JPH04505762A - Injectable composition of clarithromycin - Google Patents

Injectable composition of clarithromycin

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Publication number
JPH04505762A
JPH04505762A JP2508561A JP50856190A JPH04505762A JP H04505762 A JPH04505762 A JP H04505762A JP 2508561 A JP2508561 A JP 2508561A JP 50856190 A JP50856190 A JP 50856190A JP H04505762 A JPH04505762 A JP H04505762A
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composition
acid
clarithromycin
oil
stabilizer
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JP2963537B2 (en
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フイ，ホウ―ウアー
フス，チユン―チヤーン
キヤナン，ジヨン・ビー
ラバル，マイクル・ダブリユ
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アボツト・ラボラトリーズ
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10C—WORKING-UP PITCH, ASPHALT, BITUMEN, TAR; PYROLIGNEOUS ACID
    • C10C3/00—Working-up pitch, asphalt, bitumen
    • C10C3/002—Working-up pitch, asphalt, bitumen by thermal means
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10C—WORKING-UP PITCH, ASPHALT, BITUMEN, TAR; PYROLIGNEOUS ACID
    • C10C3/00—Working-up pitch, asphalt, bitumen
    • C10C3/06—Working-up pitch, asphalt, bitumen by distillation
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments
    • D01F9/08—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments of inorganic material
    • D01F9/12—Carbon filaments; Apparatus specially adapted for the manufacture thereof
    • D01F9/14—Carbon filaments; Apparatus specially adapted for the manufacture thereof by decomposition of organic filaments
    • D01F9/145—Carbon filaments; Apparatus specially adapted for the manufacture thereof by decomposition of organic filaments from pitch or distillation residues
    • D01F9/155—Carbon filaments; Apparatus specially adapted for the manufacture thereof by decomposition of organic filaments from pitch or distillation residues from petroleum pitch

Abstract

(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

【発明の詳細な説明】 本発明はクラリトロマイシンの注射用組成物に係る。[Detailed description of the invention] The present invention relates to injectable compositions of clarithromycin.

発明の背景 エリスロマイシンやクラリトロマイシンのような親油性薬剤は、注射部位に激し い痛みが生じるために筋肉内または静脈内注射では投与されない。この問題に対 処するために種々の手段が取られてきており、この中には親油性薬剤自体を誘導 体にする試みも含まれる。しかしながら、激しい痛みを起こすことのない親油性 薬剤の注射用組成物が引続き必要とされている。Background of the invention Lipophilic drugs like erythromycin and clarithromycin can be harsh at the injection site. It is not given by intramuscular or intravenous injection because it causes severe pain. For this problem Various measures have been taken to treat the drug, including inducing the lipophilic drug itself. It also includes attempts to make it into a body. However, lipophilic properties that do not cause severe pain There continues to be a need for injectable pharmaceutical compositions.

エリスロマイシンの脂肪エマルジョンは局所的な刺激をしないことが知られてい る。しかし、抗生物質クラリトロマイシンは油が存在しても脂肪エマルジョンに 対する溶解性が低く、この櫂のエマルジョンから析出してしまう。これまでのと ころ、クラリトロマイシンを可溶化させて、治療上有効な薬剤上の目的を達成す るのに十分な濃度の安定な注射用組成物を得ることはできなかった。例えば、特 開昭６１−２９１５２０号（１９８６年１２月２２日公開）は、安息香酸ベンジ ルを添加して植物油中のエリスロマイシン濃度を上げることを示唆している。し かし、前記特許に準じてクラリトロマイシンを調製しても、治療上許容できる濃 度（例えば５　ｍ　ｇ　／　ｍ　Ｉ　）は得られない。従って、クラリトロマイ シンの所望の全一日用量を投与するためには、各回の注射液の量を増やすか注射 回数を増やさなければならない。そこで、注射部位に疼痛を起こさない、治療上 許容される濃度のクラリトロマイシンの安定な注射用組成物が引続き必要とされ ている。Erythromycin fat emulsion is known to be non-locally irritating. Ru. However, the antibiotic clarithromycin forms in fat emulsions even in the presence of oil. It has low solubility in water and precipitates out of this paddle emulsion. So far However, clarithromycin can be solubilized to achieve therapeutically effective drug goals. It has not been possible to obtain stable injectable compositions of sufficient concentration for use. For example, Kaisho 61-291520 (published on December 22, 1986) describes benzoic acid benzene. It has been suggested that the concentration of erythromycin in vegetable oils be increased by the addition of death However, even if clarithromycin is prepared according to the patent, it is not possible to obtain a therapeutically acceptable concentration. degree (for example, 5 mg/mI) cannot be obtained. Therefore, claritromy To administer the desired total daily dose of Syn, increase the volume of each injection or I have to increase the number of times. Therefore, it is a therapeutic method that does not cause pain at the injection site. There continues to be a need for stable injectable compositions of clarithromycin at acceptable concentrations. ing.

発明の概要 本発明は注射用のクラリトロマイシンの薬剤組成物に係る。Summary of the invention The present invention relates to pharmaceutical compositions of clarithromycin for injection.

本発明の組成物は筋肉内または中心静脈もしくは末梢静脈経由で投与できる。Compositions of the invention can be administered intramuscularly or via central or peripheral veins.

より詳細には、本発明は、治療上有効濃度のクラリトロマイシン、トリグリセリ ド油及び安定剤を有する注射用油脂エマルジョンに関する。More particularly, the present invention provides therapeutically effective concentrations of clarithromycin, triglycerides, The present invention relates to an injectable fat emulsion containing an oil and a stabilizer.

発明の詳細な説明 本発明の薬剤組成物は、治療上有効濃度のクラリトロマイシン、トリグリセリド 油及び安定剤を含有する注射用油脂エマルジョンからなる組成物を含んでいる。Detailed description of the invention The pharmaceutical composition of the present invention comprises therapeutically effective concentrations of clarithromycin, triglycerides, It includes a composition consisting of an injectable fat emulsion containing an oil and a stabilizer.

