JP2003520767A - Novel formulation containing lipid regulator - Google Patents
Novel formulation containing lipid regulatorInfo
- Publication number
- JP2003520767A JP2003520767A JP2000607610A JP2000607610A JP2003520767A JP 2003520767 A JP2003520767 A JP 2003520767A JP 2000607610 A JP2000607610 A JP 2000607610A JP 2000607610 A JP2000607610 A JP 2000607610A JP 2003520767 A JP2003520767 A JP 2003520767A
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- oil
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- fatty acid
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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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Abstract
(57)【要約】 本発明は、少なくとも1種類の油と乳化剤または乳化剤混合物との中に溶解または分散させた脂質調整剤を含む製剤であって、得られた混合物は水性媒体で希釈することによってエマルションを形成することができる製剤に関する。 (57) Abstract: The present invention relates to a preparation comprising a lipid modifier dissolved or dispersed in at least one oil and an emulsifier or a mixture of emulsifiers, wherein the obtained mixture is diluted with an aqueous medium. And a formulation capable of forming an emulsion.
Description
【0001】 発明の分野 本発明は、脂質調整剤を含む新規製剤に関する。[0001] Field of the invention The present invention relates to novel formulations containing lipid regulators.
【0002】
発明の背景
2−[4−(4−クロロベンゾイル)フェノキシ]−2−メチル−プロパン酸
、1−メチルエチルエステルはフェノフィブラートとしても知られ、脂質調整剤
として医薬的に有用な広い範囲の化合物の代表である。より具体的には、この化
合物は一般的にフィブラートとして知られる脂質調整剤の化合物の種類の一部で
あり、米国特許第4,058,552号に開示されている。[0002]
BACKGROUND OF THE INVENTION
2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid
, 1-methylethyl ester, also known as fenofibrate, is a lipid regulator
As a representative of a wide range of compounds useful as pharmaceuticals. More specifically,
Compounds are part of a class of lipid regulator compounds commonly known as fibrates.
Yes, disclosed in US Pat. No. 4,058,552.
【0003】
フェノフィブラートは、米国特許第4,800,079号や米国特許第4,8
95,726号などを参照できるように数種類の異なる製剤に調製されている。
米国特許第4,895,726号にはフェノフィブラートと固体界面活性剤の同
時微粉化製剤が開示されている。Fenofibrate is described in US Pat. No. 4,800,079 and US Pat.
It has been prepared in several different formulations so as to refer to, for example, No. 95,726.
U.S. Pat. No. 4,895,726 discloses a co-micronized formulation of fenofibrate and a solid surfactant.
【0004】
米国特許第4,961,890号には、不活性マトリックスの細孔に含まれる
結晶質微粒子の形態の中間層中にフェノフィブラートを含有する徐放性製剤の調
製方法が開示されている。この製剤は、前記不活性コアを前記バインダーを主成
分とする溶液で湿らせ、次に前記湿らせたコア上に1つの層を形成するように前
記フェノフィブラート微粒子を放出し、続いて前記バインダーを主成分とする前
記溶液が前記フェノフィブラート微粒子を溶解させる前に乾燥させ、前記中間層
が形成されるまで前記3つの段階を順に繰り返す一連の工程を含む方法によって
調製される。US Pat. No. 4,961,890 discloses a method for preparing a sustained release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles contained in the pores of an inert matrix. There is. This formulation wets the inert core with a solution based on the binder, then releases the fenofibrate microparticles to form one layer on the wetted core, followed by the binder. Is prepared by a method including a series of steps of drying the fenofibrate microparticles before dissolving the fenofibrate fine particles and repeating the above three steps in sequence until the intermediate layer is formed.
【0005】
欧州特許出願EP0793958A2号には、フェノフィブラートと、界面活
性剤と、ポリビニルピロリドンとが使用されるフェノフィブラート固形剤形の製
造方法が開示されており、この方法ではフェノフィブラート粒子がポリビニルピ
ロリドン溶液と混合される。こうして得られた混合物に1種類以上の界面活性剤
の水溶液を加えて造粒し、得られた顆粒を乾燥させる。European Patent Application EP0793958A2 discloses a process for producing a fenofibrate solid dosage form in which fenofibrate, a surfactant and polyvinylpyrrolidone are used, in which the fenofibrate particles are polyvinylpyrrolidone. Mixed with solution. The mixture thus obtained is granulated by adding an aqueous solution of one or more surfactants, and the obtained granules are dried.
