WO2002009670A1 - Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient - Google Patents

Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient Download PDF

Info

Publication number
WO2002009670A1
WO2002009670A1 PCT/EP2000/007248 EP0007248W WO0209670A1 WO 2002009670 A1 WO2002009670 A1 WO 2002009670A1 EP 0007248 W EP0007248 W EP 0007248W WO 0209670 A1 WO0209670 A1 WO 0209670A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical excipient
castor oil
pharmaceutical
weight
pharmaceutical composition
Prior art date
Application number
PCT/EP2000/007248
Other languages
English (en)
Inventor
René A. DUSS
Original Assignee
Duss Rene A
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 Duss Rene A filed Critical Duss Rene A
Priority to PCT/EP2000/007248 priority Critical patent/WO2002009670A1/fr
Priority to AU2000261604A priority patent/AU2000261604A1/en
Publication of WO2002009670A1 publication Critical patent/WO2002009670A1/fr

Links

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
    • A61K47/06—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
    • 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
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • Liquid or semi-solid pharmaceutical excipient and pharmaceutical composition comprising the same
  • the present invention relates to a liquid or semi-solid pharmaceutical excipient and a pharmaceutical composition comprising this excipient and a medicament.
  • Excipients are additives used in the manufacture of pharmaceutical compositions, which allow the active ingredient or medicament to be incorporated in a pharmaceutical or galenic formulation which provides for the necessary bioavailability of the medicament upon the administration of the pharmaceutical composition.
  • compositions may be administered to the patient to be treated in a number of ways, such as by oral, parenteral, intravenous, na- sal, topical, transdermal, rectal, perlingual, ocular or resperatorical administration.
  • oral parenteral, intravenous, na- sal, topical, transdermal, rectal, perlingual, ocular or resperatorical administration.
  • non-invasive ones are preferred, specifically the oral application, which allows a simple and easy use of the ' medicament by the patient himself.
  • a number of medicaments are not suited for the oral application, specifically peptide medicaments, which are degraded upon oral administration during the gastro-intestinal passage, so that specifically with higher molecular medicaments, such as insulin, it is not possible to by oral application provide for the desired bio- availibility of the medicament.
  • the object of the present invention therefore is the provision of a pharmaceutical excipient which allows for the manufacture of pharmaceutical for- mulations which enable the peroral administration of not only low molecular weight but also high molecular weight proteinaceous and specifically peptide medicaments, such as insulin etc.
  • Subject-matter of the present invention therefore is the liquid or semi-solid pharmaceutical excipient according to claim 1.
  • the subclai s comprise specific embodiments thereof and pharmaceutical compositions comprising this pharmaceutical excipient and a medicament.
  • the present invention thus relates to a liquid or semi-solid pharmaceutical excipient comprising 0.1 to 98 % by weight, more preferably 5 to 75 % and specifically 38 to 45 % by weight of amphiphilic, nonionic, polyethoxylated castor oil mono-, di- or tri-esterified with a saturated or unsaturated, linear or branched C ⁇ -Ci8"f a t y acid (hereinafter termed "castor oil ester”) and the remainder water and/or one or more vegetable oils.
  • castor oil ester a saturated or unsaturated, linear or branched C ⁇ -Ci8"f a t y acid
  • Said castor oil preferably has a HLB value of 7 to 10.
  • R ⁇ , R2 and R3 independently are hydrogen or saturated or unsaturated, linear or branched C 1 -C i s-fatty acid residues and 1, m and n independently are integers of from 1 to 20, with the proviso that at least one of R j , R2 and R3 is a saturated or unsaturated, linear or branched C1 - Cis'fa-tt acid residue and the sum 1+m+n is at least 15, preferably at least 20.
  • R ⁇ , R2 and R3 independently are hydrogen or groups of formula:
  • said castor oil ester is polyethoxylated glycerol oleoricinoleate comprising up to 20 and specifically 20 oxyethylene groups.
  • This castor oil ester can be mixed with pharmaceutically acceptable vegetable oils to provide a clear mixture and which, as has been shown, is not toxic upon peroral administration to healthy adults as has been shown by corresponding clinical tests.
  • Said castor oil esters can be manufactured according to the methods disclosed in for example U.S. -patents 4,597,906, 5 ,618,779 and 5 ,237,080, or are available on the market, such as the product sold by Th. Gold- schmidt AG, Essen, under the trade name TAGAT® V 20, having a Hess- Ives colour number of ⁇ 30, ahydroxyl value of 43 to 53, an acid value of ⁇ 7 and a saponification value of 100 to 120.
  • the pharmaceutical excipient comprises 25 to 50 % by weight, more preferably 38 to 45 % by weight of said castor oil ester and 75 to 50 % by weight of one or more mono-, di- or tri-glycerides of saturated or unsaturated, linear or branched natural fatty acids. More preferably the excipient comprises said castor oil and said mono-, di- or tri-glycerides in a weight ratio of 10: 1 to 1 : 1 , more preferably in a weight ratio of 7.5:2.5.
  • Said mon-, di- or tri-glyceride preferably is castor oil, peanut oil, almond oil and/or corn oil.
