WO1989003671A1 - Sustained-release preparation - Google Patents
Sustained-release preparation Download PDFInfo
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- WO1989003671A1 WO1989003671A1 PCT/JP1988/001090 JP8801090W WO8903671A1 WO 1989003671 A1 WO1989003671 A1 WO 1989003671A1 JP 8801090 W JP8801090 W JP 8801090W WO 8903671 A1 WO8903671 A1 WO 8903671A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
Definitions
- the present invention relates to a formulation for maintaining the concentration of a water-soluble substance having a medicinal effect (hereinafter referred to as “water-soluble substance”) in blood, lymph, and z or lesions. About. More specifically, it is composed of at least the following three components: a sustained-release preparation (hereinafter referred to as “preparation j of the present invention”).
- JP-A-60-97918 and JP-A-60-97918 are conventionally, as a long-acting preparation, JP-A-60-97918 and JP-A-60-97918
- the present inventors have assiduously studied and found that the above-mentioned preparation of the present invention can achieve the retention of the water-soluble substance contained therein, and completed the present invention.
- the component (a) which is a component of the preparation of the present invention includes, for example, cancer necrosis factor (hereinafter referred to as “TNF”), interlocutin 1 «(J3 ⁇ 4 iL-lor j), Interferon, Macrophage activating factor, Colony stimulating factor, Tissue plasminogen activating factor, Perokinase, Bioactive proteins such as baroxin dismutase, insulin, blood coagulation factor 1, neocaltinostatin, penicillin, sefin Aroborin, Might Machine C, Adria Mine, ⁇ -cytosine arabinoside, cephalo gin, cepha Antibiotics such as lexin, bleomycin sulphate and downorubicin; analgesics such as monolephine hydrochloride and brokine hydrochloride; hydrochloric acid Click b off We Roh key cell one cerebral metabolism improving agents such bets are listed et is Ru.
- Particularly preferred substances include physiologically
- Component (a) may be a single substance, but the activity of that substance Activator and / or other components that have an additive or synergistic effect with the substance (eg, IFN, interloicin 2, lentinan in the case of TNF) , Actino Machine D, Actino Machine C or Adria Machine, etc.).
- the substance eg, IFN, interloicin 2, lentinan in the case of TNF
- Actino Machine D Actino Machine C or Adria Machine, etc.
- the component (b) has an effect of preventing the aggregation of the fine particles containing the component (a) in the preparation of the present invention and stabilizing the preparation of the present invention in vivo.
- component (b) for example, solvitan trioleate, recbitan sesquioleate, recbito monooleate , Sonobitan monostearate, recbitan monomitriminate, and solubitan monolaurate, and the HLB value.
- solvitan trioleate for example, sonolebitan sesquioleate (HLB value of 3.7) is preferred, although it is less than 4.
- Component (b) is used in an amount of 50 W /% or less, preferably 3 to 10 W / W%, more preferably 2 to 6 / W%, based on component (c). Something is better.
- the component (c) has an action of retaining the two components (a) in a living body.
- component (c) for example, sesame oil, peanut oil, cottonseed oil, soybean oil, medium chain fatty acid triglyceride, olive oil, corn oil, castor oil Oils, oxidized poppy oil fatty acid ethyl esters, tocopheryl acetate, etc., and especially sesame oil, soybean oil, and sesame oil used for injection.
- Synthetic poppy oil fatty acid Preference is given to luster, tocopherol acetate, castor oil or mixtures thereof.
- a stabilizer of the component it is preferable to add a stabilizer of the component).
- component (a) is human TNF, gelatin, albumin, globulin, protamin, trenoose, D-g
- a stabilizer described in JP-A-58-174330, JP-A-59-20225 and JP-A-59-39829 it is preferred to add a stabilizer described in JP-A-58-174330, JP-A-59-20225 and JP-A-59-39829, so that component (a) is human IL-l or If this is the case, it is advisable to add gelatin, albumin, dextran, trehalose, etc.
- component (a) components such as polyoxyethylene hardened castor oil, refined egg yolk lecithin, soy lecithin, hydrogenated lecithin, etc. It is preferable to add a surfactant, such as cholesterol, which is different from (b). Such a surfactant also has an action of micronizing the component (2).
- the stabilizer of the component (a), the release controlling agent of the component (a), the component (b) and the component (c) are not limited to one kind each, and a plurality of kinds may be used in combination. .
- aqueous solution Add the following (1) and (2) to this aqueous solution, and add a stirrer, homogenizer, ultrasonic emulsifier, phage-pet mixer, mantongo-linhomo
- the resulting emulsion is emulsified using a ginizer or the like, and the obtained emulsion is freeze-dried to microparticulate the water-soluble substance of the component).
- a release controlling agent for component (a) eg, cholesterol
- the fine particles of the present invention can be obtained by suspending the fine particles in the oil medium of the component (c) to which the surfactant of the component) is added using the above-mentioned homogenizer or the like. Can be obtained. Also, a suspension for use at the time of use in which the above-mentioned medium is attached to the fine particles can be prepared.