【0006】
PCT公開WO82/01649号には、ショ糖とデンプンの混合物である中
性コアを含む顆粒を有するフェノフィブラート製剤が開示されている。この中性
コアは賦形剤と混合されたフェノフィブラートの第1の層で覆われ、次に食用ポ
リマーの第2の微孔性外部層で覆われる。PCT Publication WO 82/01649 discloses fenofibrate formulations having granules containing a neutral core which is a mixture of sucrose and starch. The neutral core is covered with a first layer of fenofibrate mixed with an excipient and then a second microporous outer layer of edible polymer.
【0007】
米国特許第5,645,856号には、フェノフィブラートを含む疎水性薬物
用担体の使用と、これを主成分とする医薬組成物とが記載されている。この担体
は可消化油と、親水性界面活性剤を含む担体を投与した場合に生体内で油を分散
させるための医薬上許容される成分とを含み、前記界面活性剤成分は可消化油の
生体内での脂肪分解を実質的に阻害しない。US Pat. No. 5,645,856 describes the use of hydrophobic drug carriers containing fenofibrate and pharmaceutical compositions based on them. This carrier contains a digestible oil and a pharmaceutically acceptable component for dispersing the oil in vivo when a carrier containing a hydrophilic surfactant is administered, and the surfactant component is a digestible oil. It does not substantially inhibit lipolysis in vivo.
【0008】
ゲムフィブロジルは、別のフィブラート系脂質調整剤である。米国特許第4,
927,639号には、第1および第2の顆粒と、胃で部分的または完全に崩壊
させることができる崩壊賦形剤との混合物を圧縮した錠剤を含む即時放出性と徐
放性の両方を備えたゲムフィブロジルの崩壊性製剤が開示されている。第1の顆
粒は少なくとも1種類のセルロース誘導体を加えて造粒した純ゲムフィブロジル
の微粉砕粒子を含み、第2の顆粒は医薬上許容される水溶性または非水溶性ポリ
マーを加えて造粒した純ゲムフィブロジルの微粉砕粒子を含みこれを医薬上許容
される(メタ)アクリレートコポリマーで均一にコーティングしたものであって
、続いてこれを第1の顆粒と混合される。第1および第2の顆粒は約10:1か
ら約1:10の比率で最終組成物中に存在する。Gemfibrozil is another fibrate lipid regulator. US Patent No. 4,
927,639 includes both immediate release and sustained release comprising tablets compressed with a mixture of first and second granules and a disintegrating excipient that can be partially or completely disintegrated in the stomach. Disintegrating formulations of Gemfibrozil are disclosed. The first granules contain finely pulverized particles of pure gemfibrozil granulated with at least one cellulose derivative, and the second granules are pure granules prepared by adding a pharmaceutically acceptable water-soluble or water-insoluble polymer. Gemfibrozil containing finely divided particles, which is uniformly coated with a pharmaceutically acceptable (meth) acrylate copolymer, which is subsequently mixed with the first granules. The first and second granules are present in the final composition in a ratio of about 10: 1 to about 1:10.
【0009】
米国特許第4,925,676号には、ゲムフィブロジルと少なくとも1種類
の酸崩壊性結合剤との第1の顆粒と、第1の顆粒から構成されるが少なくとも1
種類の実質的にアルカリ溶解性または実質的に酸不溶解性のポリマーのアルカリ
崩壊性製剤で再造粒またはコーティングされる第2の顆粒との混合物を圧縮した
ものである即時放出性と徐放性の両方を備えた崩壊性ゲムフィブロジル錠剤が開
示されている。US Pat. No. 4,925,676 comprises a first granule of gemfibrozil and at least one acid-disintegrating binder, and at least one granule.
Immediate release and sustained release, which is a mixture of a mixture of a second granule that is re-granulated or coated with an alkali-disintegrating formulation of a class of substantially alkali-soluble or substantially acid-insoluble polymers. Disintegrating gemfibrozil tablets with both sex are disclosed.