本発明には、さらに乳化剤を含有する組成物及びトニシティ調整剤（Ｉｏｎｉｅ ｉｆ７−ｚｄｉｕ＋ｌｉｏｇ　ａｇｅｎ＋　）を含有する組成物も含んでいる。The present invention further includes a composition containing an emulsifier and a tonicity regulator (Ionie). if7-zdiu+liogagen+).

本発明組成物は具体的には抗生物質クラリトロマイシンを含有する組成物である 。本明ｌＩ！ＩＩＦ中の「クラリトロマイシン」とは、６−０−メチル−エリス ロマイシン（Ｕ、　Ｓ、　４．３３１．８０３）及び当業界公知のクラリトロマ イシンの半合成誘導体並びにその薬剤上許容される塩及びエステルを意味する。The composition of the present invention is specifically a composition containing the antibiotic clarithromycin. . Honmei lI! "Clarithromycin" in IIF is 6-0-methyl-erys Romycin (U, S, 4.331.803) and Claritroma known in the art Refers to semi-synthetic derivatives of isin and pharmaceutically acceptable salts and esters thereof.

本明細書中の「薬剤上許容される塩及びエステル」とは、正常な医学的判断の範 囲で、望ましくない毒性、過敏症、アレルギー反応等を引き起こすことなくヒト 及びより下級の動物の組成に対して使用するのに好適で、相応な利点／危険性比 に見合い、微生物感染の化学療法及び予防目的の用途に有効な塩及びエステルを 意味する。マクロライド系抗生物質の一般的な薬剤上許容できる塩及びエステル には、アセテート、ニストレード（プロピオン酸エステルのラウリル硫酸塩）、 琥珀酸エチル、グルセブテート（グルコヘプタネート）、ラクトビオネート、ス テアレート及び塩酸塩の形がある。薬剤業界で使用されている他の酸塩は次の通 りである：アジビン酸塩、アルギン酸塩、アスパラギン酸塩、安息香酸塩、ベン ゼン−スルホン酸塩、重硫酸塩、酪酸塩、クエン酸塩、しょうのう酸塩、しょう のうスルホン酸塩、シクロペンタンプロピオン酸塩、ジグルコン酸塩、ドデシル 硫酸塩、エタンスルホン酸塩、フマル酸塩、グルコン酸塩、グリセロ燐酸塩、ヘ ミ硫酸塩、工大ント酸塩、カプロン酸塩、臭化水素酸塩、ヨウ化水素酸塩、２− ヒドロキシ−エタンスルホン酸塩、乳酸塩、マレイン酸塩、メタンスルホン酸塩 、２−ナフタレンスルホン酸塩、ニコチン酸塩、蓚酸塩、パモ酸塩（ｐｃ＋ａＢ ［ｅ）、パントテン酸塩、ペクチン酸塩、ベルオクソニ硫酸塩、３−フェニルプ ロピオン酸塩、ピクリン酸塩、ピバリン酸塩、プロピオン酸塩、琥珀酸塩、酒石 酸塩、チオシアン酸塩、トシル酸塩及びウンデシル酸塩。塩基性窒素含有基は低 級アルキルハライド、例えば塩化、臭化及びヨウ化メチル、エチル、プロピル及 びブチル；硫酸ジアルキル、例えば硫酸ジメチル、ジエチル、ジブチル及びシア ミル；長鎖ハライド、例えば塩化、臭化及びヨウ化デシル、ラウリル、ミリスチ ル及びステアリル；アラルキルハライド、例えば臭化ベンジル及びフェネチル等 のような薬剤により四級化できる。The term "pharmaceutically acceptable salts and esters" as used herein refers to Can be safely used in humans without causing undesirable toxicity, hypersensitivity, allergic reactions, etc. and suitable for use on lower animal compositions, with a commensurate benefit/risk ratio. salts and esters that are suitable for use in chemotherapeutic and prophylactic purposes against microbial infections. means. Common pharmaceutically acceptable salts and esters of macrolide antibiotics Includes acetate, Nistrade (lauryl sulfate of propionate ester), Ethyl succinate, glucoheptate, lactobionate, sulphate There are tearate and hydrochloride forms. Other acid salts used in the pharmaceutical industry are: are: adibate, alginate, aspartate, benzoate, benzoate, Zen-sulfonate, bisulfate, butyrate, citrate, shodate, sulfate Nosulfonate, cyclopentanepropionate, digluconate, dodecyl Sulfates, ethanesulfonates, fumarates, gluconates, glycerophosphates, Misulfate, polychloride, caproate, hydrobromide, hydroiodide, 2- Hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate , 2-naphthalenesulfonate, nicotinate, oxalate, pamoate (pc+aB [e), pantothenate, pectate, beluoxonisulfate, 3-phenylp Ropionate, picrate, pivalate, propionate, succinate, tartrate acid salts, thiocyanate, tosylate and undecylate. Basic nitrogen-containing groups are low alkyl halides such as methyl chloride, bromide and iodide, ethyl, propyl and and butyl; dialkyl sulfates, such as dimethyl sulfate, diethyl, dibutyl and sia Mil; long chain halides such as decyl chloride, bromide and iodide, lauryl, myristic and stearyl; aralkyl halides such as benzyl bromide and phenethyl It can be quaternized by drugs such as.

本発明組成物はクラリトロマイシンの溶解度を改善するので、以前より高い濃度 が得られる。本明細書中の「治療上有効な濃度」とは、どの医学的治療に対して も使用できる相応な有用性／危険性比で、感染し易い細菌または他の微生物によ る感染を治療しまたは予防するクラリトロマイシンの有効濃度、例えば５ｍｇ／ ｍｌを意味している。もちろん、本明細書の組成物の全１日用量は正しい医学的 判断の範囲内で担当医が決定する。The composition of the invention improves the solubility of clarithromycin so that it can be used at higher concentrations than previously possible. is obtained. As used herein, "therapeutically effective concentration" refers to can also be used with a reasonable benefit/risk ratio to prevent infection by susceptible bacteria or other microorganisms. An effective concentration of clarithromycin to treat or prevent infection, e.g. It means ml. Of course, the total daily dosage of the compositions herein is within the correct medical range. The decision will be made by the attending physician within the scope of his or her judgment.

特定の患者の具体的な全１日量は、年齢、体重、全身状態、性別、食事、投与時 間、投与経路（すなわち、筋肉内または中心もしくは末梢静脈経路）、排出速度 、治療中の特定疾患の重症度及び医学界でよく知られている要素を含む種々の要 素により変化しよう。クラリトロマイシンの好ましい治療上有効濃度は約２．５ ｍｇ／ｍｌから約１０ｍｇ／ｍｌであり、最も好ましい濃度は約５　ｍ　ｇ　／ 　ｍ　ｌである。The specific total daily dose for a particular patient will depend on age, weight, general condition, gender, diet, and time of administration. time, route of administration (i.e. intramuscular or central or peripheral venous route), rate of excretion. various factors, including the severity of the particular disease being treated and factors well known in the medical community. Let's change depending on the element. A preferred therapeutically effective concentration of clarithromycin is about 2.5 mg/ml to about 10 mg/ml, with the most preferred concentration being about 5 mg/ml. It is ml.

本発明の注射用エマルジョンの脂質はトリグリセリド油が提供する。本明細書中 の「トリグリセリド油」とは、室温（２２℃）で液体であり、主としてＣ６’１ ｇ脂肪酸のトリグリセリドからなるトリグリセリド組成物を意味する。トリグリ セリド油は短１１（Ｃ−Ｃ’Ｉでも長鎖（ＣＩ４−　Ｃｌ８）でもよいが、好ま しいものはＣ−Ｃ１２脂肪族脂肪酸である。これらのトリグリセリド油は一般に 約２％から約４０％存在する。The lipid in the injectable emulsion of the present invention is provided by triglyceride oil. In this specification "Triglyceride oil" is a liquid at room temperature (22°C) and is mainly composed of C6'1 g means a triglyceride composition consisting of triglycerides of fatty acids. Trigri Ceride oil may be short-chain (C-C'I) or long-chain (CI4-Cl8), but is preferably The most important ones are C-C12 aliphatic fatty acids. These triglyceride oils are generally Present from about 2% to about 40%.

５ｇ！鐘脂肪酸の１つの好ましい種類のトリグリセリド油の代表例は、主として Ｃ６”−０１０脂肪酸のグリセリントリエステルからなる油である。このような 油はよく知られた方法で合成することもでき、ヤシ油のような好ましい天然油か ら所望の低融点トリグリセリドの多い画分を得るための熱分別または溶媒分別法 の公知の手法で天然源から得ることもできる。好ましい低融点、低分子量トリグ リセリド油は、カプリル（オクタン）酸とカプリン（デカン）酸のエステル混合 物を多く含むヤシ油の低分子量画分である。このような油はニューシャーシー、 ブーントンのＮＯＩｎｔｅｒｎ山ｏｎｔｌ　Ｉｎｃ、、から１ｌｅｏｂｅｅ　Ｒ ト５油として市販されている。ヤシ油の他の低融点画分も好適である。5g! Representative examples of one preferred class of triglyceride oils of bell fatty acids are primarily It is an oil consisting of glycerol triester of C6”-010 fatty acid. Oils can also be synthesized by well-known methods, or from preferred natural oils such as coconut oil. thermal or solvent fractionation to obtain the desired low-melting triglyceride-enriched fraction. It can also be obtained from natural sources using known techniques. Preferred low melting point, low molecular weight trig Lyceride oil is a mixture of esters of caprylic (octanoic) and capric (decanoic) acids. It is a low molecular weight fraction of coconut oil that is rich in organic compounds. Such oil is New Chassis, 1 leobee R from Boonton's NOIntern Inc. It is commercially available as 5 oil. Other low melting fractions of coconut oil are also suitable.

もう１つの好ましい種類のトリグリセリド油は、不飽和またはポリ不飽和Ｃ−Ｃ １８脂肪酸のグリセリントリエステルを高い割合で含むトリグリセリド油からな る。このような油の好ましい例は、９０％以上がオレイン酸及びリノール酸から なる脂肪酸組成を一般に有しているす７ラワー油である。これらの酸のトリグリ セリドは２０℃で液体であり、−力対応の飽和トリグリセリドのトリステアリン は室温では螺状の固体であり、約７２℃で溶解する。このような油の別の好まし い例は大豆油である。慣用の熱分別または溶媒分別で得られる他の低融点植物油 または油の低融点画分も好適である。このような不飽和またはポリ不飽和植物油 は本発明の組成物を処方する際に経費を低くできるという利点を提供できるが、 酸化により劣化する傾向が大きく、トコフェロールのような油溶性抗酸化剤の添 加を必要とすることがある。Another preferred class of triglyceride oils are unsaturated or polyunsaturated C-C Made from triglyceride oil containing a high proportion of glycerol triester of 18 fatty acids. Ru. Preferred examples of such oils include 90% or more of oleic acid and linoleic acid. It is a sour 7 laurel oil that generally has a fatty acid composition of Triglycerides of these acids Cerides are liquid at 20°C, and the corresponding saturated triglyceride tristearin is a spiral solid at room temperature and melts at about 72°C. Another preference for such oils A good example is soybean oil. Other low melting point vegetable oils obtained by conventional thermal or solvent fractionation Alternatively, low melting fractions of oils are also suitable. unsaturated or polyunsaturated vegetable oils such as may offer the advantage of lower costs in formulating the compositions of the present invention, It has a strong tendency to deteriorate due to oxidation, and the addition of oil-soluble antioxidants such as tocopherols may require addition.

一般に大豆油またはサフラワー油から製造した、主として不飽和脂肪酸を含有す る中性トリグリセリド混合物を含む静注用エマルジョンも好ましい。このような エマルシランの例には、市販のトリグリセリド油と水のエマルジョンである　Ｌ ｉｐｏｓｙ＋ＲＩ＋がある。この主要成分脂肪酸はリノール酸、オレイン酸、パ ルミチン酸、ステアリン酸及びリルン酸である。さらに、これらの製品は乳化剤 としての卵黄の燐脂質とトニシティを調整するためのグリセリンとを含むことが できる。乳化した脂肪粒子は一般に天然の乳微球と同様に直径０．３３−０．５ ミクロンである。Generally made from soybean oil or safflower oil and containing primarily unsaturated fatty acids. Also preferred are intravenous emulsions containing neutral triglyceride mixtures. like this Examples of emulsilanes include L, which is a commercially available emulsion of triglyceride oil and water. There is iposy+RI+. The main fatty acids are linoleic acid, oleic acid, and These are lumitic acid, stearic acid and lylunic acid. Additionally, these products contain emulsifiers Contains egg yolk phospholipids as a phospholipid and glycerin to adjust tonicity. can. Emulsified fat particles generally have a diameter of 0.33-0.5, similar to natural milk microspheres. It is micron.

本発明組成物の一部では、トリグリセリド油に少量のモノ−及び／またはジグリ セリドを加えて成分の溶解度を高めまたは乳化を促進することができる。本発明 の他の組成物では、油の極性は低いのが好ましい。このような場合、好ましいト リグリセリド油では、極性の非常に高いモノ−及びジグリセリド並びに燐脂質含 量が低い。In some compositions of the invention, the triglyceride oil contains small amounts of mono- and/or diglyceride oils. Cerides can be added to increase the solubility of ingredients or promote emulsification. present invention In other compositions, it is preferred that the oil has low polarity. In such cases, the preferred Liglyceride oils contain highly polar mono- and diglycerides and phospholipids. Quantity is low.

本発明組成物は少なくとも１つの安定剤も含んでいる。本明細書中の「安定剤」 とは、トリグリセリド油槽中のクラリトロマイシンの溶解度を上昇させて治療上 許容されるクラリトロマイシン濃度を得るための添加剤を意味している。安定剤 には、脂肪酸（Ｃ−Ｃ飽和脂肪酸、またはＣ１８−０１８不飽和脂肪酸）、Ｎ− メチルピロリドン（ＮＭＰ）及びベンジルアルコールを含んでいる。好ましい脂 肪酸はオレイン酸、カプリン酸、カプリル酸及びカプロン酸である。塩化メチレ ンも使用できるが、最終生成物を得るためには蒸発させる必要がある。安定剤を 含まないときには、エマルシランは不安定で、短時間すなわち１力月以内にエマ ルシランからクラリトロマイシンが析出される傾向にあることが判った。安定剤 にはエマルシヨンの安定性を高め、懸濁液を少なくとも６力月維持する作用があ る。The composition of the invention also includes at least one stabilizer. "Stabilizer" herein is a therapeutic drug that increases the solubility of clarithromycin in triglyceride oil baths. Refers to additives to obtain acceptable clarithromycin concentrations. stabilizer includes fatty acids (C-C saturated fatty acids or C18-018 unsaturated fatty acids), N- Contains methylpyrrolidone (NMP) and benzyl alcohol. preferred fat Fatty acids are oleic acid, capric acid, caprylic acid and caproic acid. methylene chloride can also be used, but must be evaporated to obtain the final product. stabilizer Without it, emulsilan is unstable and loses its emulsion within a short period of time, i.e. within 1 month. It was found that clarithromycin tends to be precipitated from Luciran. stabilizer has the effect of increasing the stability of the emulsion and maintaining the suspension for at least 6 months. Ru.

本発明は乳化剤を含有する組成物も含んでいる。本明細書中の「乳化剤」とは、 注射用組成物が個々の脂質相と水相とに分離することを防ぐ化合物を意味してい る。好適な乳化剤には卵黄の燐脂質（約０．５−５％）ｆグリコデオキシコール 酸またはグリココール酸またはその混合物；及び非イオン表面活性剤（例えば、 ポリソルベート、ソルビタンモノステアレート及びその混合物）を含むが、これ に限定されるものではない。The invention also includes compositions containing emulsifiers. The "emulsifier" in this specification is refers to a compound that prevents the injectable composition from separating into separate lipid and aqueous phases. Ru. Preferred emulsifiers include egg yolk phospholipids (approximately 0.5-5%) and glycodeoxycol. acids or glycocholic acids or mixtures thereof; and nonionic surfactants (e.g. polysorbate, sorbitan monostearate and mixtures thereof), but this It is not limited to.

本発明組成物は微量添加剤、例えばグリセリン（１−５％）及びプロピレングリ コール（１−１０％）のようなトニシティー調整化合物も含んでよい。The composition of the invention may contain minor additives such as glycerin (1-5%) and propylene glycerin. Tonicity adjusting compounds such as kohl (1-10%) may also be included.

以下の実施例は本発明の実施を限定することなく本発明を説明するためのもので ある。The following examples are intended to illustrate the invention without limiting its implementation. be.

実施例１ 本発明の代表的な組成物を次のように製造した：化門物　量 クラリド０フィシンのＮ　Ｍ　Ｐ溶液　１’６７ｍｇ／ｍｌｘ３ｍｌＬｆｐｏｓ ｙｎ　ｒｌ　２０％　１００ｍ１クラリトロマインンベース（５００ｍｇ、　Ａ ｂｂｏｔ）Ｌｘ＆ｏｒｓ＋ｏｒｉｅｘ、イリノイ）をＮ　Ｍ　Ｐ　（Ｎ−メチル ビクリトン、ＧＡＦ社、１Ｂａｅ　Ｎ、　Ｉ、　）　’３　ｍ　ｌに溶解した。Example 1 Representative compositions of the invention were prepared as follows: Chemical amount Claride 0 ficin NMP solution 1'67mg/ml x 3ml Lfpos yn rl 20% 100ml 1 Claritromine Inbase (500mg, A bbot) Lx&ors+oriex, Illinois) to NMP (N-methyl Vicriton, GAF Co., Ltd., 1Bae N, I, ) was dissolved in 3 ml.

次ニコの溶液をＬＩｐｏＨｎＲＩＩ　２０％（２０％油／８０％水エマルジタン ）９７’ｍｌに加え、混合物を振とうした。クラリトロマイシン濃度を計算する と約５　ｍ　ｇ　／　ｍ　ｌであった。Next, add Nico's solution to LIpoHnRII 20% (20% oil/80% water emulgitan) ) and the mixture was shaken. Calculate clarithromycin concentration and about 5 mg/ml.

実施例２ 実施例２の組成物は一般に次の比率で各成分を含有する。Example 2 The composition of Example 2 generally contains each component in the following proportions.

化合物　量（組成物に対する％） ＬｏｂｅｓＲ油　１０−４０ カプリン酸　０．５−３ クラリトロマインンベース　０．５−３卵の燐脂質　０．５−３ 溶液Ａはクラリトロマイシン２．５グラムとカプリン酸５．６グラムをｌｌ！ｏ ｂｅ！Ｒ油（中鎖トリグリセリド）ＩＣＩＯダラムに加えて調製した。次に溶解 するまで溶液を加熱（約４０℃）撹拌した。Compound amount (% of composition) LobesR oil 10-40 Capric acid 0.5-3 Claritromine base 0.5-3 Egg phospholipid 0.5-3 Solution A contains 2.5 grams of clarithromycin and 5.6 grams of capric acid! o Be! Prepared by adding R oil (medium chain triglycerides) to ICIO Durham. then dissolve The solution was heated and stirred (approximately 40° C.) until

溶液Ｂは卵の燐脂質６グラムとグリセリン１２グラムを水２００ｍ１中で撹拌し て調製した。Solution B is made by stirring 6 grams of egg phospholipid and 12 grams of glycerin in 200 ml of water. It was prepared using

溶１ｔ）−ＢをＭｉｅｒｏｆｌｕｉｄｉ＋ｅｒ　１１１１０（Ｍｉｅｒｏｆｌｕ ｉｄｉｃｓ　Ｃｏｒｐ、　）に３回通した。次に、溶液Ａをシリンジポンプを介 して１ｍｌ／分の速度で加えながら、混合物を微小流動床に通した。添加終了後 、混合物をさらに５回微小流動床に通し・ＮａＯＨでｐＨ７，５に調整し、水で 希釈して５００ｍ１とした。クラリトロマイシン濃度を計算すると約５　ｍ　ｇ 　／　ｍ　ｌであった。Mierofluidi+er 11110 (Mieroflu idics Corp.) three times. Next, add solution A via the syringe pump. The mixture was passed through a microfluidized bed while adding at a rate of 1 ml/min. After addition , the mixture was passed through the microfluidized bed five more times, adjusted to pH 7.5 with NaOH, and diluted with water. Diluted to 500ml. Calculating the clarithromycin concentration is approximately 5 mg /ml.

実施例３ 本発明の塩化メチレン含有例は次のように製造した：化合物　量 クラリトロマイシンベース　”　１−２０ｍｇ／ｍｌ（最終濃度）塩化メチレン 中の卵の燐脂質　０．５−３％ＮｅｏｂｓｅＲ油　１０−４０％ 水　残量 クラリトロマイシン（２，５グラム）と卵の燐脂質６グラムを塩化メチレン１５ ０ｍ１に溶解した。溶液をロータリー・エバポレータで蒸発乾固させ、残った薄 いフィルムを渦動しつつ２００ｍ１の水に溶かした。次に、ＮｏｅｂｅｅＲ油（ １００グラム）をシリンジポンプと微小流動床を介して実施例２の薬剤−燐脂ｉ ｒａ合物に加えた。最終エマルジタンはＮａ　ＯＨでｐＨ７，５に調整し、水で ５００ｍ　ｌにまで希釈した。Example 3 Examples containing methylene chloride of the present invention were prepared as follows: Compound Amount Clarithromycin base 1-20mg/ml (final concentration) methylene chloride Egg phospholipid inside: 0.5-3% NeobseR oil: 10-40% Water remaining amount Clarithromycin (2.5 grams) and 6 grams of egg phospholipid in methylene chloride 15 Dissolved in 0ml. The solution was evaporated to dryness on a rotary evaporator and the remaining thin The film was dissolved in 200 ml of water with vortexing. Next, NoebeeR oil ( 100 grams) of Example 2 drug-phospholipid i via a syringe pump and a microfluidized bed. Added to ra compound. The final emulgitane was adjusted to pH 7.5 with NaOH and added with water. Diluted to 500ml.

実施例４ 可溶化剤カプリル酸を使用して実施例２を繰り返すことができる。溶液Ａはクラ リトロマイシンベース２．５グラムとカプリル酸４．７グラムをＭｏｔｂｅｅＲ 油１００グラムに加えて製造する。次に、溶解するまで、溶液を加熱しながら撹 拌する。Example 4 Example 2 can be repeated using the solubilizer caprylic acid. Solution A is MotbeeR 2.5 grams of ritromycin base and 4.7 grams of caprylic acid Prepare by adding 100 grams of oil. Then stir the solution while heating until dissolved. Stir.