- the preparation of the present invention is in a suspension state before administration, it is naturally emulsified in the living body after administration and the water-soluble substance is suspended in oil droplets.
- the water-soluble substance absorbs and dissolves water in the living body over time.
- the formulation of the present invention achieves a sustained concentration of a water-soluble substance by forming a w / 0 / w emulsion in a living body when administered.
- the route of administration of the preparation of the present invention includes parenteral administration such as injection, external application, rectal, nasal, and transdermal administration.
- Injection is preferred, especially local injection, intramuscular injection, subcutaneous injection, intradermal injection, and intraarterial injection.
- FIGS. 1 and 2 are both the release curves of human I- ⁇ in a phosphate-buffered physiological saline solution at pH 7 in vitro, where the circles indicate the present invention. And the square mark is the control I preparation.
- Figure 3 shows the change in blood concentration after intramuscular administration to the mouse extensor muscle
- Figure 4 shows the change in lymph concentration after administration to rat stomach wall.
- the white circle is the control
- EXPERIMENTAL EXAMPLE 1- In vitro release tests were performed on the present preparation 'produced in Example 1 described below and a control preparation having human IL-1 or the same titer, respectively. The time course of the release was measured by the EIA method.
- the control preparation was prepared as follows. 15 ml of human I prepared in Example 2 of JP-A-61-271222 and 5 ml of a 20 W / V% gelatin solution (0.05 M, pH7 phosphate buffer) were mixed uniformly. The mixture was stirred to obtain an aqueous solution.
- Example 2 An in vitro release test was performed on the preparation prepared in Example 2 described below. The time course of the release was measured by the EIA method. The result is shown in figure 2. From Figure 2, it can be seen that about 30% of the formulation of Example 2 using tocofuryl acetate as the component (c) was released only after 30 hours. You can see this. Therefore, it is clear that the use of tocofurol acetate has a higher sustainability than the use of soybean oil as the component (c) (Example 1). , RU.
- purified egg yolk lecithin (0.25 g) and cholesterol (0.25 g) were dissolved in cyclohexane (50 ml) to obtain a silk mouth hexane solution (B).
- aqueous solution A and the cyclohexane solution B were mixed and stirred, and emulsified by an ultrasonic homogenizer to obtain an emulsion.
- the emulsion was freeze-dried.
- 7 ml of soybean oil containing 4 W / V% solvitan sesquioleate was added. Powder particles are evenly suspended using a modifier. By doing so, an oily suspension-type sustained product containing human I or L was obtained.
- compositions of the present invention are stable for 5 months and 3 months.
- Example 2 To 0.24 g of the powder containing human IL-1 obtained in Example 1 was added 7 m1 of tocophere acetate containing 4 W / V3 ⁇ 4 of sorbitan sesquioleate. Then, the powder particles were uniformly suspended in the oil phase using a homogenizer, whereby an oily suspension-type sustained-release preparation containing human IL-1 or 1 was obtained.
- Example 3 The oil-based suspension preparation prepared in Example 3 to be described later and the human prepared in Example 3 of JP-A-60-232097 having the same titer as a control.
- TNF aqueous solution was administered into the mouse extensor extensor muscle, and the time course of blood concentration was measured by the EIA method.
- mice Four mice were used at each time point, and the dose was 3 ⁇ 10 + JRU (abbreviation for Japan Reference Unit; the same applies hereinafter). The measured value was the average of four animals.
- Example 3 The oil-based suspension prepared in Example 3 described below was used as a control.
- the TNF aqueous solution used in Experimental Example 3 of the same titer was administered to the rat stomach wall, respectively, and the time course of the concentration in the lumper solution, which was probed from the thoracic duct resonator, was determined by the EIA method. It was measured.
- Fig. 4 shows the results obtained when four rats were used and the dose was 1 ⁇ 10 s JRU.
- the oil-based suspension-type formulation shows a tendency to persist, and the concentration of 920 JRU / ml in the solution was maintained even after 8 hours.
- cyclohexane solution B (0.05 M, PH7 phosphate buffer) 5 ml was uniformly mixed and stirred to obtain an aqueous solution A. Separately, 0.25 g of purified egg yolk lecithin and 0.25 g of cholesterol were dissolved in 50 ml of cyclohexane to obtain cyclohexane solution B.
- the aqueous solution A and the cyclohexane solution B were mixed and stirred, and emulsified by an ultrasonic homogenizer to obtain an emulsion.
- the freeze-dried powder was mixed with 0.24 g of the powder, and 6 W / V% of sonolethan sesquioleate was added with 7 m 1- of soybean oil, and the above homogenizer was added.
- the powder particles were uniformly suspended in the oil phase using the above method to obtain an oil-based suspension-type continuous preparation containing human TNF.
- the preparations of the present invention are stable for 5 months and 3 months.
- the formulation of the present invention maintains the concentration of the aqueous substance in the blood, in the liver solution and / or in the disease, effective treatment of the aqueous substance can be expected.