【0010】
別の種類の脂質調整剤としてはスタチン類として一般に知られるものが挙げら
れ、プラバスタチンとアトルバスタチンがこれに含まれる。米国特許第5,03
0,447号および第5,180,589号には、水に分散させた場合にpHが
少なくとも9となり、低pH環境に対して敏感であるプラバスタチンなどの薬物
、ラクトースおよび/または微結晶性セルロースなどの1種類上の増量剤、微結
晶性セルロース(乾式結合剤)またはポリビニルピロリドン(湿式結合剤)など
の1種類以上の結合剤、クロスカルメロースナトリウムなどの1種類以上の崩壊
剤、ステアリン酸マグネシウムなどの1種類以上の滑沢剤、および酸化マグネシ
ウムなどの1種類以上の塩基性化剤を含有する安定な医薬組成物が開示されてい
る。[0010] Another class of lipid regulators includes those commonly known as statins, including pravastatin and atorvastatin. US Patent No. 5,03
0,447 and 5,180,589, drugs such as pravastatin, lactose and / or microcrystalline cellulose that have a pH of at least 9 when dispersed in water and are sensitive to low pH environments. One or more binders such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder), one or more disintegrants such as croscarmellose sodium, stearic acid Stable pharmaceutical compositions containing one or more lubricants such as magnesium and one or more basifying agents such as magnesium oxide are disclosed.
【0011】
本発明の目的は、市販の製剤と比較した場合にバイオアベイラビリティが向上
し半減期が延長した脂質調整剤の製剤を提供することである。[0011] An object of the present invention is to provide formulations of lipid regulators with improved bioavailability and extended half-life when compared to commercially available formulations.
【0012】
発明の概要
本発明は、油に溶解させた後に1種類以上の乳化剤を使用して乳化させた脂質
調整剤を含む製剤に関する。この製剤は微細で安定なエマルションを形成する。
このようなエマルションが形成されることで、薬剤の溶解性、経口バイオアベイ
ラビリティ、および半減期が増大する。[0012]
Summary of the invention
The present invention relates to lipids which are dissolved in oil and then emulsified using one or more emulsifiers.
It relates to formulations containing regulators. This formulation forms a fine and stable emulsion.
The formation of such an emulsion may result in drug solubility, oral bioavailability.
Improves stability and half-life.
【0013】
本発明の製剤は、直接投与することができるし、適当な投与用媒体で希釈する
ことができるし、投与用の軟質または硬質ゼラチンシェルあるいはカプセルでカ
プセル化することもできるし、当業者には明らかである他の手段によって投与す
ることもできる。The formulations of the invention can be administered directly, can be diluted with a suitable vehicle for administration, can be encapsulated in a soft or hard gelatin shell or capsule for administration, It can also be administered by other means apparent to those of skill in the art.
【0014】
図面の簡単な説明
図1は、絶食させたイヌにおける実施例1と基準化合物の製剤の血漿濃度を示
すグラフである。[0014]
Brief description of the drawings
Figure 1 shows the plasma concentration of Example 1 and reference compound formulations in fasted dogs.
It is a graph.
【0015】
発明の詳細な説明
脂質調整剤自体は任意の有用な方法によって調製可能であり、例えば化合物フ
ェノフィブラートは米国特許第4,058,552号または米国特許第4,73
9,101号(両者の記載内容を本明細書に引用する)に開示される手順によっ
て調製可能である。[0015]
Detailed Description of the Invention
The lipid modifier itself can be prepared by any useful method, such as the compound profile.
Enofibrate is described in US Pat. No. 4,058,552 or US Pat.
According to the procedure disclosed in No. 9,101 (the contents of which are cited herein).
Can be prepared.
【0016】
脂質調整剤を含む溶液は、十分に混合することによって前記薬剤を油に溶解さ
せることで調製される。乳化剤または乳化剤混合物を前記混合物に加え、均一に
なるまで混合する。希望するのであれば、得られた混合物に撹拌しながら水を加
えて均一なエマルションを得ることができる。The solution containing the lipid modifier is prepared by dissolving the drug in an oil by thorough mixing. Add the emulsifier or emulsifier mixture to the mixture and mix until uniform. If desired, water can be added to the resulting mixture with stirring to obtain a uniform emulsion.
【0017】
本発明の送達システムは、脂質調整剤の溶解性、半減期、およびバイオアベイ
ラビリティを増大させる。これは別の液体でさらに希釈することができるし、あ
るいは既存の種々の特性を変化させる種々の医薬賦形剤によって増粘および/ま
たは安定化させることができる。The delivery system of the present invention increases the solubility, half-life, and bioavailability of lipid modulating agents. It can be further diluted with another liquid, or it can be thickened and / or stabilized by various pharmaceutical excipients that alter various existing properties.