溶液Ｂは卵の燐脂質６グラムとグリセリン１２グラムを水２００ｍ１中に撹拌し て調製する。Solution B is made by stirring 6 grams of egg phospholipids and 12 grams of glycerin into 200 ml of water. Prepare.

溶液Ｂを１１ｉｃｒｏｔｌｕｉｄｉｒｅ＋　ＭＩＩＱ（Ｍｉｅ＋ｏｆｌａｉｄｉ ｃｓ　Ｃｏｒｐ、　）に３回通す。次に、溶液Ａをシリンジポンプを介して加え ながら、混合物・を微小流動床に通す。添加終了後、混合物をさらに５回微小流 動床に通し、ＮａＯＨでｐＨ７，５に調整し、水で希釈して５００ｍ１とする。Solution B was mixed with 11icrotluidire+MIIQ(Mie+oflaidi cs Corp, ) three times. Next, add solution A via the syringe pump. while passing the mixture through the microfluidized bed. After the addition is complete, microflow the mixture five more times. Pass through a moving bed, adjust the pH to 7.5 with NaOH, and dilute to 500 ml with water.

クラリトロマイシン濃度を計算すると約５　ｍ　ｇ　／　ｍ　ｌである。The calculated clarithromycin concentration is approximately 5 mg/ml.

実施例５ 本発明組成物の別の例は次のように製造した：クラリトロマイシンベース（５グ ラム）と大豆油（２０グラム）を滑らかな懸濁液になるまで混合した。撹拌しな がらオレイン酸とカプロン酸（各々、６グラム及び３グラム）を加え、油相混合 物を４５℃で透明になるまで加熱した。Example 5 Another example of a composition of the invention was prepared as follows: Clarithromycin base (5 g rum) and soybean oil (20 grams) were mixed into a smooth suspension. Do not stir Add oleic acid and caproic acid (6 grams and 3 grams, respectively) and mix with the oil phase. The material was heated at 45° C. until transparent.

別に、卵のレシチン（５０グラム）を予熱した水（５００ｍｌ）に溶解し、水５ ０ｍ１中の１２．２グラムＮａＯＨを加えながら、加熱せずに溶液を撹拌した。Separately, dissolve egg lecithin (50 grams) in preheated water (500 ml) and The solution was stirred without heating while adding 12.2 grams of NaOH in 0 ml.

次に、グリセリン（２５グラム）を撹拌しながら加え、混合物を６０−６５℃で 半透明になるまで、冷却せずに（約１０−１５分間）　Ｇａａｌｉｎト１５ホモ ジェナイザーで循環させた。分散液をビーカーに移し、４０℃未満にする必要の あるときには冷却しながら、できるだけ高速でＳｉｔマ！ｔｓｏｎ　ミキサーで 上記油相を徐々に混和させた。Next, glycerin (25 grams) was added with stirring and the mixture was heated to 60-65 °C. Gaalin 15 homogenate without cooling (about 10-15 minutes) until translucent. I circulated it with Genizer. Transfer the dispersion to a beaker and keep the temperature below 40°C. At times, sit as fast as possible while cooling! tson mixer The oil phase was gradually mixed.

温度を４０℃未満に維持しながら、混合物をさらに３０分混和した。The mixture was mixed for an additional 30 minutes while maintaining the temperature below 40°C.

次に、得られた混合物を（３５−４０℃で６０００−７００Ｑ　ｐ、　１．　ｉ 、に３０回通して）均一化し、ホモジェナイザーを水４５０ｍ１ですすぎ、すす ぎ液をエマルジョン中に撹拌して入しタ。７％ＮａＯＨ’ｔ’ｐＨを７．７−７ ．９に調整した後、水で全量を１リツトルに合わせ、エマルジョンを約３Ｑｐ、 ｓ、ｉ。Next, the obtained mixture (6000-700Q p at 35-40℃, 1.i , 30 times) and rinse the homogenizer with 450 ml of water. Stir the liquid into the emulsion. 7% NaOH't'pH 7.7-7 ．． After adjusting the emulsion to 9, adjust the total volume to 1 liter with water and make the emulsion about 3Qp, s,i.

のＮ２ガス下で、０．２μナイロン膜を通して濾過した。of N2 gas through a 0.2μ nylon membrane.

スクラッチテスト マウスでスクラッチテストを実施して過敏症感覚への反応すなわち注射に伴う痛 みを測定した。クラリトロマイシン、を、体重各１６−３０ｇのマウス群（１０ 匹／群）に５ｍｌ／ｋｇの用量で皮下注射した。実施例５のオレイン酸／カプロ ン酸系を含有する第二の本発明組成物とクラリトロマイシンラクトビオネート標 準物質も同様にテストした。次に、各マウスが注射部位を引っかいた回数を正確 に５分間の量測定した。結果は本発明化合物では低いスクラッチ応答が得られる ことを示しており、下記第１表にまとめた。scratch test A scratch test was performed on mice to determine the hypersensitivity response, i.e. pain associated with injection. The results were measured. Clarithromycin was administered to groups of mice weighing 16-30 g each (10 mice/group) were injected subcutaneously at a dose of 5 ml/kg. Oleic acid/capro of Example 5 A second composition of the present invention containing an acid system and a clarithromycin lactobionate label. Quasi-substances were similarly tested. Next, accurately count the number of times each mouse scratched the injection site. The amount was measured for 5 minutes. The results show that the compound of the present invention provides a low scratch response. This is summarized in Table 1 below.