  • the pharmaceutical excipient additionally comprises one or more physiologically acceptable synthetic or semi-synthetic ester oils, preferably esters of saturated Cg-C ⁇ g fatty acids, if desired in combination with linoleic acid and succinic acid with glycerol or propylene glycol, specifically caprylic/capric triglyce- rides, caprylic/capric /linoleic triglycerides, caprylic/capric /succinic tri- glycerides and propylene glycol dicaprylates/dicaprates, such as the products obtainable from CONDEA CHEMIE GmbH under the tradenames Miglyol® 810, 812, 829 and 840, or 4-methyl- l ,3-dioxalan-2-one.
  • one or more physiologically acceptable synthetic or semi-synthetic ester oils preferably esters of saturated Cg-C ⁇ g fatty acids, if desired in combination with linoleic acid and succinic acid with gly
  • the pharmaceutical excipient can further comprise 0.1 to 5 % by weight, more preferably 0.2 to 2 % by weight of a physiologically acceptable co-surfactant and/or a natural phospholipid.
  • co-surfactant polyethoxylated sorbitan esters may be used, more preferably Polysorbate 60 or natural, semi-synthetic or synthetic phospholipids, preferably those which can provide liposomes.
  • a physiologically acceptable antioxidant preferably a tocopherol derivative, such as tocopherol acetate.
  • the above pharmaceutical excipient allows the manufacture of orally administrable pharmaceutical compositions comprising a medicament or ac- tive agent.
  • Subject-matter of the present invention therefore is as a further embodiment a pharmaceutical composition
  • a pharmaceutical composition comprising the above pharmaceutical excipient and a medicament.
  • said pharmaceutical composition is perorally administrable and comprises the medicament dissolved or dispersed in said excipient.
  • said pharmaceutical composition comprises the medicament in a hydrophilic ethanol/water phase dis- persed by said emulsifying castor oil ester as a water-in-oil emulsion, preferably in the form of a microdispersion in the hydrophobic vegetable oil phase.
  • the medicament is a peptide type medicament, more preferably human or animal insulin, such as human or animal insulin in the form of an ethanol/water solubilized insulin preparation. It has been found by means of clinical tests on healthy adults that the oral administration of such an insulin dispersion applied in the form of an oral gelatine capsule comprising unit doses of up to 50 I.E. yields for 70 % of the test persons in comparison to placebo formulations a pharmacologically relevant and quick and very good reproducable reduction of the blood glucose level combined with a long activity duration.
  • the pharmaceutical excipient of the present invention allows for the manufacture of a perorally administrable insulin formulation providing the desired bioavailability of the active agent in that obviously the formulation enables a large percentage of the intact molecules of the active agent to transgress the biological barriers of the intestine.
  • the invention is explained in more detail on the basis of the following examples.
  • the following components are used for the manufacture of the insulin microdispersion:
  • Component Amount (% by weight)
  • Polyethoxylated glycerol oleorizinoleate comprising 20 oxyethylene groups (TAGAT® V20) 36.85
  • a 150 ml beaker is charged with the glycerol oleorizinoleate, the Polysorbitan 60 and the castor oil and is heated to 30°C while stirring with a magnetic stirrer to provide a clear mixture.
  • the mixture is cooled to room tempera- ture following which the corn oil is added under stirring with the magnetic stirrer to provide a golden yellow transparent surfactant-oil-phase.
  • a 20 ml beaker is charged with the purified water whereafter the sodium chloride is added and dissolved under stirring with a magnetic stirrer at room temperature. Thereafter the absolute alcohol is added at room temperature to provide a clear colorless solution to which the porcine insulin is added in 2 to 3 portions at room temperature while stirring with the magnetic stirrer until a homogenous, weakly opalescent insulin solubilisate is obtained.
  • step I. The product of step I. is introduced in a beaker following which the hydrophilic insulin solubilisate is added slowly and continuously by means of a plastic syringe below the liquid surface under stirring at room temperature. Upon a preliminary turbidity a homogenous, weakly opalescent dispersion of the active agent is obtained, comprising 1.4 ml porcine insulin per gram of said dispersion.
  • Said dispersion can be incorporated into gelatine capsules for the peroral administration of the medicament.
  • Polyethoxylated glycerol oleorizinoleate comprising 20 oxyethylene groups (TAGAT® V 20) 37.70
  • Oleum rizini (Ph. EU II) 25.20
  • a 150 ml beaker is charged with the castor oil ester, the oleum rizini and corn oil in this sequence and is mixed at room temperature with a magnetic stirrer to provide a clear surfactant-oil-phase.
  • the cetyl al- cohol is added to said mixture while heating to 40°C and stirring by means of a magnet stirrer to provide a clear solution, following which the silica is added in 4 to 5 portions under stirring, whereafter any air bubbles are removed, if necessary by applying a vacuum.
  • microdisperse insulin formulation for peroral administration the following components are used:
  • Components Amount (% by weight)
  • Anhydrous lipogel (as manufactured in step I. above) 99.65 solid Porcine Insulin (28.5 I.U. / mg) 0.35
  • the anhydrous lipogel For the manufacture of the pharmaceutical formulation 1 /3 of the anhydrous lipogel is introduced into a 150 ml beaker, whereafter the solid porcine insulin is added in small portions while stirring by means of a RPG- stirrer. Thereafter the residual amount of the anhydrous lipogel is added while stirring at room temperature and is then homogenized.