【0018】
好適な油としては、限定するものではないが、任意の医薬上許容される油が挙
げられ、例えば、ダイズ油、ヤシ油、カノーラ油、トウモロコシ油、パーム核油
、綿実油、オリーブ油、ラッカセイ油、ベニバナ油、およびゴマ油が挙げられる
。Suitable oils include, but are not limited to, any pharmaceutically acceptable oil such as soybean oil, coconut oil, canola oil, corn oil, palm kernel oil, cottonseed oil, olive oil, Peanut oil, safflower oil, and sesame oil are included.
【0019】
好適な乳化剤としては、任意の医薬上許容される親水性または親油性の乳化剤
またはそれらの組み合わせが挙げられ、例えば、リン脂質、ポリオキシエチレン
ソルビタン脂肪酸誘導体、ソルビタン脂肪酸誘導体、ポリオキシル−35−ヒマ
シ油(polyoxyl−35−castor oil)(クレモホルEL(C
remophor EL)、BASFより入手可能)、ヒマシ油または硬化ヒマ
シ油エトキシレート、脂肪酸のポリグリセロールエステル、脂肪酸エトキシレー
ト、アルコールエトキシレート、ポリオキシエチレン−ポリオキシプロピレンコ
ポリマーおよびブロックコポリマー、ならびにTPGS(d−αトコフェリルポ
リエチレングリコール1000スクシネート)が挙げられる。好ましい乳化剤と
しては、ポリオキシエチレンソルビタン脂肪酸誘導体、ソルビタン脂肪酸誘導体
、およびポリオキシル−35−ヒマシ油(クレモホルEL、BASFより入手可
能)が挙げられる。Suitable emulsifiers include any pharmaceutically acceptable hydrophilic or lipophilic emulsifiers or combinations thereof, for example phospholipids, polyoxyethylene sorbitan fatty acid derivatives, sorbitan fatty acid derivatives, polyoxyl-35. -Castor oil (polyoxyl-35-castor oil) (cremophor EL (C
remophor EL), available from BASF), castor oil or hydrogenated castor oil ethoxylates, polyglycerol esters of fatty acids, fatty acid ethoxylates, alcohol ethoxylates, polyoxyethylene-polyoxypropylene copolymers and block copolymers, and TPGS (d- α-tocopheryl polyethylene glycol 1000 succinate). Preferred emulsifiers include polyoxyethylene sorbitan fatty acid derivatives, sorbitan fatty acid derivatives, and polyoxyl-35-castor oil (available from Cremophor EL, BASF).
【0020】
本発明の組成物に加えることができる他の任意の成分は、油系薬物送達システ
ムで従来使用されている成分であり、例えばトコフェロール、アスコルビン酸パ
ルミテート、アスコルビン酸、ブチル化ヒドロキシトルエン、ブチル化ヒドロキ
シアニソール、没食子酸プロピルなどの酸化防止剤;クエン酸、酒石酸、フマル
酸、酢酸、グリシン、アルギニン、リシン、リン酸水素カリウムなどのpH安定
剤;水素化植物油、蜜蝋、コロイド状二酸化ケイ素、ゴム類、セルロース類、ケ
イ酸塩、ベントナイトなどの増粘剤/懸濁剤;チェリー、レモン、アニシードの
香料などの着香料;アスパルテーム、サッカリン、シクラミン酸塩などの甘味料
;ならびにエタノール、プロピレングリコール、ポリエチレングリコール、ジメ
チルイソソルビドなどの共溶媒が挙げられる。Other optional ingredients that can be added to the compositions of the present invention are those ingredients conventionally used in oil-based drug delivery systems such as tocopherol, ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, Antioxidants such as butylated hydroxyanisole and propyl gallate; pH stabilizers such as citric acid, tartaric acid, fumaric acid, acetic acid, glycine, arginine, lysine and potassium hydrogen phosphate; hydrogenated vegetable oil, beeswax, colloidal silicon dioxide , Thickeners / suspending agents such as gums, celluloses, silicates and bentonites; flavoring agents such as cherry, lemon and aniseed flavors; sweeteners such as aspartame, saccharin, cyclamate; and ethanol, propylene Glycol, polyethylene glycol, dimethyl iso Cosolvents such as sorbide are included.
