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WO1999045946A1 - Preconcentres d'emulsions comprenant une cyclosporine et des glycerides - Google Patents

Preconcentres d'emulsions comprenant une cyclosporine et des glycerides Download PDF

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Publication number
WO1999045946A1
WO1999045946A1 PCT/CA1999/000192 CA9900192W WO9945946A1 WO 1999045946 A1 WO1999045946 A1 WO 1999045946A1 CA 9900192 W CA9900192 W CA 9900192W WO 9945946 A1 WO9945946 A1 WO 9945946A1
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WIPO (PCT)
Prior art keywords
composition
solvent
surfactant
polyethylene glycol
glycerides
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PCT/CA1999/000192
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English (en)
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Bernard Charles Sherman
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Classifications

    • 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
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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

Definitions

  • the invention is directed to pharmaceutical compositions which facilitate the administration of cyclosporins.
  • solvent system refers to a carrier in which an active drug (i.e. a cyclosporin) is dissolved.
  • the solvent system may be a single solvent or a mixture of ingredients included as solvents, surfactants, diluents, or for other purposes.
  • cyclosporin refers to any member of a class of nonpolar polypeptides, as defined in the Merck Index, Twelfth Edition.
  • One suchcyclosporin is cyclosporin A, also known as “cyclosporine” and hereinafter referred to as “cyclosporine”, known to be therapeutically active as an immunosuppressant.
  • Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions (i.e. dosage forms) comprising cyclosporins which exhibit satisfactory absorption into systemic circulation after oral administration, or absorption into the target tissue upon topical administration.
  • the cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous medium, the cyclosporin will precipitate.
  • an organic solvent e.g. ethanol or propylene glycol
  • U.S. patent 4388307 discloses such compositions.
  • a commercial product that has been sold under the trademark "Sandimmune” is made according to U.S. patent 4388307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol as hydrophilic solvent, a vegetable oil as lipophilic solvent, and a surfactant.
  • the ethanol is required to dissolve the cyclosporine in the compositions as the vegetable oil has inadequate capacity to dissolve cyclosporins. While this composition is superior to previously known compositions, it still exhibits abso ⁇ tion that is less than the maximum possible and is variable.
  • the use of ethanol has disadvantages, as ethanol is volatile, and Sandimmune capsules must be individually packaged in metallic pouches to avoid evaporation of the ethanol.
  • U.S. patent 5342625 discloses compositions that are superior in certain respects to the compositions taught in U.S. patent 4388307.
  • the compositions of U.S. patent 5342625 comprise (in addition to the cyclosporin, a lipophilic solvent and surfactant) a hydrophilic solvent which is of either propylene glycol or an alkyl ortetrahydrofurfuryl di- or partial- ether of a low molecular weight mono- or poly-oxy-alkanediol.
  • compositions according to U.S. patent 5342625 when added to water, disperse into emulsions with droplet size of lessthan 2000 , which is smaller than obtained with prior art compositions, thus leading to improved absorption.
  • microemulsion preconcentrates Compositions that, upon addition to water, disperse into microemulsions are called “microemulsion preconcentrates”.
  • Canadian Patent 2072509 discloses microemulsion preconcentrates comprising a cyclosporin dissolved in a carrier which comprises:
  • hydrophilic solvent propylene glycol either alone or with other lower alkanols e.g. ethanol;
  • compositions taught by Canadian Patent 2072509 appear to be within the scope of Claim 1 of US Patent 5342625, but limited to propylene glycol as hydrophilic solvent and a mixed mono-, di- and tri-glyceride as lipophilic solvent.
  • a composition made according to the disclosure of Canadian patent 2072509 is now marketed under the trademark "Neoral", in the form of both an oral liquid which is a microemulsion preconcentrate intended to be diluted into an aqueous drink before ingestion, and a soft gelatin capsule containing the microemulsion preconcentrate.
  • the labelling indicates that the "Neoral" emulsion preconcentrate comprises cyclosporine dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil glycerides as lipophilic solvent, and polyoxyl 40 hydrogenated castor oil as surfactant. It also contains dl-alpha-tocopherol at a level of about one percent by weight as antioxidant.
  • Canadian patent 2072509 includes some examples without ethanol, the use of ethanol inthe commercial "Neoral" product indicates that compositions without ethanol either were not found to give adequate stability or were not found to give adequate absorption upon ingestion. While Neoral does enable improved absorption relative to Sandimmune, it still has certain undesirable properties. Specifically, ethanol is volatile, so that the compositions have to be specially packaged to prevent evaporation of the ethanol.
  • W094/25068 discloses improved compositions in the form of microemulsion preconcentrates in which the principal solvent for the cyclosporin is an alcohol which is selected from alcohols having a boiling point above 100 C and a solubility in water of under 10 g per 100 g at 20 C. Because such alcohols are good solvents for cyclosporine, they eliminate the need for ethanol.