Abstract

L'invention concerne un excipient pharmaceutique liquide ou semi-solide comprenant 0,1 à 98 % en poids d'huile de ricin amphiphilique, non ionique, polyéthoxylée, qui est monoestérifiée, diestérifiée ou triestérifiée avec un acide gras C14-C18 saturé ou insaturé, linéaire ou ramifié, ainsi que de l'eau restante et/ou une ou plusieurs huiles végétales. L'invention concerne également une composition pharmaceutique constituée d'un excipient et d'un médicament.
PCT/EP2000/007248 2000-07-27 2000-07-27 Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient WO2002009670A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/EP2000/007248 WO2002009670A1 (fr) 2000-07-27 2000-07-27 Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient
AU2000261604A AU2000261604A1 (en) 2000-07-27 2000-07-27 Liquid or semi-solid pharmaceutical excipient and pharmaceutical composition comprising the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2000/007248 WO2002009670A1 (fr) 2000-07-27 2000-07-27 Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient

Publications (1)

Publication Number Publication Date
WO2002009670A1 true WO2002009670A1 (fr) 2002-02-07

Family

ID=8164040

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/007248 WO2002009670A1 (fr) 2000-07-27 2000-07-27 Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient

Country Status (2)

Country Link
AU (1) AU2000261604A1 (fr)
WO (1) WO2002009670A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8062676B2 (en) * 2005-08-02 2011-11-22 Thomas Besendorfer Pesticide composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0872542A2 (fr) * 1997-04-15 1998-10-21 Th. Goldschmidt AG Produit de nettoyage émulsionné et alcalin à faible viscosité

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0872542A2 (fr) * 1997-04-15 1998-10-21 Th. Goldschmidt AG Produit de nettoyage émulsionné et alcalin à faible viscosité

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MULLER, FELIX ET AL: "Thickening by dilution. New attempts for alkaline gel cleansers", SOFW J. (1997), 123(11), 746,748,750,752-753, XP000990080 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8062676B2 (en) * 2005-08-02 2011-11-22 Thomas Besendorfer Pesticide composition
US20120064171A1 (en) * 2005-08-02 2012-03-15 Bedo Holding Ag Pesticide Composition

Also Published As

Publication number Publication date
AU2000261604A1 (en) 2002-02-13

Similar Documents

Publication Publication Date Title
US6441050B1 (en) Palatable oral coenzyme Q liquid
US6300377B1 (en) Coenzyme Q products exhibiting high dissolution qualities
KR100622285B1 (ko) 나노분산액을 사용한 약제학적 최종 제형의 제조 방법, 나노분산액의 예비상 및 나노분산액
AU2006324219B2 (en) Butylphthalide intravenous emulsion and application thereof
CA2383916C (fr) Preparations de dispersion contenant des inhibiteurs de lipases
JPH11505257A (ja) 親油性薬物の自己乳化性製剤
EP1558214B1 (fr) Concentre a administration orale de microemulsion de medicament anti-rhume hydrosoluble
CA2079233A1 (fr) Formules pharmaceutiques
JPH0647533B2 (ja) ４−ビフエニリル酢酸系化合物含有脂肪乳剤
RU2560677C2 (ru) Кожная композиция, включающая аналог витамина d и смесь растворителя и поверхностно-активных веществ
JP2688235B2 (ja) 医薬物質含有脂肪乳剤の用時調製型キットおよび医薬物質含有脂肪乳剤の調製方法
US20100130619A1 (en) Pharmaceutical composition for parenteral administration of idebenone
EP4062904A1 (fr) Composition d'acides gras oméga 3 formant une structure cristalline liquide
JP3132085B2 (ja) 脂肪乳剤
JP2948111B2 (ja) 経口投与用油性組成物
JP4690334B2 (ja) ビフェニルジメチルジカルボキシレート及びシリビンを含む経口用マイクロエマルション組成物
KR100426346B1 (ko) 자가미세유화형 약물전달시스템을 이용한 고지혈증치료용약제 조성물
WO2002009670A1 (fr) Excipient pharmaceutique liquide ou semi-solide et composition pharmaceutique comprenant cet excipient
CA3180468A1 (fr) Composition injectable comprenant des derives de gnrh
KR20040047056A (ko) 비페닐디메틸디카복실레이트의 경구용 마이크로에멀젼조성물
KR100524700B1 (ko) 자가미세유화형 약물전달시스템을 이용한 고지혈증치료용약제 조성물
JP2973077B2 (ja) ビタミンｅ製剤組成物
JP4638053B2 (ja) レトロウイルスプロテアーゼインヒビター用医薬エマルジョン
KR100569595B1 (ko) 가용성 심바스타틴의 연질캡슐제 조성물 및 그의제조방법
KR100187652B1 (ko) 지방성 유화액

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ 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 MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP