WO1989003671A1 - Preparation a liberation entretenue - Google Patents

Preparation a liberation entretenue Download PDF

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Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
component
sustained
preparation according
release preparation
release
Prior art date
Application number
PCT/JP1988/001090
Other languages
English (en)
Japanese (ja)
Inventor
Motokazu Iwata
Terukazu Tanaka
Kenji Kojima
Original Assignee
Dainippon Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dainippon Pharmaceutical Co., Ltd. filed Critical Dainippon Pharmaceutical Co., Ltd.
Publication of WO1989003671A1 publication Critical patent/WO1989003671A1/fr

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Classifications

    • 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
    • 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
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparation à libération entretenue qui comprend au moins les trois composants suivants: (a) une substance soluble dans l'eau possédant une action médicamenteuse; (b) un agent tensio-actif possédant une valeur HLB allant jusqu'à 5; et (c) un véhicule huileux. Cette préparation peut maintenir à niveau efficace dans le sang, dans la lymphe et/ou dans le foyer la concentration de la substance à action médicamenteuse soluble dans l'eau. Par conséquent, cette préparation permet à la substance d'exercer son action dans les sites mentionnés et empêche la survenance d'effets négatifs à d'autres endroits du corps, ce qui la rend utile en pharmacothérapie.
PCT/JP1988/001090 1987-10-29 1988-10-27 Preparation a liberation entretenue WO1989003671A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP27434587 1987-10-29
JP62/274345 1987-10-29
JP22732988 1988-09-09
JP63/227329 1988-09-09

Publications (1)

Publication Number Publication Date
WO1989003671A1 true WO1989003671A1 (fr) 1989-05-05

Family

ID=26527614

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1988/001090 WO1989003671A1 (fr) 1987-10-29 1988-10-27 Preparation a liberation entretenue

Country Status (1)

Country Link
WO (1) WO1989003671A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589167A (en) * 1993-02-23 1996-12-31 Genentech, Inc. Excipient stabilization of polypeptides treated with organic solvents
WO1998041188A2 (fr) * 1997-03-18 1998-09-24 Quadrant Holdings Cambridge Limited Particule stable dans des formulations liquides
US6992065B2 (en) 2000-04-19 2006-01-31 Genentech, Inc. Sustained release formulations
JP2006213727A (ja) * 1993-04-07 2006-08-17 Scios Inc ペプチドの持続放出
US7824700B2 (en) 2001-02-23 2010-11-02 Genentech, Inc. Erodible polymers for injection
US8067020B2 (en) 2001-06-21 2011-11-29 Genetech, Inc. Sustained release formulation
US8604076B2 (en) * 2000-08-24 2013-12-10 Ucb Pharma Gmbh Method for producing a pharmaceutical composition comprising rotigotine
JP2019528248A (ja) * 2016-07-18 2019-10-10 ティシュージェン， インク． 生体分子の立体配座及び構造健全性を維持するための方法及び組成物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4888220A (fr) * 1972-03-04 1973-11-19
JPS5244222A (en) * 1975-09-30 1977-04-07 Yamanouchi Pharmaceut Co Ltd Method of making insulin preparations for rectal application
JPS5287218A (en) * 1976-01-01 1977-07-20 Yamanouchi Pharmaceut Co Ltd Insulin composition for rectal administration
JPS5581812A (en) * 1978-12-13 1980-06-20 Kowa Co Suppository for remedying diabetes
JPS6150923A (ja) * 1984-08-17 1986-03-13 Dainippon Pharmaceut Co Ltd ヒト癌壊死因子
JPS6232887A (ja) * 1985-08-02 1987-02-12 Dainippon Pharmaceut Co Ltd インタ−ロイキン１活性を示すポリペプチド及びそれをコ−ドするｄｎａ

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4888220A (fr) * 1972-03-04 1973-11-19
JPS5244222A (en) * 1975-09-30 1977-04-07 Yamanouchi Pharmaceut Co Ltd Method of making insulin preparations for rectal application
JPS5287218A (en) * 1976-01-01 1977-07-20 Yamanouchi Pharmaceut Co Ltd Insulin composition for rectal administration
JPS5581812A (en) * 1978-12-13 1980-06-20 Kowa Co Suppository for remedying diabetes
JPS6150923A (ja) * 1984-08-17 1986-03-13 Dainippon Pharmaceut Co Ltd ヒト癌壊死因子
JPS6232887A (ja) * 1985-08-02 1987-02-12 Dainippon Pharmaceut Co Ltd インタ−ロイキン１活性を示すポリペプチド及びそれをコ−ドするｄｎａ

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Iyakuhin Tenkabutsu Kenyukai-hen, (Jitsuyo Iyakuhin Tenkabutsu), 5 March 1974 (05.03.74), Kagaku Kogyo-sha Kabushiki Kaisa, P. 4, 112-113. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589167A (en) * 1993-02-23 1996-12-31 Genentech, Inc. Excipient stabilization of polypeptides treated with organic solvents
US5753219A (en) * 1993-02-23 1998-05-19 Genentech, Inc. Excipient stabilization of polypeptides treated with organic solvents
US5804557A (en) * 1993-02-23 1998-09-08 Genentech, Inc. Excipient stabilization of polypeptides treated with organic solvents
JP4610503B2 (ja) * 1993-04-07 2011-01-12 サイオス インコーポレイテッド ペプチドの持続放出
JP2006213727A (ja) * 1993-04-07 2006-08-17 Scios Inc ペプチドの持続放出
JP2010006841A (ja) * 1993-04-07 2010-01-14 Scios Inc ペプチドの持続放出
WO1998041188A3 (fr) * 1997-03-18 1998-12-10 Eastbridge Limited Particule stable dans des formulations liquides
WO1998041188A2 (fr) * 1997-03-18 1998-09-24 Quadrant Holdings Cambridge Limited Particule stable dans des formulations liquides
US6992065B2 (en) 2000-04-19 2006-01-31 Genentech, Inc. Sustained release formulations
US8604076B2 (en) * 2000-08-24 2013-12-10 Ucb Pharma Gmbh Method for producing a pharmaceutical composition comprising rotigotine
US7824700B2 (en) 2001-02-23 2010-11-02 Genentech, Inc. Erodible polymers for injection
US8501216B2 (en) 2001-02-23 2013-08-06 Genentech, Inc. Bioerodible polymers for injection
US8067020B2 (en) 2001-06-21 2011-11-29 Genetech, Inc. Sustained release formulation
JP2019528248A (ja) * 2016-07-18 2019-10-10 ティシュージェン， インク． 生体分子の立体配座及び構造健全性を維持するための方法及び組成物

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