  • Preferred alcohols within the scope of the disclosure of W094/25068, are saturated alkyl alcohols having 8 to 14 carbon atoms per molecule, including 1-octyl, 2-octyl, 1-decyl, 1-dodecyl and 1- tetradecyl alcohols.
  • a problem with such compositions is that they are more toxic than other lipophilic solvents generally used in the art.
  • New Zealand Patent Application No. 280689 discloses improved microemulsion preconcentrates in which a cyclosporin is dissolved in a solvent system comprising a lipophilic solvent, a hydrophilic solvent and a surfactant, wherein the lipophilic solvent is selected from tocol, tocopherols and tocotrienols, and derivatives thereof, including specifically Vitamin E.
  • New Zealand Patent Application No. 280689 further discloses use of propylene carbonate as hydrophilic solvent.
  • Preferred compositions within the scope of New Zealand Patent application No. 280689 comprise both a lipophilic solvent selected fromtocoi, tocopherols and tocotrienols and derivatives thereof, including specifically Vitamin E. While these compositions exhibit improved properties over the prior art, the disclosed lipophilic solvent such as Vitamin E are relatively expensive.
  • New Zealand Patent Application No. 314701 provides a pharmaceutical composition in the form of a microemulsion preconcentrate comprising a cyclosporin dissolved in a solvent system comprising propylene carbonate as hydrophilic solvent, a lipophilic solvent selected from glycerides, and at least one surfactant.
  • a pharmaceutical composition in the form of a microemulsion preconcentrate comprising a cyclosporin dissolved in a solvent system comprising propylene carbonate as hydrophilic solvent, a lipophilic solvent selected from glycerides, and at least one surfactant.
  • propylene carbonate is not an ingredient presently approved by the United States Food and Drug Administration (“FDA”) for oral ingestion.
  • FDA United States Food and Drug Administration
  • microemulsion preconcentrate comprising a cyclosporin, which has all the following properties:
  • the present invention provides a pharmaceutical composition in the form of an emulsion preconcentrate or microemulsion preconcentrate comprising a cyclosporin dissolved in a solvent system which is free of ethanol and comprises:
  • a lipophilic solvent selected from glycerides.
  • a co-surfactant selected from polyoxyethylene-sorbitan-fatty acid esters.
  • composition will optimally and preferably also comprise benzyl alcohol as hydrophilic co-solvent.
  • compositions within the scope of the present invention will comprise a lipophilic solvent selected from glycerides.
  • glycerides is to be understood to include mono-, di-, and tri-esters of glycerol with fatty acids, and mixtures thereof.
  • Fatty acids will be understood to include both medium chain (e.g. G3 - C 0) fatty acids and long chain (e.g. C 2 - C18) fatty acids, both unsaturated and saturated.
  • mono- and di-glycerides formed by glycerol and fatty acids are capable of further esterification at the remaining one or two hydroxyls.
  • glycerides is to be understood to include compounds formed by furtheresterification of fatty acid mono- and di-glycerides with acids other than fatty acids. This will include, for example, acetylated monoglycerides which are formed by reacting fats with glycerol and triacetin.
  • Glycerides useable within the scope of the invention will thus include, but not be limited to, the following:
  • a mixed mono-, di-, andtriglyceride which will preferably comprise a mixture of c 12-20 fatt y acid mono-, di- and triglycerides.
  • these mixed glycerides are predominantly comprised of unsaturated fatty acid residues, in particular C ⁇ s unsaturated fatty acid residues such as linolenic, linoleic and oleic acid residues.
  • the mixed mono-, di-, and tri-glycerides are preferably predominantly comprised of mono- and di-glycerides.
  • the mixed mono-, di-, and tri-glycerides may be prepared by admixing individual mono-, di, and tri-glycerides in appropriate relative proportions.
  • the mixed glycerides comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil, soybean oil, corn oil, sunflower oil or safflower oil, with glycerol.
  • vegetable oils for example almond oil, ground nut oil, olive oil, peach oil, palm oil, soybean oil, corn oil, sunflower oil or safflower oil, with glycerol.
  • the vegetable oil is corn oil.
  • mixtures of the oils may be transesterified with glycerol. 8
  • the transesterification products are generally obtained by heating the selected vegetable oil with glycerol to effect transesterification or glycerolysis. This may be carried out at high temperature in the presence of an appropriate catalyst, under an inert atmosphere and with continuous agitation. In addition to the mono-, di- and tri-glyceride components, the transesterification products also generally comprise minor amounts of free glycerol.
  • Transesterification products of corn oil and glycerol provide particularly suitable mixed mono-, di-, and tri-glycerides.
  • An example of a suitable mixed glyceride product is the transesterification product commercially available under the trade name MAISINE (available from the company Etablatoriums Gattefosse, of 36 Chemin de Genas, P.O. Box 603, 69804 Saint-Priest, Cedex (France)).
  • MAISINE available from the company Etablatoriums Gattefosse, of 36 Chemin de Genas, P.O. Box 603, 69804 Saint-Priest, Cedex (France)
