the drug. Caseins 1, 2 and 3 had almost the same peptide chain length and therefore showed almost the same effect in drug solubilization.
固体分散体の調製 薬物とカゼイン加水分解物（重量比１：１、１：３）を
メノウ乳鉢中で混和し、適量の水を加えて、１時間混練
した。調製された固体分散体は、室温にて減圧下で３日
間乾燥し、100 メッシュ篩を通過した粉末をサンプルと
した。Preparation of Solid Dispersion The drug and casein hydrolyzate (weight ratio 1: 1, 1: 3) were mixed in an agate mortar, an appropriate amount of water was added, and the mixture was kneaded for 1 hour. The prepared solid dispersion was dried at room temperature under reduced pressure for 3 days, and the powder that passed through a 100-mesh sieve was used as a sample.
溶出挙動 日局パドル法に従い溶出試験を行った。37℃の水600 ml
にサンプル粉末を添加して、100rpmで攪拌した。経時的
に試料溶液をサンプリングして有機溶媒で抽出後の薬物
濃度を定量した。薬物添加量および抽出溶媒は次の通り
である。Dissolution behavior Dissolution tests were conducted according to the Japanese Pharmacy Paddle Method. 600 ml of water at 37 ℃
Sample powder was added to and stirred at 100 rpm. The sample solution was sampled over time to quantify the drug concentration after extraction with an organic solvent. The amount of drug added and the extraction solvent are as follows.
添加量(mg) 抽出溶媒 ジクロフェナック 10 クロロホルム フェニトイン 13 クロロホルム− ｎ−ブタノール （４：１容量比） プレドニゾロン 100 クロロホルム ベタメサゾン 20 クロロホルム ジアゼパム 20 ヘキサン ジゴキシン 19 クロロホルム 各種カゼイン加水分解物と薬物（ジクロフェナック、ジ
アゼパム、プレドニゾロン）との固体分散体の溶出挙動
を第４〜６図に示す。酸性（ジクロフェナック）、塩基
性（ジアゼパム）、中性（プレドニゾロン）の全ての薬
物のカゼイン加水分解物固体分散体の溶出速度は薬物単
独に比べて著しく速くなった。カゼイン加水分解物４の
場合、カゼイン加水分解物の含量の増大とともに、溶出
速度は上昇した。一方、カゼイン加水分解物１、２、３
の場合には１：１固体分散体で充分な溶出速度の増大が
もたらされた。Addition amount (mg) Extraction solvent Diclofenac 10 Chloroform Phenytoin 13 Chloroform-n-Butanol (4: 1 volume ratio) Prednisolone 100 Chloroform Betamethasone 20 Chloroform Diazepam 20 Hexane Digoxin 19 Chloroform Various casein hydrolysates and drugs (Diclofenac, Diazepam, Prednisolone) The elution behavior of the solid dispersions of and are shown in FIGS. The dissolution rates of casein hydrolyzate solid dispersions of all acidic (diclofenac), basic (diazepam) and neutral (prednisolone) drugs were significantly faster than the drug alone. In the casein hydrolyzate 4, the elution rate increased as the content of the casein hydrolyzate increased. On the other hand, casein hydrolysates 1, 2, 3
In the case of, the 1: 1 solid dispersion provided a sufficient increase in elution rate.
そこで、カゼイン加水分解物３の１：１固体分散体の溶
出挙動を他の３種の薬物（ジゴキシン、フェニトイン、
ベタメサゾン）において検討した。Therefore, the elution behavior of the 1: 1 solid dispersion of casein hydrolyzate 3 was evaluated using three other drugs (digoxin, phenytoin,
Betamethasone).
結果を第７〜９図に示した。図に示すように、いずれの
薬物においても顕著な溶出速度の上昇が認められた。こ
れらの溶出速度の上昇は薬物粒子表面の水に対する漏れ
の改善、結晶性の低下、拡散定数などの因子が複雑に関
与しているものと考えられる。The results are shown in Figs. As shown in the figure, a remarkable increase in the dissolution rate was observed for all the drugs. It is considered that factors such as improvement of leakage of water on the surface of drug particles, deterioration of crystallinity, and diffusion constant are involved in the increase of the dissolution rate.