１．０．９％食塩溶液　２．６　１．６２、　ＬｉｐｏＢｎ　ｌＩ＋Ｎ１１Ｐ中 のクラリトロマイシンベース（２ｍｇ／ｍｌ）　７．０　４．３３、　Ｌｉｐｏ ｌＴａ　ＩＩ＋ＮｖＰ中のクラリトロマイシンベース（５ｍｇ／ｍり　９．７　 ４．２４、オレイン酸／カプロン酸系中の クラリトロマイシンベース （５ｍｇ／ｍ＋）　１１．　１　−− ５、クラリド亀マイシン ラクトビオネート　５２、Ｑ＊＊−一 本Ｓ、Ｄ、＝標準偏差 ＊＊＝１−４ｍｇ／ｍｌからの外挿 静脈過敏症テスト Ｌｉｐｏｍａ　ＩＩ中のクラリトロフィシン（５ｍ　ｇ　／　ｍ　Ｉ　）をウサ ギでの急性静脈過敏症について評価した。テスト組成物８ｍｌ／ｋｇを雌雄各２ 匹のウサギに１ｍｌ／分の速度で耳縁静脈に注入した。治療中及び治療後局所過 敏症の徴候についてウサギを頻繁に観察した。１時間、３時間及び２１時間後の 注射部位外観は正常であり、明かな発赤は認められず、従って組成物は局所過敏 症を引き起こさないと結論した。1.0.9% salt solution 2.6 1.62, in LipoBn lI+N11P Clarithromycin base (2mg/ml) 7.0 4.33, Lipo Clarithromycin base in lTa II + NvP (5 mg/m 9.7 4.24 in oleic acid/caproic acid system clarithromycin-based (5mg/m+) 11.　1　-- 5. Clarid Kammycin Lactobionate 52, Q**-1 Book S, D, = standard deviation Extrapolation from **=1-4mg/ml venous hypersensitivity test Claritrophicin (5 mg/mI) in Lipoma II was administered to rabbits. Acute venous hypersensitivity was evaluated. 8 ml/kg of the test composition was added to each male and female. One rabbit was injected into the marginal ear vein at a rate of 1 ml/min. Local hypersensitivity during and after treatment Rabbits were observed frequently for signs of sensitivity. After 1 hour, 3 hours and 21 hours The injection site appearance is normal, with no obvious redness, and therefore the composition does not cause local hypersensitivity. It was concluded that it did not cause any illness.

抗菌活性 静脈内投与用のＬｉｐｏｓＢ　ＩＩ中のクラリトロマイシンベース組成物５ｍｇ ／ｍｌ（組成物Ａ）の抗菌活性を、クラリトロマイシンベースラクトビオネート （組成物Ｂ）の活性とマウス保護テストで比較した。マウスは黄色ブドウ球菌（ Ｈｔｐｈ７１ｏｅｏｃｅｏ＋ｘａｔｅｕＩ）、化膿連鎖法！　［Ｓｔ＋ｅｐｔｏ ｃｏｃｃｕｓ　ｐｙｏｇｅｎｅｓ　）または肺炎法［（Ｈｒｅｐｊｏｅｏｃｃｕ ＋　ｐｎｅｕｍ＋ｎ１ｚｅ）　（各々、群１−２及び３）をＬ　Ｄ　ｓ　Ｏの１ ００倍量腹腔内投与して感染させ、感染の１時間後に尾の静脈から（Ａ）または （Ｂ）のいずれかを静注して治療した。感染後６日目の累積致死率からＥ　Ｄ　 ｓ　Ｏを計算した。結果から、第２表に示すように組成物が抗菌活性を有してい るこＡ　１６．８　２．５　０．６ Ｂ　４０．０　２．１　１．３ ＊′＝接種サイズ５．０ＩＸＬ０６コａニー形成単位　（ＣＦＵ’　＋１＊＊＝ 接種サイズ１９９５　ＣＦＵ’　＋＊本＊＝接種サイズ６３１０　ＣＦＵ’＋実 施例５のオレイン酸／カプロン酸系とクラリトロマイシンラクトビオネートとを 比較する同様のマウス保護テストでは抗菌活性について顕著な差異は認められな かった。Antibacterial activity Clarithromycin base composition 5 mg in Lipos B II for intravenous administration /ml (composition A) compared with clarithromycin-based lactobionate. (Composition B) was compared in a mouse protection test. Mice are infected with Staphylococcus aureus ( Htph71oeoceo+xateuI), suppuration chain method! [St+epto coccus pyogenes) or pneumonia method [(Hrepjoeoccu +pneum+n1ze) (groups 1-2 and 3, respectively) to 1 of LDsO Infection was carried out by intraperitoneal administration of 0.00 times the dose, and 1 hour after infection, the injection was carried out via the tail vein (A) or Treatment was performed by intravenously injecting either (B). E D from the cumulative fatality rate on the 6th day after infection sO was calculated. The results show that the composition has antibacterial activity as shown in Table 2. Ruko A 16.8 2.5 0.6 B 40.0 2.1 1.3 *'=Inoculation size 5.0IXL06 cony forming units (CFU'+1**= Inoculation size 1995 CFU' + * book * = inoculation size 6310 CFU' + fruit The oleic acid/caproic acid system of Example 5 and clarithromycin lactobionate A similar mouse protection test showed no significant difference in antibacterial activity. won.

動態薬学的活性 ６匹のピーグル犬を１晩絶食させた。２０％Ｌｉｐｏ＋７ｎ　Ｉｔ中のり５＋） 　トａマイシン（１００ｍｇ）（５ｍｇ／ｍ　１）を犬に静脈内注入した。２４ 時間定期的に血液サンプルを採取し、高性能液体クロマトグラフィーを使用する 電気化学的検出で血漿すンブル中のクラリトロマイシン濃度を測定した。結果は クラリトロマイシンの血漿白濃度が良好であることを示しており、下記第３表に まとめる。kinetic pharmacological activity Six Peagle dogs were fasted overnight. 20%Lipo+7n It medium glue 5+) Tomycin (100 mg) (5 mg/m1) was injected intravenously into the dog. 24 Collect blood samples at regular intervals and use high performance liquid chromatography Clarithromycin concentration in plasma samples was measured by electrochemical detection. Result is This shows that the plasma white concentration of clarithromycin is good, as shown in Table 3 below. Summarize.

罵３表 犬の番号　２４時間ＡＵＧ　（時間×μｇ／ｍ１）５　３２．４０ ６　２１．０４ ＡＵＧ＝曲線下の面積 平均　３１．７２ 標準偏差　９．３７ Ｓ、Ｅ、Ｍ、　３．８２ 別の動態薬学的研究でも、実施例５のオレイン酸／カプロン酸系を使用して得ら れた血漿中濃度はクラリトロマイシンラクトビオネートで得られるものに匹敵す ることを確認した。４匹のピーグル大をこれらの組成物で前記と同様に治療した 。血液サンプルを採取し、標準のミクロアッセイ法で分析した。下記第４表に示 す結果は本発明化合物のバイオアベイラビリティ−を示している。3 swear words Dog number 24 hour AUG (hour x μg/m1) 5 32.40 6 21.04 AUG = area under the curve Average 31.72 Standard deviation 9.37 S, E, M, 3.82 In another kinetic pharmacological study, the results were obtained using the oleic acid/caproic acid system of Example 5. The plasma concentrations obtained were comparable to those obtained with clarithromycin lactobionate. I was sure that. Four peagle-sized animals were treated with these compositions as described above. . Blood samples were collected and analyzed using standard microassay methods. Shown in Table 4 below The results demonstrate the bioavailability of the compounds of the invention.

茶４表 組成物　２４時間ＡＵＣＣｍｘｔ　Ｔｌｌ！（時間×μｇ／ｍｌ）　（μｇ／＋ ｌ）　（時間）オレイン酸／　４１．０７　５．３６　１．３３カプロン酸系 クラリトロマイシン　３７．１６　３．８４　１．６７ラクトビオネート　／ 本発明を詳細に示した具体的実施態様で説明した。しかし、これらの実施態様は 説明のためだけのものであり、本発明はこれに限定されるものではない。クラリ トロマイシンと同様の溶解度パラメータを有する薬剤例えばロキシトロマイシン は同等な親油性薬剤であると理解される。添付の請求の範囲の精神や範囲内での 変更や変形はこの開示から当業者には容易に明らかになろう。4 tables of tea Composition 24 hours AUCCmxt Tll! (Time x μg/ml) (μg/+ l) (hour) Oleic acid/41.07 5.36 1.33 Caproic acid system Clarithromycin 37.16 3.84 1.67 Lactobionate / The invention has been described in terms of specific embodiments shown in detail. However, these implementations This is for illustrative purposes only and the invention is not limited thereto. Clary Drugs with similar solubility parameters to tromycin e.g. roxithromycin is understood to be an equivalent lipophilic drug. within the spirit and scope of the appended claims. Modifications and variations will become readily apparent to those skilled in the art from this disclosure.

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Claims (13)

【特許請求の範囲】[Claims] １．治療上有効濃度のクラリトロマイシン、トリグリセリド油及び少なくとも１ 種の安定剤からなる注射用脂質エマルジョンを含有する薬剤組成物。1. a therapeutically effective concentration of clarithromycin, a triglyceride oil, and at least one A pharmaceutical composition containing an injectable lipid emulsion consisting of a stabilizer of seeds. ２．さらに乳化剤を含む請求項１の組成物。2. The composition of claim 1 further comprising an emulsifier. ３．乳化剤が卵の燐脂質である請求項２の組成物。3. 3. The composition of claim 2, wherein the emulsifier is an egg phospholipid. ４．トリグリセリド油がＣ６−Ｃ１８脂肪族脂肪酸を有する油である請求項１の 組成物。4. Claim 1, wherein the triglyceride oil is an oil having C6-C18 aliphatic fatty acids. Composition. ５．安定剤をＣ６−Ｃ１２飽和脂肪酸またはＣ１６−Ｃ１８不飽和脂肪酸から選 択する請求項１の組成物。5. The stabilizer is selected from C6-C12 saturated fatty acids or C16-C18 unsaturated fatty acids. The composition of claim 1 which selects. ６．安定剤をカプリン酸、カプリル酸、オレイン酸、カプロン酸、Ｎ−メチルピ ロリドン、ベンジルアルコール及び塩化メチレンから選択する請求項１の組成物 。6. Stabilizers include capric acid, caprylic acid, oleic acid, caproic acid, and N-methylpyric acid. The composition of claim 1 selected from lolidone, benzyl alcohol and methylene chloride. . ７．安定剤がカブリン酸である請求項６の組成物。7. 7. The composition of claim 6, wherein the stabilizer is cabric acid. ８．安定剤がＮ−メチルピロリドンである請求項６の組成物。8. 7. The composition of claim 6, wherein the stabilizer is N-methylpyrrolidone. ９．安定剤がオレイン酸とカプロン酸の混合物である請求項６の組成物。9. 7. The composition of claim 6, wherein the stabilizer is a mixture of oleic acid and caproic acid. １０．治療上有効濃度が約２．５ｍｇ／ｍｌ−約１０ｍｇ／ｍｌである請求項１ の組成物。10. Claim 1, wherein the therapeutically effective concentration is between about 2.5 mg/ml and about 10 mg/ml. Composition of. １１．治療上有効濃度が約５ｍｇ／ｍｌである請求項１０の組成物。11. 11. The composition of claim 10, wherein the therapeutically effective concentration is about 5 mg/ml. １２．さらにトニシティ調整剤を含む請求項２の組成物。12. 3. The composition of claim 2 further comprising a tonicity modifier. １３．治療上有効濃度のクラリトロマイシン、大豆油、卵の燐脂質、オレイン酸 、カブロン酸及びグリセリンからなる注射用脂肪エマルジョンを含有する薬剤組 成物。13. Therapeutically effective concentrations of clarithromycin, soybean oil, egg phospholipids, and oleic acid. , a drug combination containing an injectable fat emulsion consisting of cabroic acid and glycerin A product.
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