WO2009150530A2 - Nouvelle composition de mousse - Google Patents

Nouvelle composition de mousse Download PDF

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Publication number
WO2009150530A2
WO2009150530A2 PCT/IB2009/006005 IB2009006005W WO2009150530A2 WO 2009150530 A2 WO2009150530 A2 WO 2009150530A2 IB 2009006005 W IB2009006005 W IB 2009006005W WO 2009150530 A2 WO2009150530 A2 WO 2009150530A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
foam
silicone oil
asa
Prior art date
Application number
PCT/IB2009/006005
Other languages
English (en)
Other versions
WO2009150530A3 (fr
Inventor
Jean Marc Aiache
Original Assignee
Ferring International Center Sa
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 Ferring International Center Sa filed Critical Ferring International Center Sa
Publication of WO2009150530A2 publication Critical patent/WO2009150530A2/fr
Publication of WO2009150530A3 publication Critical patent/WO2009150530A3/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams

Definitions

  • the present invention relates to novel pharmaceutical compositions suitable for use as foams, notably rectal foams.
  • Topically administered medicaments for use via the rectum are especially useful in the treatment of diseases that occur in the lower gastrointestinal tract, i.e. the colon or the rectum.
  • diseases may include rectal and haemorrhoidal inflammation, and inflammatory bowel diseases including Crohn's disease and ulcerative colitis. Additionally, such diseases may be associated with an increased risk of subsequent gastrointestinal cancer, especially colorectal cancer, as described in WO 95/18622.
  • 5 -aminosalicylic acid [5 -ASA] is a known medicament for the treatment and maintenance of remission of inflammatory bowel diseases. Additionally, it has recently been associated with a significant statistical decrease in the risk of cancer development, as described by J. Eaden in "Colorectal carcinoma, and inflammatory bowel disease” Alimentary Pharmacology & Therapeutics (2004) , 4:24-30.
  • Rectal foams In comparison with alternative rectal administration systems, i.e. suppositories and enemas, rectal foams have several advantages. Rectal foams enable immediate delivery of the active principle to the rectum and/or colon upon administration, whereas alternative systems require time for the excipient to melt or dissolve. Rectal foams also deliver a reliable arid reproducible dose, in contrast to rectally administered solutions which may not be retained in the rectum. Rectal foams are less rigid than suppositories and readily adapt to the contours of the rectum and/or colon and are thus less irritating.
  • EP 0 395 329 discloses foams containing 15 to 25 percent by weight of 5 -ASA (particle size less than 60 ⁇ m) , and containing self-emulsifying waxes, glycerol, surfactants, colloidal silica and water, together with conventional additives.
  • EP 0 735 8SO Bl discloses foams containing more than 25 percent by weight of an active ingredient, wherein the active principle is in a micronized powder form, with a particle size which does not exceed 20 ⁇ m.
  • the present invention provides a pharmaceutical composition suitable for use as a foam that may remain substantially fluid under pressure for, e.g. up to three months, while avoiding significant crystallisation of the active principle.
  • the pharmaceutical composition also provides further physical advantages such as dose reproducibility of the active principle and, if crystallisation does occur, ease of re-suspension.
  • the invention additionally provides a complementary delivery device and/or enhanced foam- forming properties of the pharmaceutical composition.
  • a pharmaceutical composition suitable for use as a foam comprising 5 -ASA or a pharmaceutically acceptable salt thereof and a silicone oil .
  • the pharmaceutical composition may remain substantially fluid upon pressurisation, avoiding, for example, significant crystallisation of the active principle.