【0021】
製造された脂質調整剤含有液体は、直接経口投与することができるし、適当な
経口用媒体で希釈することができるし、経口投与用の軟質または硬質シェルある
いはカプセルに充填することができるし、当業者には明らかである他の手段によ
って送達することもできる。前記液体は、経口バイオアベイラビリティを向上さ
せ、前記脂質調整剤の半減期と溶解性を増大させるために使用することができる
。The produced lipid-modifying agent-containing liquid can be directly orally administered, diluted with a suitable oral medium, or filled in a soft or hard shell or capsule for oral administration. Yes, and can be delivered by other means apparent to those of skill in the art. The liquid can be used to improve oral bioavailability and increase the half-life and solubility of the lipid regulator.
【0022】
以下の非限定的で代表的な実施例によって、より明確に本発明を理解できるで
あろう。The invention will be more clearly understood by the following non-limiting and representative examples.
【0023】
実施例1
SRダイズ油(24.33g)をビーカーに加え、撹拌してこの油にフェノフ
ィブラート(0.67g)を溶解した。ソルビタンモノオレエート(2.5g)
をビーカーに加え、均一になるまで混合した。続いてポリソルベート80(0.
5g)を加え、均一になるまで混合した。最後に、均一なエマルションが得られ
るまで絶えず混合しながらゆっくり水(72g)を加えた。[0023]
Example 1
Add SR soybean oil (24.33g) to a beaker, stir and add to this oil Phenov
The ibrate (0.67 g) was dissolved. Sorbitan monooleate (2.5 g)
Was added to a beaker and mixed until uniform. Then polysorbate 80 (0.
5 g) was added and mixed until uniform. Finally, a uniform emulsion is obtained
Water (72 g) was added slowly with constant mixing until.
【0024】
実施例2
SRダイズ油(24g)をビーカーに加え、撹拌してこの油にプラバスタチン
(1g)を分散させた。ソルビタンモノオレエート(2.5g)をビーカーに加
え、均一になるまで混合した。続いてポリソルベート80(0.5g)を加え、
均一になるまで混合した。最後に、均一なエマルションが得られるまで絶えず混
合しながらゆっくり水(72g)を加えた。[0024]
Example 2
Add SR soybean oil (24g) to a beaker and stir to add pravastatin to this oil.
(1 g) was dispersed. Add sorbitan monooleate (2.5g) to a beaker
Well, mixed until uniform. Then add polysorbate 80 (0.5 g),
Mix until uniform. Finally, constantly mix until a uniform emulsion is obtained.
Water (72 g) was added slowly while combining.
【0025】
実施例3
SRダイズ油(24g)をビーカーに加え、、撹拌してこの油にアトルバスタ
チン(1g)を分散させた。ソルビタンモノオレエート(2.5g)をビーカー
に加え、均一になるまで混合した。続いてポリソルベート80(0.5g)を加
え、均一になるまで混合した。最後に、均一なエマルションが得られるまで絶え
ず混合しながらゆっくり水(72g)を加えた。[0025]
Example 3
Add SR soybean oil (24g) to a beaker, stir and mix with this oil.
Chin (1 g) was dispersed. Beaker with sorbitan monooleate (2.5 g)
And mixed until uniform. Then add polysorbate 80 (0.5 g)
Well, mixed until uniform. Finally, continue until a uniform emulsion is obtained.
Water (72 g) was added slowly with no mixing.
【0026】
実施例4
実施例1に記載の方法によって調製したエマルション、および市販のフェノフ
ィブラート組成物であるリパンチル(Lipanthyl)67M(Group
e Fournier)(基準組成物)から調製したエマルションを、67mg
フェノフィブラート/匹(エマルション10mlまたは1カプセル/匹)の投与
量で1群のイヌに投与した。フェノフィブル酸の血漿濃度をHPLCによって求
めた。各イヌについて6.7mg/kgの投与量に濃度を規格化した。図1は得
られたデータをグラフで表したものである。平均±SD、n=6として、結果を
以下の示す。[0026]
Example 4
Emulsion prepared by the method described in Example 1 and commercially available Fenof
Ipanate composition Lipantyl 67M (Group
67 mg of emulsion prepared from eFournier) (reference composition)
Administration of fenofibrate / animal (emulsion 10 ml or 1 capsule / animal)
Dose was administered to one group of dogs. Plasma concentration of fenofibric acid was determined by HPLC.
I have The concentration was normalized to a dose of 6.7 mg / kg for each dog. Figure 1 is profitable
This is a graph of the obtained data. Mean ± SD, n = 6
Shown below.