  • This product is comprised predominantly of linoleic and oleic acid mono-,di- and triglycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides.
  • Acetylated monoglycerides which consist of glycerol esterified with fatty acids at one of the three hydroxyl functions, with the other two hydroxyls replaced by an acetyl moieties.
  • Acetylated monoglycerides are sold in the United States under thetradename "Myvacet” by Eastman Chemical Products Inc. They are made by reacting fats with glycerine and triacetin.
  • Fully acetylated monoglycerides prepared from unsaturated mono-glycerides are liquids at room temperature.
  • the phrase Dfully acetylated ⁇ is intended to mean having a minimum acetylation of about 96%.
  • Fully acetylated monoglycerides are currently available from Eastman Chemical Products Inc. under the designations Myvacet 9-08 and Myvacet 9-45.
  • Myvacet 9-08 the fat source is hydrogenated coconut oil.
  • Myvacet 9-45 the fat source is partially hydrogenated soybean oil.
  • Myvacet 9-08 and Myvacet 9-45 are both liquids at room temperature, having melting points of 4 C to 12 C. Both are well suited for use as lipophilic solvent, but Myvacet 9-45 is especially preferred because of its lower cost.
  • the preferred glycerides are mixed mono-, di- and tri-glycerides and acetylated monoglycerides because of the advantages of low cost and being good solvents for cyclosporins.
  • compositions with the scope of the present invention will further comprise as hydrophilic solvent, either propylene glycol or polyethylene glycol.
  • hydrophilic solvent either propylene glycol or polyethylene glycol.
  • polyethylene glycol it will preferably have a mean molecular weight of less than 1000. More preferably the mean molecular weight will be from about 400 to about 200, even more preferably from about 300 to about 200, and most preferably it will be about 200.
  • the composition will optimally and preferably also contain benzyl alcohol as hydrophilic co-solvent.
  • compositions within the scope of the present invention will further comprise, as surfactant, a polyoxyethylene glycolated natural or hydrogenated vegetable oil; for example, polyoxyethylene glycolated natural or hydrogenated castor oil.
  • surfactant designated in the United States Pharmacopoeia and National Formulary as Polyoxyl 40 Hydrogenated Castor Oil, which is available under the tradename "Cremophor RH40". 10
  • co-surfactant are selected from polyoxyethylene-sorbitan-fatty acid esters; e.g. mono- and trMauryl, palmityl, stearyl and oieyl esters; e.g. products of the type known aspolysorbates and available under the tradename "Tween".
  • co-surfactant are polyoxyethylene (20) sorbitan monolaurate, which is also known as polysorbate 20, and polyoxyethylene (20) sorbitan monooieate, which is also known as polysorbate 80.
  • compositions in accordance with the present invention may also contain other ingredients.
  • the composition may include, in addition to the foregoing, one or more other ingredients that are included as diluents, thickening agents, anti-oxidants, flavouring agents, and so forth.
  • compositions in accordance with the invention may comprise dosage forms for direct administration as emulsion preconcentrates or microemulsion preconcentrates.
  • an emulsion preconcentrate or microemulsion preconcentrate may be directly used as liquid for oral ingestion, parenteral use, or topical application, or it may be encapsulated into gelatin capsules for oral ingestion.
  • the present invention also provides pharmaceutical compositions in which the emulsion preconcentrate or microemulsion preconcentrate is further processed into an emulsion or a microemulsion.
  • emulsions or microemulsions obtained e.g. by diluting a preconcentrate with water or other aqueous medium (for example, a sweetened or flavoured preparation for drinking), may be employed as formulations for drinking.
  • aqueous medium for example, a sweetened or flavoured preparation for drinking
  • compositions comprising an emulsion preconcentrate, a thickening agent, and water will provide an aqueous emulsion in gel, paste, cream or like form. 11
  • compositions in accordance with the present invention may be employed for administration in any appropriate manner and form; e.g. orally, parenterally, topically; or rectally.
  • the relative proportion of the cyclosporin and other ingredients in the compositions of the invention will, of course, vary considerably depending on the particular type of composition concerned; e.g. whether it is an emulsion preconcentrate, microemulsion preconcentrate, emulsion, or microemulsion, the route of administration, and so forth.
  • the relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the composition; e.g. in the case of a composition for topical use, whether this is to be a free flowing liquid or a paste. Determination of workable proportions in any particular instance will generally be within the capability of persons skilled in the art.
  • the ingredients were weighed into a test tube in the proportions shown, the test tubes and contents were warmed to 100 C in a water bath, and then the test tubes were shaken until the contents of each tube wereinterdissolved to form a clear solution.
  • Polysorbate 80 1.0 1.0 1.0
  • the transmittance is that of an emulsion or microemulsion made by dispersing 1 g of the composition in about 20 ml of warm (37 C) water.
  • the density of the preconcentrate was about 1.06 to 1.07 g/ml, so that each ml of the preconcentrate contained about 100 mg of cyclosporine.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
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Abstract