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Abstract
Description
明 柳 持続性製剤 技術分野 Akira Yanagi Permanent formulation Technical field
本発明は、 水溶性で薬効を有す る 物質 （以下 「 水溶性物 質」 と い う ） の血中、 リ ン パ液中及び z又 は病巣中濃度の 持続を 目的 と す る 製剤に関す る。 更に詳 し く は、 少な く と も次の 3 成分か ら な る .持続性製剤 （以下 「 本発明 の製剤 j と い う ） に関す る 。 The present invention relates to a formulation for maintaining the concentration of a water-soluble substance having a medicinal effect (hereinafter referred to as "water-soluble substance") in blood, lymph, and z or lesions. About. More specifically, it is composed of at least the following three components: a sustained-release preparation (hereinafter referred to as “preparation j of the present invention”).
(a)水溶性で薬効を有する 物質 (a) Water-soluble and medicinal substances
(b) H L B 値が 5 以下であ る 界面活性剤 (b) Surfactant with HLB value of 5 or less
(c)油性媒体 (c) Oily medium
背景技術 Background art
従来、 持続性製剤 と して、 特開昭 60 - 97918号， 同 60- Conventionally, as a long-acting preparation, JP-A-60-97918 and JP-A-60-97918
12617 号及び同 62 - 230729 号記載の も のがあ る が、 いずれ も成分（b)を含んで い な い点で、 本発明 と は全 く 異な る 。 Nos. 12617 and 62-230729, which are completely different from the present invention in that none of them contain component (b).
一方、 界面活性剤を用 い た 持続性製剤 と し て は、 ポ リ オ キ シ エ チ レ ン · ボ リ ォ キ シ プ ロ ピ レ ン · ブ ロ ッ ク 共重合体 のゲル形成を利用 し た製剤の報告 （ Int. J . Pharm. , 32_, 223 ( 1986) ) があ る 。 こ れに は成分（c)が含ま れて お ら ず、 従 っ て それに伴 う 作用 も本発明の製剤 と は全 く 異な る 。 発明の開示 生体内で不安定な物質は半減期が短い た め、 血中， リ ン パ液中及びノ又は病巣中濃度の持続が困難で あ る 。 一方、 生体内で安定な物質の 中に も 、 病巣近傍で の滞留時間の短 い も のがあ り こ の持続化が望まれて い る 。 On the other hand, as a long-acting preparation using a surfactant, the gel formation of a polyoxyethylene / polypropylene / block copolymer is used. There is a report on the formulation (Int. J. Pharm., 32_, 223 (1986)). It does not contain component (c) and, therefore, its associated effects are completely different from those of the formulation of the present invention. Disclosure of the invention Substances that are unstable in the living body have a short half-life, so that it is difficult to maintain the concentration in the blood, in the lymph solution, and in the blood or lesion. On the other hand, even among substances that are stable in the living body, some of them have a short residence time in the vicinity of the lesion, and it is desired to maintain this.
本発明者等は鋭意研究の結果、 上記本発明 の製剤が、 そ こ に舍ま れて い る 水溶性物質の持統化を達成でき る こ と を 見出 し、 本発明を完成 した。 The present inventors have assiduously studied and found that the above-mentioned preparation of the present invention can achieve the retention of the water-soluble substance contained therein, and completed the present invention.
本発明の製剤の構成成分で あ る 成分（a) と して は、 例え ば 癌壊死因子 （以下 「 TNF 」 と い う ） ， イ ン タ 一 ロ イ キ ン 1 « ( J¾下 iL-lor j と略す），イ ン タ ー フ ェ ロ ン ， マ ク ロ フ ァ ー ジ活性化因子， コ ロ ニ ー剌激因子， 組織プ ラ ス ミ ノ ー ゲン活性化因子， ゥ ロ キナーゼ， ス ーバーオ キ サ イ ドデ ィ ス ム タ ーゼ ， イ ン ス リ ン ， 血液凝固第 \1因子， ネ オ カ ル チ ノ ス タ チ ン等の生理活性蛋白、 ペ ニ シ リ ン ， セ フ ァ ロ ス ボ リ ン ， マ イ ト マ イ シ ン C , ア ド リ ア マ イ シ ン ， β - シ ト シ ン ァ ラ ビ ノ サ イ ド ， セ フ ァ ロ リ ジ ン ， セ フ ァ レ キ シ ン ， 硫 酸ブ レ オ マ イ シ ン ， ダ ウ ノ ル ビ シ ン等の抗生物質、 塩酸モ ノレヒ ネ ， 塩酸ブ ロ カ イ ン等の鎮痛剤、 塩酸メ ク ロ フ ヱ ノ キ セ一 ト 等の脳代謝改善剤が挙げ ら れ る 。 特に好ま し レ '、物質 と して は、 ヒ ト TNF 及び ヒ ト IL-1 or等の生理活性蛋白が挙 げ ら れる 。 成分（a)の使用量は成分（b) と成分（c)の総量に対 し て、 15W/W%以下で あ る こ とが好ま し い。 The component (a) which is a component of the preparation of the present invention includes, for example, cancer necrosis factor (hereinafter referred to as “TNF”), interlocutin 1 «(J¾ iL-lor j), Interferon, Macrophage activating factor, Colony stimulating factor, Tissue plasminogen activating factor, Perokinase, Bioactive proteins such as baroxin dismutase, insulin, blood coagulation factor 1, neocaltinostatin, penicillin, sefin Aroborin, Might Machine C, Adria Mine, β-cytosine arabinoside, cephalo gin, cepha Antibiotics such as lexin, bleomycin sulphate and downorubicin; analgesics such as monolephine hydrochloride and brokine hydrochloride; hydrochloric acid Click b off We Roh key cell one cerebral metabolism improving agents such bets are listed et is Ru. Particularly preferred substances include physiologically active proteins such as human TNF and human IL-1 or. The amount of component (a) used is preferably 15 W / W% or less, based on the total amount of component (b) and component (c).
成分（a)は単独の物質であ っ て も よ いが、 そ の物質の活性 賦活剤及び / 又は そ の物質 と 相加又 は相乗的効果を有す る 他の成分 （例え ば、 T N F の場合に は、 I F N， イ ン タ 一 ロ イ キ ン 2 , レ ン チ ナ ン ， ァ ク チ ノ マ イ シ ン D , ァ ク チ ノ マ イ シ ン C 又 はァ ド リ ア マ イ シ ン等） の 1 種以上 と の組み合わせ で あ.つ て も よ い。 Component (a) may be a single substance, but the activity of that substance Activator and / or other components that have an additive or synergistic effect with the substance (eg, IFN, interloicin 2, lentinan in the case of TNF) , Actino Machine D, Actino Machine C or Adria Machine, etc.).
成分（b)は本発明 の製剤中 の成分（a)を含有す る 微粒子の凝 集を防止 し、 更に生体内で本発明 の製剤を安定化す る 作用 を有す る。 The component (b) has an effect of preventing the aggregation of the fine particles containing the component (a) in the preparation of the present invention and stabilizing the preparation of the present invention in vivo.
成分（b)と して は、 例.えば ト リ オ レ イ ン酸 ソ ル ビ タ ン， セ ス キ ォ レ イ ン 酸 ソ ノレ ビ タ ン ， モ ノ ォ レ イ ン 酸 ソ ノレ ビ タ ン ， モ ノ ス テ ア リ ン酸 ソ ル ビ タ ン ， モ ノ ノヾル ミ チ ン 酸 ソ ノレ ビ タ ン ， モ ノ ラ ウ リ ン 酸 ソ ル ビ タ ン等が挙げ ら れ、 H L B 値が 4 以下であ る も の、 例え ばセ ス キ ォ レ イ ン 酸 ソ ノレ ビ タ ン ( H L B 値 3.7 ) が好ま し い。 As component (b), for example, solvitan trioleate, sonorebitan sesquioleate, sonorebito monooleate , Sonobitan monostearate, sonorebitan monomitriminate, and solubitan monolaurate, and the HLB value. For example, sonolebitan sesquioleate (HLB value of 3.7) is preferred, although it is less than 4.
成分（b)の使用量は成分（c)に対 して 50 W/ % 以下で あ り 、 3 〜 ： 10 W/W% であ る こ と が好ま し く 、 2 〜 6 /W% で あ る こ と がよ り 好ま し い。 Component (b) is used in an amount of 50 W /% or less, preferably 3 to 10 W / W%, more preferably 2 to 6 / W%, based on component (c). Something is better.
成分（c)は生体内てニ成分（a)を保持す る作用 を有す る 。 The component (c) has an action of retaining the two components (a) in a living body.
成分（c) と して は、 例え ば、 ゴマ油 ， 落花生油， 綿実油 ， 大豆油， 中鎖脂肪酸 ト リ ダ リ セ ラ イ ド ， ォ リ ーブ油 ， と う も ろ こ し油 ， ひま し油 ， ョ ー ド化ケ シ油脂肪酸ェ チ ル エ ス テ ル ， 酢酸 ト コ フ ヱ ロ ー ル等が挙 げ られ、 特に注射用 と し て用 い ら れる ゴマ油 ， 大豆油 ， ョ ー ド化ケ シ油脂肪酸ェ チ ルエ ス テ ル， 酢酸 ト コ フ ェ ロ ール， ひま し油又は こ れ ら の 混合物が好ま し い。 As component (c), for example, sesame oil, peanut oil, cottonseed oil, soybean oil, medium chain fatty acid triglyceride, olive oil, corn oil, castor oil Oils, oxidized poppy oil fatty acid ethyl esters, tocopheryl acetate, etc., and especially sesame oil, soybean oil, and sesame oil used for injection. Synthetic poppy oil fatty acid Preference is given to luster, tocopherol acetate, castor oil or mixtures thereof.
本発明の効果を よ り 高め る に は、 成分 ）の安定化剤を加 え る の が好ま しい。 特に成分（a)が ヒ ト TNF で あ る と き に は、 ゼ ラ チ ン ， ア ル ブ ミ ン ， グ ロ ブ リ ン， プ ロ タ ミ ン ， ト レ ノヽ ロ ー ス ， D —グ ル コ ー ス他の、 特開昭 58- 174330 号， 同 59- 20225 号及び同 59-39829号記載の安定化剤を添加する のが よ く 、 成分（a)がヒ ト IL-l or であ る と き に は、 ゼ ラ チ ン ， ァ ルブ ミ ン ， デ キ ス ト ラ.ン， ト レハ ロ 一 ス等を添加す る の が よ い。 In order to further enhance the effects of the present invention, it is preferable to add a stabilizer of the component). In particular, when component (a) is human TNF, gelatin, albumin, globulin, protamin, trenoose, D-g It is preferred to add a stabilizer described in JP-A-58-174330, JP-A-59-20225 and JP-A-59-39829, so that component (a) is human IL-l or If this is the case, it is advisable to add gelatin, albumin, dextran, trehalose, etc.
成分（a)の放出を制御す る に は、 ポ リ オ キ シエ チ レ ン硬 化ヒ マ シ油， 精製卵黄 レ シ チ ン ， 大豆 レ シ チ ン ， 水素添加 レ シ チ ン等の成分（b) と は異な る界面活性剤ゃコ レ ス テ ロ一 ル等を添加す る のが好ま し い。 こ の よ う な界面活性剤は、 成分 ）の微粒子化作用を も有する 。 To control the release of component (a), components such as polyoxyethylene hardened castor oil, refined egg yolk lecithin, soy lecithin, hydrogenated lecithin, etc. It is preferable to add a surfactant, such as cholesterol, which is different from (b). Such a surfactant also has an action of micronizing the component (2).
成分（a)の安定化剤 ， 成分（a)の放出制御剤 ， 成分（b)及び成 分（c) はそれぞれ 1 種に限ら れず、 複数種の も のを組み合わ せて用 いて も よ い。 The stabilizer of the component (a), the release controlling agent of the component (a), the component (b) and the component (c) are not limited to one kind each, and a plurality of kinds may be used in combination. .
本発明の製斉 ijの製造概略の一例を以下に説明す る 。 成分 (a)の水溶性物質及び そ の安定化剤を水に加えて よ く 撹拌 し、 必要に応 じて加温又は冷却 して、 均一な水溶液 と す る 。 こ の と き 、 安定化剤の P Hによ っ て は、 緩衝液を加えて成分（a) を最 も 安定化させ る PH付近に も っ て く る 必要があ る 。 こ の水溶液に次の① ， ②を加え、 撹拌機， ホ モ ジ ナ イ ザ 一， 超音波乳化機， フ ロ ー ジ ヱ ッ ト ミ キ サ ー ， マ ン ト ン ゴ — リ ン ホ モ ジ ナ イ ザー等を用 いて 乳化 し 、 得 ら れた ェ マ ル シ ヨ ン を凍結乾燥す る こ と に よ り 、 成分 ）の水溶性物質を 微粒子化す る 。 凍結乾燥前に成分（a) の放出制御剤 （ 例え ば コ レ ス テ ロ ー ル等） を加えて も よ い。 An example of the outline of production of the production ij of the present invention will be described below. Add the water-soluble substance of component (a) and its stabilizer to water, stir well, and heat or cool as necessary to obtain a uniform aqueous solution. At this time, depending on the pH of the stabilizing agent, it is necessary to bring a buffer solution close to the pH at which component (a) is most stabilized. Add the following (1) and (2) to this aqueous solution, and add a stirrer, homogenizer, ultrasonic emulsifier, phage-pet mixer, mantongo-linhomo The resulting emulsion is emulsified using a ginizer or the like, and the obtained emulsion is freeze-dried to microparticulate the water-soluble substance of the component). Before freeze-drying, a release controlling agent for component (a) (eg, cholesterol) may be added.
①水 と 混 じ ら ず、 水溶性物質を凍結乾燥す る た め に用 い得 る 有機溶媒 ① An organic solvent that is not miscible with water and can be used to freeze-dry water-soluble substances
②成分（b) の界面活性剤. ② Surfactant of component (b).
こ の微粒子を、 上記の ホ モ ジナ イ ザー等を用 い、 成分 ） の界面活性剤を加え た成分（c)の油性媒体中に懸濁 さ せ る こ と に よ り 、 本発明の製剤を得 る こ と がで き る.。 又、 こ の微 粒子に上記媒体を添付 した用時懸濁型の製剤 と す る こ と も で き る 。 The fine particles of the present invention can be obtained by suspending the fine particles in the oil medium of the component (c) to which the surfactant of the component) is added using the above-mentioned homogenizer or the like. Can be obtained. Also, a suspension for use at the time of use in which the above-mentioned medium is attached to the fine particles can be prepared.
本発明の製剤 は、 投与前に はサ ス ペ ン シ ョ ン状態で あ る が、 投与後生体内で 自 然乳化 して油滴内 に水溶性物質が懸 濁さ れた 0 / W エ マ ル シ ョ ン と な り 、 更に時間の経過 と共に、 水溶性物質が生体内 の水分を吸収， 溶解す る こ と に よ り 、 Although the preparation of the present invention is in a suspension state before administration, it is naturally emulsified in the living body after administration and the water-soluble substance is suspended in oil droplets. The water-soluble substance absorbs and dissolves water in the living body over time.
W / 0 / W エ マ ル シ ヨ ン の形を と る 。 本発明 の製剤は、 投与 し た と き 、 生体内で w/ 0 / w エ マ ル シ ョ ンを形成す る こ と に よ り 、 水溶性物質の濃度持続化を達成する 。 It takes the form of a W / 0 / W emulation. The formulation of the present invention achieves a sustained concentration of a water-soluble substance by forming a w / 0 / w emulsion in a living body when administered.
本発明の製剤の投与経路 と して は、 注射， 外用 ， 直腸 ， 経鼻， 経皮投与等の 非経口投与が挙 げ ら れ る が、 中で も 注 射が好ま し く 、 特に局所注射， 筋肉内注射， 皮下注射， 皮内注射， 動脈内注射が好ま しい。 The route of administration of the preparation of the present invention includes parenteral administration such as injection, external application, rectal, nasal, and transdermal administration. Injection is preferred, especially local injection, intramuscular injection, subcutaneous injection, intradermal injection, and intraarterial injection.
図面の簡単な説明 BRIEF DESCRIPTION OF THE FIGURES
図 1 , 2 は と も に、 i n V i tro にお け る pH 7 の リ ン酸緩 衝生理食 ¾液中で の ヒ ト Iい 1 α の放出曲線で あ り 、 丸印が 本発明の製剤、 四角 印が対照 Iい lor製剤であ る。 FIGS. 1 and 2 are both the release curves of human I-α in a phosphate-buffered physiological saline solution at pH 7 in vitro, where the circles indicate the present invention. And the square mark is the control I preparation.
図 3 はマ ウ ス大腿伸筋内投与後の血中濃度の推移を、 図 4 は ラ ッ ト 胃壁内投与後の リ ンパ液中濃度の推移を示し た も の で、 いずれも黒丸.印が本発明の製剤、 白丸印が対照 Figure 3 shows the change in blood concentration after intramuscular administration to the mouse extensor muscle, and Figure 4 shows the change in lymph concentration after administration to rat stomach wall. Is the preparation of the present invention, the white circle is the control
TNF 水溶液で あ る 。 It is a TNF aqueous solution.
発明を実施す る た め の最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下に実験例， 実施例を挙げて、 本発明 の製剤の効果を 説明する が、 本発明 は こ れ ら に限定さ れる も ので はない。 実験例 1- 後記実施例 1 で作製 した本製剤'と、 同力価の ヒ ト IL-1 or を舍有する 対照製剤について、 それぞれ in vitro で放岀 試験を行っ た。 放出量の時間的推移を E I A 法によ っ て測定 した。 対照製剤は次の様に じて調製 した。 特開昭 61 -271222 の実施例 2 で調製 し た ヒ ト Iい 1 5 mlと 20W/V%ゼ ラ チ ン水 溶液 （0.05M，pH7 リ ン酸緩衝液舍有） 5mlを均一に混合撹拌 し、 水溶液を得た。 こ れを凍結乾燥後粉碎 し、 で き た粉末 0.2 gに大豆油 7 m 1を加え、 ホ モ ジ ナ イ ザーを用 い て粉末粒 子を均一に懸濁さ せ る こ と に よ り 製造 し た。 結果を 図 1 に示す。 図 1 か ら わかる よ う に、 本製剤 は持続 傾向を示 し、 90分後の ヒ ト Iい 1 or放出量 は、 対照製剤で約 80% で あ る の に対 し、 本製剤で は約 30 % で あ っ た。 Hereinafter, the effects of the preparation of the present invention will be described with reference to experimental examples and examples, but the present invention is not limited to these. EXPERIMENTAL EXAMPLE 1- In vitro release tests were performed on the present preparation 'produced in Example 1 described below and a control preparation having human IL-1 or the same titer, respectively. The time course of the release was measured by the EIA method. The control preparation was prepared as follows. 15 ml of human I prepared in Example 2 of JP-A-61-271222 and 5 ml of a 20 W / V% gelatin solution (0.05 M, pH7 phosphate buffer) were mixed uniformly. The mixture was stirred to obtain an aqueous solution. This is freeze-dried and then pulverized, and 0.2 g of the resulting powder is added with 7 ml of soybean oil, and the powder particles are uniformly dispersed using a homogenizer to produce the powder. did. The results are shown in Figure 1. As can be seen from Fig. 1, this product shows a sustained tendency, and the release of human I or 1 after 90 minutes is about 80% in the control product, whereas this product does not. It was about 30%.
実験例 2 Experimental example 2
後記実施例 2 で作製 した本製剤について、 in vi troで放 出試験を行 っ た。 放出量の時間的推移を E I A 法に よ っ て測 定 し た。 結果を図 2 に示す。 図 2 か ら、 成分（c)と し て酢酸 ト コ フ ユ ロー ルを用 い た実施例 2 の製剤 は、 30時間かか つ て よ う や く 約 30% が放.出 さ れた こ と がわかる 。 従 っ て、 成 分 (c) と して大豆油を用 い る （実施例 1 ) よ り も、 酢酸 ト コ フ ユ ロ ー ルを用 い る 方が持続度が高い こ と がわ力、る 。 An in vitro release test was performed on the preparation prepared in Example 2 described below. The time course of the release was measured by the EIA method. The result is shown in figure 2. From Figure 2, it can be seen that about 30% of the formulation of Example 2 using tocofuryl acetate as the component (c) was released only after 30 hours. You can see this. Therefore, it is clear that the use of tocofurol acetate has a higher sustainability than the use of soybean oil as the component (c) (Example 1). , RU.
実施例 1 Example 1
特開昭 61 - 271222 の実施例 2 で調製 し た ヒ ト Iい 1 α し力 8.5 mg/ml ) 5 >!11と 201^/ ％ゼ ラ チ ン水溶液 （ 0.05M, PH7 リ ン酸緩衝液舍有） 5 m 1を均一に混合撹拌 し、 水溶液 A を 得た。 JP 61 - 271222 human I physician 1 alpha to force 8.5 mg / ml prepared in Example 2 of) 5> 11 201 ^ /% peptidase La Ji emissions solution (0.05 M, P H7-phosphate 5 ml was uniformly mixed and stirred to obtain an aqueous solution A.
別に、 精製卵黄 レ シ チ ン 0.25 g ,コ レ ス テ ロ ー ル 0.25 g を シ ク ロ へキ サ ン 50 m 1に溶解 し、 シ ク 口 へ キ サ ン溶液 B を得 た。 次に水溶液 A及び シ ク ロ へキ サ ン溶液 B を混合撹拌 し、 超音波ホ モ ジ ナ イ ザー に よ り 乳化 して エ マ ル シ ョ ン を得た 。 こ の エ マル シ ョ ン を凍結乾燥 し得 ら れた粉末 0.24g に 4 W/V%の セ ス キ ォ レ イ ン酸ソ ル ビタ ン を舍む大豆油 7 mlを加 え、 上記ホ モ ジナ イ ザーを用 いて粉末粒子を均一に懸濁 さ せる こ と に よ り 、 ヒ ト Iい l or を舍む油性の懸濁型持繞性製 剤を得た。 Separately, purified egg yolk lecithin (0.25 g) and cholesterol (0.25 g) were dissolved in cyclohexane (50 ml) to obtain a silk mouth hexane solution (B). Next, the aqueous solution A and the cyclohexane solution B were mixed and stirred, and emulsified by an ultrasonic homogenizer to obtain an emulsion. The emulsion was freeze-dried. To 0.24 g of the obtained powder, 7 ml of soybean oil containing 4 W / V% solvitan sesquioleate was added. Powder particles are evenly suspended using a modifier. By doing so, an oily suspension-type sustained product containing human I or L was obtained.
本発明の製剤はそ の ま ま 投与で き る形の も の、 用時懸濁 型の も のの いずれ も、 5 て で 3 か月 間安定で あ る 。 The preparations of the present invention, both in the form that can be administered as is and the suspension form before use, are stable for 5 months and 3 months.
実施例 2 Example 2
実施例 1 で得た ヒ ト IL- 1 を舍有する 粉末 0.24g に 4 W/V¾の セ ス キ ォ レ イ ン酸ソ ルビタ ンを舍む酢酸 ト コ フ エ 口 ール 7 m 1を加え、 ホ モ ジナ イ ザーを用 いて粉末粒子を油相 中に均一に懸濁させる .こ と に よ り 、 ヒ ト I L - 1 or を舍む油性 の懸濁型持続性製剤を得た。 To 0.24 g of the powder containing human IL-1 obtained in Example 1 was added 7 m1 of tocophere acetate containing 4 W / V¾ of sorbitan sesquioleate. Then, the powder particles were uniformly suspended in the oil phase using a homogenizer, whereby an oily suspension-type sustained-release preparation containing human IL-1 or 1 was obtained.
実験例 3 Experiment 3
後記実施例 3 で作製 した油性懸濁型製剤 と、 対照 と して 同力価の、 特開昭 60-232097 の実施例 3 で調製 し た ヒ ト The oil-based suspension preparation prepared in Example 3 to be described later and the human prepared in Example 3 of JP-A-60-232097 having the same titer as a control.
TNF 水溶液を それぞれマ ウ ス大腿伸筋内 に投与し、 血中濃 度の時間的推移を E I A 法に よ っ て測定 した。 Each TNF aqueous solution was administered into the mouse extensor extensor muscle, and the time course of blood concentration was measured by the EIA method.
マ ウ ス は各時点において それぞれ 4 匹ずつ用 い、 投与量 は各 々 3 X 10+JRU (Japan Reference Uni tの略； 以下同様） と し た。 測定値は 4 匹の平均値を用 いた。 Four mice were used at each time point, and the dose was 3 × 10 + JRU (abbreviation for Japan Reference Unit; the same applies hereinafter). The measured value was the average of four animals.
結果を図 3 に示す。 図 3 か らわかる様に、 油性懸濁型の 本製剤 は持続傾向を示 し、 14時間後 も 380 JBU/mlの血中濃 度が持続さ れてい る 。 The results are shown in Figure 3. As can be seen from Fig. 3, the oil-based suspension-type preparation showed a tendency to persist, and the blood concentration of 380 JBU / ml was maintained after 14 hours.
実験例 4 Experiment 4
後記実施例 3 で作製 した油性懸濁型製剤 と 、 対照 と して 同力価の実験例 3 で用 いた TNF 水溶液を そ れぞれ ラ ッ ト 胃 壁内 に投与 し、 胸管 リ ンバよ り 探取 した リ ンパ液中 の濃度 の時間的推移を E I A 法 によ っ て測定 した。 The oil-based suspension prepared in Example 3 described below was used as a control. The TNF aqueous solution used in Experimental Example 3 of the same titer was administered to the rat stomach wall, respectively, and the time course of the concentration in the lumper solution, which was probed from the thoracic duct resonator, was determined by the EIA method. It was measured.
ラ ッ ト は 4 匹を用 い、 投与量は各 々 1 X 10s JRU と し た 結果を図 4 に示す。 図 4 力、.ら わかる 様に、 油性懸濁型の本 製剤 は持続傾 向を示 し、 8 時間後 も 920 JRU/mlの リ ンバ液 中濃度が持続さ れて い る 。 Fig. 4 shows the results obtained when four rats were used and the dose was 1 × 10 s JRU. As can be seen from Fig. 4, the oil-based suspension-type formulation shows a tendency to persist, and the concentration of 920 JRU / ml in the solution was maintained even after 8 hours.
実施例 3 Example 3
特開昭 60- 232097 の.実施例 3 で調製 し た ヒ ト TNF 水溶液 (力価 2 X 107 JRU/m 1 ) 5 mlと 20W/V2ゼ ラ チ ン水溶液 Japanese Patent Application Laid-Open No. 60-232097, 5 ml of human TNF aqueous solution (titer 2 × 10 7 JRU / m 1) prepared in Example 3 and 20 W / V2 gelatin aqueous solution
(0.05M, PH7リ ン 酸緩衝液舍有） 5 mlを均一に混.合撹拌 し 水溶液 Aを得た。 別に、 精製卵黄 レ シ チ ン 0 · 25g ,コ レ ス テ ロ ーノレ 0.25g を シ ク ロ へキ サ ン 50mlに溶解 し、 シ ク ロ へ キ サ ン溶液 B を得た。 (0.05 M, PH7 phosphate buffer) 5 ml was uniformly mixed and stirred to obtain an aqueous solution A. Separately, 0.25 g of purified egg yolk lecithin and 0.25 g of cholesterol were dissolved in 50 ml of cyclohexane to obtain cyclohexane solution B.
次に、 水溶液 A及び シ ク ロ へキ サ ン溶液 B を混合撹拌 し 超音波ホ モ ジ ナ イ ザー によ り 乳化 してエ マ ル シ ヨ ン を得た， こ の ヱ マル シ ヨ ンを凍結乾燥 し得 ら れた粉末 0· 24g に 6 W/ V %の セ ス キ ォ レ イ ン酸ソ ノレ タ ンを舍 大豆油 7 m 1-を加 え、 上記ホ モ ジ ナ イ ザーを用 いて粉末粒子を 油相中 に均一 に懸濁 させ る こ と に よ り 、 ヒ ト T N F を舍む油状懸濁型の持 続性製剤を得た。 Next, the aqueous solution A and the cyclohexane solution B were mixed and stirred, and emulsified by an ultrasonic homogenizer to obtain an emulsion. The freeze-dried powder was mixed with 0.24 g of the powder, and 6 W / V% of sonolethan sesquioleate was added with 7 m 1- of soybean oil, and the above homogenizer was added. The powder particles were uniformly suspended in the oil phase using the above method to obtain an oil-based suspension-type continuous preparation containing human TNF.
本発明の製剤は、 そ の ま ま 投与で き る 形の も の、 用時懸 濁型の も の の いずれ も 、 5 て で 3 か月 間安定で あ る 。 産業上の利用 可能性 The preparations of the present invention, both in a form that can be administered as it is and a suspension form at the time of use, are stable for 5 months and 3 months. Industrial applicability
本発明の製剤は、 水溶液物質の血中 ， リ ンバ液中及び / 又は病巢内濃度が持続す る の で、 水溶液物質の効果的な治 療が期待で き る 。 Since the formulation of the present invention maintains the concentration of the aqueous substance in the blood, in the liver solution and / or in the disease, effective treatment of the aqueous substance can be expected.
Claims
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27434587 | 1987-10-29 | ||
| JP62/274345 | 1987-10-29 | ||
| JP63/227329 | 1988-09-09 | ||
| JP22732988 | 1988-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1989003671A1 true WO1989003671A1 (en) | 1989-05-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1988/001090 Ceased WO1989003671A1 (en) | 1987-10-29 | 1988-10-27 | Sustained-release preparation |
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| Country | Link |
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| WO (1) | WO1989003671A1 (en) |
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