【0027】 リパンチル67M(基準): Cmax=1.88±0.97mcg/ml Tmax=1.6±0.9時間 t1/2=4.5時間 AUC(0−24)=11.08±9.42mcg・時/ml 実施例1のエマルション: Cmax=4.97±3.13mcg/ml Tmax=1.1±0.5時間 t1/2=7.8時間 AUC(0−24)=24.21±11.69mcg・時/ml 基準に対するAUC=2.2Repanchill 67M (reference): Cmax = 1.88 ± 0.97 mcg / ml Tmax = 1.6 ± 0.9 hours t 1/2 = 4.5 hours AUC (0-24) = 11.08 ± 9.42 mcg · hour / ml Emulsion of Example 1: Cmax = 4.97 ± 3.13 mcg / ml Tmax = 1.1 ± 0.5 hours t 1/2 = 7.8 hours AUC (0-24) = 24.21 ± 11.69 mcg · hour / ml AUC against standard = 2.2
【図1】
絶食させたイヌにおける実施例1と基準化合物の製剤の血漿濃度を示すグラフ
である。1 is a graph showing plasma concentrations of Example 1 and reference compound formulations in fasted dogs.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61K 47/10 A61K 47/10 47/14 47/14 47/24 47/24 47/34 47/34 47/44 47/44 47/46 47/46 A61P 3/06 A61P 3/06 (81)指定国 EP(AT,BE,CH,CY, DE,DK,ES,FI,FR,GB,GR,IE,I T,LU,MC,NL,PT,SE),OA(BF,BJ ,CF,CG,CI,CM,GA,GN,GW,ML, MR,NE,SN,TD,TG),AP(GH,GM,K E,LS,MW,SD,SL,SZ,TZ,UG,ZW ),EA(AM,AZ,BY,KG,KZ,MD,RU, TJ,TM),AE,AG,AL,AM,AT,AU, AZ,BA,BB,BG,BR,BY,CA,CH,C N,CR,CU,CZ,DE,DK,DM,DZ,EE ,ES,FI,GB,GD,GE,GH,GM,HR, HU,ID,IL,IN,IS,JP,KE,KG,K P,KR,KZ,LC,LK,LR,LS,LT,LU ,LV,MA,MD,MG,MK,MN,MW,MX, NO,NZ,PL,PT,RO,RU,SD,SE,S G,SI,SK,SL,TJ,TM,TR,TT,TZ ,UA,UG,UZ,VN,YU,ZA,ZW (72)発明者 リパリ,ジヨン・エム アメリカ合衆国、ウイスコンシン・53406、 ラシーン、アポロ・ドライブ・6600 (72)発明者 リーランド,トーマス・エル アメリカ合衆国、イリノイ・60030、ゲイ ジズ・レイク、ノース・レイク・シヨア・ ドライブ・33974 Fターム(参考) 4C076 AA17 AA53 BB01 CC21 DD15 DD37 DD38 DD45 DD46 EE23 EE48 EE49 EE53 FF15 FF32 4C086 AA01 BC05 MA03 MA05 MA22 MA37 MA52 NA02 NA10 NA11 ZC33 4C206 AA01 DB03 DB25 DB43 DB56 MA03 MA05 MA42 MA57 MA72 NA02 NA10 NA11 ZC33 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61K 47/10 A61K 47/10 47/14 47/14 47/24 47/24 47/34 47/34 47 / 44 47/44 47/46 47/46 A61P 3/06 A61P 3/06 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL , IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Lipari , Jiyoung M United States, Wisconsin 53406, Racine, Apollo Drive 6600 (72) Inventor Leland, Thomas El United States, Illinois 60030, Gage's Lake, North Lake Sjoa Drive 33974 F-term (three ) 4C076 AA17 AA53 BB01 CC21 DD15 DD37 DD38 DD45 DD46 EE23 EE48 EE49 EE53 FF15 FF32 4C086 AA01 BC05 MA03 MA05 MA22 MA37 MA52 NA02 NA10 NA11 ZC33 4C206 AA01 DB03 DB25 DB43 DB56 MA03 MA05 MA42 MA57 MA72 NA02 NA10 NA11 ZC33
Claims (18)
または分散させた脂質調整剤を含み、その混合物は水相で希釈した場合にエマル
ションを形成可能である組成物。1. A composition comprising a lipid modifier dissolved or dispersed in at least one oil using one or more emulsifiers, the mixture being capable of forming an emulsion when diluted with an aqueous phase.
物。2. The composition according to claim 1, wherein the lipid modifier is a fibrate.
載の組成物。3. The composition of claim 2, wherein the fibrate is fenofibrate.