Cette invention se rapporte à des compositions pharmaceutiques se présentant sous la forme d'un préconcentré d'émulsion exempt d'éthanol, qui renferme une cyclosporine comme principe actif, un solvant lipophile choisi parmi des glycérides, un solvant hydrophile choisi entre du propylène-glycol et du polyéthylène-glycol, un tensioactif choisi entre une huile naturelle glycolée de polyoxyéthylène ou une huile végétale hydrogénée, ainsi qu'un cotensioactif de préférence choisi parmi des polyoxyéthylène-sorbitan-esters d'acide gras.
PCT/CA1999/000192 1998-03-09 1999-03-05 Preconcentres d'emulsions comprenant une cyclosporine et des glycerides Ceased WO1999045946A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NZ329929 1998-03-09
NZ32992998A NZ329929A (en) 1998-03-09 1998-03-09 Pharmaceutical emulsion preconcentrate containing cyclosporin in a solvent system containing glycerides, propylene or polyethylene glycol, a surfactant and a co-surfactant

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WO1999045946A1 true WO1999045946A1 (fr) 1999-09-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1181035B1 (fr) * 1999-05-28 2005-03-30 Novartis AG Compositions pharmaceutiques
WO2024014959A3 (fr) * 2022-07-15 2024-02-22 Seranovo Holding B.V. Formulations générant des micelles avec une hydrophobicité améliorée

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0760237A1 (fr) * 1995-08-30 1997-03-05 Cipla Limited Microémulsions huile-dans-l'eau
WO1997022358A1 (fr) * 1995-12-15 1997-06-26 Bernard Charles Sherman Preconcentres en microemulsion comprenant des cyclosporines
WO1997048410A1 (fr) * 1996-06-19 1997-12-24 Novartis Ag Preparations de gelules molles contenant de la cyclosporine
NZ314701A (en) * 1997-04-29 1998-07-28 Bernard Charles Sherman Pharmaceutical compositions comprising a cyclosporin dissolved in propylene carbonate, a lipophilic solvent comprising glycerides and a surfactant
WO1998048779A1 (fr) * 1997-04-29 1998-11-05 Bernard Charles Sherman Preconcentre pour emulsion contenant une cyclosporine et un monoglyceride acetyle

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0760237A1 (fr) * 1995-08-30 1997-03-05 Cipla Limited Microémulsions huile-dans-l'eau
WO1997022358A1 (fr) * 1995-12-15 1997-06-26 Bernard Charles Sherman Preconcentres en microemulsion comprenant des cyclosporines
WO1997048410A1 (fr) * 1996-06-19 1997-12-24 Novartis Ag Preparations de gelules molles contenant de la cyclosporine
NZ314701A (en) * 1997-04-29 1998-07-28 Bernard Charles Sherman Pharmaceutical compositions comprising a cyclosporin dissolved in propylene carbonate, a lipophilic solvent comprising glycerides and a surfactant
CA2236131A1 (fr) * 1997-04-29 1998-10-29 Bernard Charles Sherman Preconcentre en emulsion renfermant une cyclosporine, du carbonate de propylene et des glycerides
WO1998048779A1 (fr) * 1997-04-29 1998-11-05 Bernard Charles Sherman Preconcentre pour emulsion contenant une cyclosporine et un monoglyceride acetyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Derwent World Patents Index; Class A96, AN 98-465354, XP002104875 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1181035B1 (fr) * 1999-05-28 2005-03-30 Novartis AG Compositions pharmaceutiques
WO2024014959A3 (fr) * 2022-07-15 2024-02-22 Seranovo Holding B.V. Formulations générant des micelles avec une hydrophobicité améliorée

Also Published As

Publication number Publication date
NZ329929A (en) 1999-10-28

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