イン・ヴィヴォ（In vivo）吸収実験 次にプレドニゾロン単独（Ａ）、プレドニゾロン−カゼ
イン加水分解物３の１：１混練体（Ｂ）、プレドニゾロ
ン−カゼイン加水分解物５の１：１混練体（Ｃ）の吸収
挙動を比較した。雄性ビーグル犬（年令１〜２歳、体重
10〜13kg）４頭に経腸栄養剤ベスビオン（雪印乳業
（株）製）を２日間投与し、24時間絶食してプレドニゾ
ロンとして２mg／kg相当量を含む（Ａ）、（Ｂ）、
（Ｃ）をそれぞれオブラートに包んで水20mlとともに経
口投与した。一定時間毎に肢静脈より４ml採血し、遠心
分離して血清１mlを得た。血清からのプレドニゾロンの
抽出およびＨＰＬＣ条件は以下の通りである。In vivo absorption experiment Next, prednisolone alone (A), 1: 1 kneaded product of prednisolone-casein hydrolyzate 3 (B), 1: 1 kneaded product of prednisolone-casein hydrolyzate 5 (C). The absorption behavior of each was compared. Male Beagle dog (age 1 to 2 years, weight
(10 to 13 kg) 4 animals were administered enteral nutritional agent Vesuvion (manufactured by Snow Brand Milk Products Co., Ltd.) for 2 days, fasted for 24 hours, and contained 2 mg / kg equivalent amount as prednisolone (A), (B),
(C) was wrapped in wafers and orally administered with 20 ml of water. 4 ml of blood was collected from the limb vein at regular intervals and centrifuged to obtain 1 ml of serum. Extraction of prednisolone from serum and HPLC conditions are as follows.
血清１mlに2N NaOH 10μｌおよびジクロロメタン６ml
（内部標準：ベタメサゾン 0.2μｇ／ml）を加え、１分
間振盪した。得られた混合液を3,000rpmで５分間、遠心
分離にかけた。ジクロロメタン相を４ml取り出し、これ
に0.01N H2SO4１mlを加え30秒間振盪した。3,000rpmで
５分間、遠心分離にかけ、ジクロロメタン相を３mlを取
り出し、エバポレートした。残渣をMeOH 100μｌで溶解
し、ＨＰＬＣ試料とした。ＨＰＬＣ条件として、装置：
日立655 、カラム：Lichrosorb RP-18、移動相：H2O-Me
OH(1:1)、検出器：UV、250ｎｍを用いた。10 μl of 2N NaOH and 6 ml of dichloromethane per 1 ml of serum
(Internal standard: betamethasone 0.2 μg / ml) was added and shaken for 1 minute. The resulting mixture was centrifuged at 3,000 rpm for 5 minutes. 4 ml of the dichloromethane phase was taken out, 1 ml of 0.01NH 2 SO 4 was added thereto, and the mixture was shaken for 30 seconds. Centrifugation at 3,000 rpm for 5 minutes, 3 ml of the dichloromethane phase was removed and evaporated. The residue was dissolved in 100 μl of MeOH and used as an HPLC sample. As HPLC conditions, the equipment:
Hitachi 655, column: Lichrosorb RP-18, mobile phase: H 2 O-Me
OH (1: 1), detector: UV, 250 nm was used.
第10図および表２にビーグル犬に経口投与後のプレドニ
ゾロンの血清中濃度推移を示す。図から明らかなよう
に、薬物単独投与の場合に比べてカゼイン加水分解物固
体分散体投与後の薬物の血清中濃度は、投与後初期にお
いては低下しているが、投与後１時間以降は著しく増大
した。また、血清中濃度−時間曲線下面積は薬物単独の
1.27μｇ・h/mlに比べて、固体分散体では2.38μｇ・h/
mlに増大した。FIG. 10 and Table 2 show changes in the serum concentration of prednisolone after oral administration to Beagle dogs. As is clear from the figure, the serum concentration of the drug after administration of the casein hydrolyzate solid dispersion was lower in the initial period after administration than in the case of single administration of the drug, but markedly after 1 hour after administration. Increased. The area under the serum concentration-time curve is
Compared to 1.27 μg · h / ml, 2.38 μg · h / in solid dispersion
increased to ml.
また、カゼイン加水分解物５の場合は、薬物単独投与の
場合と同様の血清中濃度の立ち上がりを示し、単独投与
に比べて吸収量が増大している。従って、カゼインの分
解率およびペプチドの長さを調節することにより、吸収
性の異なる製剤を調製することが可能である。Further, in the casein hydrolyzate 5, the rise in serum concentration was observed as in the case of single administration of the drug, and the absorption amount was increased as compared with the case of single administration. Therefore, by adjusting the degradation rate of casein and the length of the peptide, it is possible to prepare formulations having different absorbability.
薬物の溶出速度の増大だけに基づいて吸収性が向上する
場合には、吸収速度の上昇に伴い、初期血清中濃度が増
大し、最高血清中濃度はわずかに上昇するに過ぎない。
しかしながら、カゼイン加水分解物固体分散体投与の場
合、投与初期の血清中濃度が低下し最高血清中濃度が約
２倍増大していることから、カゼイン加水分解物は通常
の水溶性薬物担体と異なり、薬物の消化管膜透過性を向
上させ、吸収経路に影響を与える等の作用を持つものと
考えられる。 When the absorbability is improved solely based on the increase in the dissolution rate of the drug, the initial serum concentration increases and the maximum serum concentration increases only slightly with the increase in the absorption rate.
However, in case of solid dispersion of casein hydrolyzate, casein hydrolyzate is different from usual water-soluble drug carrier because the serum concentration at the initial stage of administration is decreased and the maximum serum concentration is increased about 2 times. It is thought to have actions such as improving the gastrointestinal tract membrane permeability and affecting the absorption pathway.
（発明の効果） 本発明によれば、蛋白質であるカゼインを加水分解し、
得られたカゼイン加水分解物の水溶性担体に難溶性薬物
を分散させるので、安全性が高く、経済的に薬物の溶解
性および吸収性を改善することができ、広範囲の薬物に
応用できる。(Effects of the Invention) According to the present invention, protein casein is hydrolyzed,
Since the sparingly soluble drug is dispersed in the water-soluble carrier of the obtained casein hydrolyzate, it is highly safe and can improve the solubility and absorbability of the drug economically, and can be applied to a wide range of drugs.
第１〜３図は、カゼイン加水分解物（１、２、３、４）
添加による各薬物（第１図はジクロフェナック、第２図
はジアゼパム、第３図はプレドニゾロン）の溶解度変化
を示すグラフである。○はカゼイン加水分解物４、●は
カゼイン加水分解物３、黒い△はカゼイン加水分解物
１、白い△はカゼイン加水分解物２であり、縦軸は、薬
物の濃度(×103Ｍ)を示し、横軸は、カゼイン加水分解
物の濃度（％）を示す。 第４〜６図は、各種カゼイン加水分解物と薬物（第４図
はジクロフェナック、第５図はジアゼパム、第６図はプ
レドニゾロン）との固体分散体の溶出挙動を示すグラフ
である。×は薬物単独、●は薬物：カゼイン加水分解物
４(1:1)、○は薬物：カゼイン加水分解物４(1:3)、白い
□は薬物：カゼイン加水分解物３（重量比１：１）、黒
い□は薬物：カゼイン加水分解物３（重量比1:3）、白
い△は薬物：カゼイン加水分解物１（重量比1:1）、黒
い△は薬物：カゼイン加水分解物２（重量比1:1）であ
り、縦軸は溶解度（％）、横軸は溶出時間（分）を示
す。 第７〜９図は、薬物単独（○）と薬物：カゼイン加水分
解物３（重量比1:1）固体分散体（●）の溶出挙動を示
すグラフであり、縦軸は溶出率（％）を、横軸は時間
（分）を示す。第７図はジゴキシン、第８図はフェニト
イン、第９図はベタメサゾンの場合である。 第10図は、ビーグル犬に経口投与後のプレドニゾロンの
血清中濃度推移を示すグラフである。●はプレドニゾロ
ン単独、黒い△はプレドニゾロン−カゼイン加水分解物
３の１：１混練体、○はプレドニゾロン−カゼイン加水
分解物５の１：１混練体の吸収挙動を示す。縦軸は、血
清中のプレドニゾロン濃度（mg／ml）を、横軸は時間
（時）を示す。Figures 1-3 show casein hydrolysates (1, 2, 3, 4)
FIG. 1 is a graph showing changes in solubility of each drug (FIG. 1 shows diclofenac, FIG. 2 shows diazepam, and FIG. 3 shows prednisolone) by addition. ○ represents casein hydrolyzate 4, ● represents casein hydrolyzate 3, black Δ represents casein hydrolyzate 1, white Δ represents casein hydrolyzate 2, and the vertical axis represents the drug concentration (× 10 3 M). The horizontal axis shows the concentration (%) of the casein hydrolyzate. FIGS. 4 to 6 are graphs showing the elution behavior of solid dispersions of various casein hydrolysates and drugs (FIG. 4 is diclofenac, FIG. 5 is diazepam, and FIG. 6 is prednisolone). ×: drug alone, ●: drug: casein hydrolyzate 4 (1: 1), ○: drug: casein hydrolyzate 4 (1: 3), white □: drug: casein hydrolyzate 3 (weight ratio 1: 1), black □ is drug: casein hydrolyzate 3 (weight ratio 1: 3), white Δ is drug: casein hydrolyzate 1 (weight ratio 1: 1), black Δ is drug: casein hydrolyzate 2 ( The weight ratio is 1: 1), the vertical axis represents solubility (%), and the horizontal axis represents elution time (minutes). 7 to 9 are graphs showing the dissolution behavior of the drug alone (○) and the drug: casein hydrolyzate 3 (weight ratio 1: 1) solid dispersion (●), and the vertical axis represents the dissolution rate (%). The horizontal axis represents time (minutes). FIG. 7 is for digoxin, FIG. 8 is for phenytoin, and FIG. 9 is for betamethasone. FIG. 10 is a graph showing changes in the serum concentration of prednisolone after oral administration to Beagle dogs. The black circles show the absorption behavior of prednisolone alone, the black triangles show the absorption behavior of the 1: 1 mixture of prednisolone-casein hydrolyzate 3, and the open circles show the absorption behavior of the 1: 1 mixture of prednisolone-casein hydrolyzate 5. The vertical axis represents the concentration of prednisolone in serum (mg / ml), and the horizontal axis represents time (hours).
Claims (2)
加水分解物を水溶性担体として、この担体に難溶性薬物
を分散させることを特徴とする薬物の溶解性および吸収
性の改善方法。1. A method for improving the solubility and absorption of a drug, which comprises hydrolyzing casein and using the obtained casein hydrolyzate as a water-soluble carrier to disperse a poorly soluble drug in the carrier.
求項１記載の改善方法。2. The method according to claim 1, wherein the hydrolysis rate of casein is 3% or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1045107A JPH0635394B2 (en) | 1989-02-28 | 1989-02-28 | Method for improving drug solubility and absorption |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1045107A JPH0635394B2 (en) | 1989-02-28 | 1989-02-28 | Method for improving drug solubility and absorption |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02225423A JPH02225423A (en) | 1990-09-07 |
| JPH0635394B2 true JPH0635394B2 (en) | 1994-05-11 |
Family
ID=12710049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1045107A Expired - Lifetime JPH0635394B2 (en) | 1989-02-28 | 1989-02-28 | Method for improving drug solubility and absorption |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0635394B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR004014A1 (en) * | 1995-10-13 | 1998-09-30 | Meiji Seika Kaisha | AN ANTIBACTERIAL COMPOSITION OF CEFDITOREN PIVOXILO FOR ORAL ADMINISTRATION AND METHOD TO OBTAIN SUCH COMPOSITION |
| AUPP494798A0 (en) * | 1998-07-29 | 1998-08-20 | Pacific Biolink Pty Limited | Protective protein formulation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61157340A (en) * | 1984-12-28 | 1986-07-17 | Morinaga Milk Ind Co Ltd | Oil in water type emulsion and preparation thereof |
-
1989
- 1989-02-28 JP JP1045107A patent/JPH0635394B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02225423A (en) | 1990-09-07 |
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