物。5. The composition of claim 4, wherein the statin is pravastatin.
成物。6. The composition of claim 4, wherein the statin is atorvastatin.
シエチレンソルビタン脂肪酸誘導体、ソルビタン脂肪酸誘導体、ポリオキシル−
35−ヒマシ油(クレモホルEL(Cremophor EL)、BASFより
入手可能)、ヒマシ油または硬化ヒマシ油エトキシレート、脂肪酸のポリグリセ
ロールエステル、脂肪酸エトキシレート、アルコールエトキシレート、ポリオキ
シエチレン−ポリオキシプロピレンコポリマーおよびブロックコポリマー、なら
びにTPGS(d−αトコフェリルポリエチレングリコール1000スクシネー
ト)から選択される請求項1に記載の組成物。7. At least one of the emulsifiers is phospholipid, polyoxyethylene sorbitan fatty acid derivative, sorbitan fatty acid derivative, polyoxyl-
35-castor oil (Cremophor EL, available from BASF), castor oil or hydrogenated castor oil ethoxylates, polyglycerol esters of fatty acids, fatty acid ethoxylates, alcohol ethoxylates, polyoxyethylene-polyoxypropylene copolymers and The composition of claim 1 selected from block copolymers, as well as TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate).
ソルビタン脂肪酸誘導体、ソルビタン脂肪酸誘導体、およびポリオキシル−35
−ヒマシ油である請求項7に記載の組成物。8. At least one of the emulsifiers is a polyoxyethylene sorbitan fatty acid derivative, a sorbitan fatty acid derivative, and polyoxyl-35.
-Composition according to claim 7, which is castor oil.
、パーム核油、綿実油、オリーブ油、ラッカセイ油、ベニバナ油、およびゴマ油
から選択される請求項1に記載の組成物。9. The composition according to claim 1, wherein the oil is selected from soybean oil, coconut oil, canola oil, corn oil, palm kernel oil, cottonseed oil, olive oil, peanut oil, safflower oil, and sesame oil.
はポリエチレングリコールである請求項11に記載の組成物。12. The composition according to claim 11, wherein the co-solvent is ethanol, propylene glycol, or polyethylene glycol.
の送達システム。14. The delivery system of claim 13, wherein the delivery system is an emulsion.
達システム。15. The delivery system of claim 13, wherein the delivery system is a capsule.
血症の治療方法。16. A method for treating hyperlipidemia, comprising administering the composition according to claim 1 to a patient.
血症の治療方法。17. A method for treating hyperlipidemia, which comprises administering the composition according to claim 3 to a patient.
脂血症の治療方法。18. A method of treating hyperlipidemia, comprising administering to a patient the composition of claim 14.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28251399A | 1999-03-31 | 1999-03-31 | |
US09/282,513 | 1999-03-31 | ||
PCT/US2000/007650 WO2000057859A1 (en) | 1999-03-31 | 2000-03-23 | Novel formulations comprising lipid-regulating agents |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2003520767A true JP2003520767A (en) | 2003-07-08 |
Family
ID=23081844
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000607610A Withdrawn JP2003520767A (en) | 1999-03-31 | 2000-03-23 | Novel formulation containing lipid regulator |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1162954A1 (en) |
JP (1) | JP2003520767A (en) |
AU (1) | AU4021100A (en) |
CA (1) | CA2365128A1 (en) |
HK (1) | HK1043936A1 (en) |
MX (1) | MXPA01009840A (en) |
WO (1) | WO2000057859A1 (en) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
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US6372251B2 (en) * | 1999-06-11 | 2002-04-16 | Abbott Laboratories | Formulations comprising lipid-regulating agents |
US6982281B1 (en) | 2000-11-17 | 2006-01-03 | Lipocine Inc | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US7276249B2 (en) | 2002-05-24 | 2007-10-02 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
US20040235935A1 (en) * | 2001-06-12 | 2004-11-25 | Francis Vanderbist | Oral pharmaceutical composition containing a statin derivative |
ES2255426B1 (en) | 2004-10-19 | 2007-08-16 | Gp Pharm, S.A. | PHARMACEUTICAL FORMULATION THAT INCLUDES MICROCAPSULES OF STATINS SUSPENDED IN ESTER ALKYLS OF POLYINSATURATED FATTY ACIDS (PUFA). |
BRPI0614378A2 (en) * | 2005-08-04 | 2011-03-22 | Transform Pharmaceuticals Inc | formulations comprising fenofibrate and a statin, and related treatment methods |
US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
EP2400840A4 (en) * | 2009-02-24 | 2012-08-01 | Madeira Therapeutics | Liquid statin formulations |
US9744132B2 (en) | 2010-10-29 | 2017-08-29 | Infirst Healthcare Limited | Solid solution compositions and use in chronic inflammation |
US10695431B2 (en) | 2010-10-29 | 2020-06-30 | Infirst Healthcare Limited | Solid solution compositions and use in cardiovascular disease |
US9271950B2 (en) | 2010-10-29 | 2016-03-01 | Infirst Healthcare Limited | Compositions for treating chronic inflammation and inflammatory diseases |
US8895536B2 (en) | 2010-10-29 | 2014-11-25 | Infirst Healthcare Ltd. | Compositions and methods for treating chronic inflammation and inflammatory diseases |
US11730709B2 (en) | 2010-10-29 | 2023-08-22 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
US11202831B2 (en) | 2010-10-29 | 2021-12-21 | Infirst Healthcare Limited | Solid solution compositions and use in cardiovascular disease |
US11224659B2 (en) | 2010-10-29 | 2022-01-18 | Infirst Healthcare Limited | Solid solution compositions and use in severe pain |
US9308213B2 (en) | 2010-10-29 | 2016-04-12 | Infirst Healthcare Limited | Solid solution compositions and use in chronic inflammation |
US10695432B2 (en) | 2010-10-29 | 2020-06-30 | Infirst Healthcare Limited | Solid solution compositions and use in severe pain |
US9504664B2 (en) | 2010-10-29 | 2016-11-29 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
US9737500B2 (en) | 2010-10-29 | 2017-08-22 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9034858B2 (en) | 2010-11-30 | 2015-05-19 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
SG192621A1 (en) * | 2011-02-04 | 2013-09-30 | Biocopea Ltd | Compositions and methods for treating cardiovascular diseases |
CN103110594A (en) * | 2013-02-02 | 2013-05-22 | 台州职业技术学院 | Atorvastatin calcium nano freeze-dried powder and preparation method thereof |
WO2015185240A1 (en) | 2014-06-04 | 2015-12-10 | Sigma-Tau Industrire Farmaceutiche Riunite S.P.A. | Compositions containing simvastatin in omega-3 polyunsaturated fatty acids |
WO2016033556A1 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS |
WO2016033549A2 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
CA3078723A1 (en) | 2016-11-28 | 2018-05-31 | Nachiappan Chidambaram | Oral testosterone undecanoate therapy |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1590864A (en) * | 1978-05-16 | 1981-06-10 | Lilly Industries Ltd | Thixotropic filling medium for hard gelatin capsules |
EP0031603A1 (en) * | 1979-12-31 | 1981-07-08 | American Cyanamid Company | Pharmaceutical composition of matter |
DE3680507D1 (en) * | 1985-08-02 | 1991-08-29 | Byk Gulden Lomberg Chem Fab | USE OF OXIRANCARBONIC ACIDS FOR TREATING HYPERLIPAEMIA. |
GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
CA2153553A1 (en) * | 1994-07-13 | 1996-01-14 | Hidekazu Suzuki | Stable lipid emulsion |
WO1999029300A1 (en) * | 1997-12-10 | 1999-06-17 | Rtp Pharma Inc. | Self-emulsifying fenofibrate formulations |
-
2000
- 2000-03-23 JP JP2000607610A patent/JP2003520767A/en not_active Withdrawn
- 2000-03-23 AU AU40211/00A patent/AU4021100A/en not_active Abandoned
- 2000-03-23 CA CA002365128A patent/CA2365128A1/en not_active Abandoned
- 2000-03-23 EP EP00919545A patent/EP1162954A1/en not_active Withdrawn
- 2000-03-23 MX MXPA01009840A patent/MXPA01009840A/en unknown
- 2000-03-23 WO PCT/US2000/007650 patent/WO2000057859A1/en not_active Application Discontinuation
-
2002
- 2002-05-30 HK HK02104038.4A patent/HK1043936A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
CA2365128A1 (en) | 2000-10-05 |
HK1043936A1 (en) | 2002-10-04 |
AU4021100A (en) | 2000-10-16 |
EP1162954A1 (en) | 2001-12-19 |
MXPA01009840A (en) | 2002-06-21 |
WO2000057859A1 (en) | 2000-10-05 |
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