  • 'silicone oil' includes polymeric silicone fluids and oils corresponding to the structural unit (CH 3 ) 3 Si ⁇ [-Si (R) 2 O-] n Si (CH 3 ) 3 where n is an integer of from 20 to 400 and R may be one or more of: hydrogen; hydroxyl; linear, branched, unsaturated or cyclic optionally substituted C 1 -C 6 alkyl; or aryl, such as phenyl or optionally substituted phenyl.
  • the silicone oil may have a viscosity of or greater than 10 centistokes, for example from 10 to 90 centistokes, for example from 10 to 30 centistokes, and for example from 70 to 90 centistokes; such silicone oils may include dimeticone, dimethiconol, phenyl trimethicone, and derivatives or mixtures thereof . Synonyms of dimeticone include ⁇ - (trimethylsilyl) -methyl -poly (oxy (dimethylsilylene) ) , polydimethylsiloxane, dimethicone, simethicone, polysilane, silicone rubber, silicone latex and silbar .
  • the silicone oil may be dimeticone [Dow Corning ® Q7-9120 silicone Fluid] and derivatives and mixtures thereof, for example dimeticone 20 and dimeticone 80.
  • the .silicone oil may be present in an amount from 0.05% and io% by weight of the total pharmaceutical composition; for example below 1% by weight, for example from 0.4% and 0.6% by weight, and for example 0.5% by weight of the total composition.
  • the active principle may be 5 -ASA, or a pharmaceutically acceptable salt thereof. Synonyms of 5-ASA include 5-aminosalicylic acid, mesalazine or mesalamine.
  • 5-ASA may be substituted with a 5-ASA derivative such as ipsalazine, balsalazine, sulfalazine, salazopyrine, salazosulfapyridine, olsalazine, 4 -ASA, oxidation products of 5-ASA, and mixtures thereof, including mixtures of 5-ASA and its derivatives.
  • a 5-ASA derivative such as ipsalazine, balsalazine, sulfalazine, salazopyrine, salazosulfapyridine, olsalazine, 4 -ASA, oxidation products of 5-ASA, and mixtures thereof, including mixtures of 5-ASA and its derivatives.
  • the active principle is micronized and may have a mean particle size below 20 ⁇ m, for example 5-9 ⁇ m, and a bulk density of from 150 to 450 g/dm 3 , for example from 200 to 250 g/dm 3 .
  • the active principle represents from 20% to 50% by weight of the total weight of the pharmaceutical composition; for example, 30% to 45% by weight of the total weight of the pharmaceutical composition.
  • a pharmaceutical composition comprising 5-ASA, or pharmaceutically acceptable salt thereof, a silicone oil and further comprising one or more of an excipient, preservative, buffering agent, propellant and a pressurisation agent.
  • the excipient may be a surfactant, stabilising agent and/or thickening agent and is one or more of caprocaproyl macrogolglycerides, carboxymethyl cellulose, Poloxamer 188 and Polysorbate 80.
  • the physical properties of these excipients may fall into one or more classes, for example both surfactants and thickening agents may provide a stabilising effect on the composition.
  • the surfactant may be a caprylocaproyl macrogolglyceride.
  • Caprylocaproyl macroglycerides are mixtures of monoesters, diesters and triesters of glycerol, or monoesters or diesters of macrogols with a mean relative molecular mass of from 350 to 450 and for example 400.
  • the caprylocaproyl macrogolglyceride may include for example Labrasol ® , Labrafil ® and Tefose ® and mixtures thereof .
  • caprylocaproyl macrogolglyceride surfactant may be from 2.0% to 7.0% by weight, for example from 3.0% to 6.0%, for example from 4.5% to 5.5% by weight of the total weight of the pharmaceutical composition and, for example, have an HLB value of from 12 to 15, for example 14.
  • the surfactant may be a poloxamer.
  • Poloxamers also referred to as polyethylene-polypropylene glycol, are non-ionic polyoxyethylene- polyoxypropylene block co-polymers of the type ABA, with the general formula HO (C 2 H 4 O) a (-C 3 H 6 O) 13 (C 2 H 4 O) a H, and with a molecular mass of from 1000 to above 16000, for example 8600.
  • the poloxamer may comprise, for example, a 4:1 ratio of poIyoxyethylene to polyoxypropylene .
  • the surfactant may be poloxamer 188, for example Lutrol ® F68, and comprise from 0.50% to 2% by weight of the total weight of the pharmaceutical composition.
  • the surfactant may be polysorbate 80, also known as polyoxyethylene sorbitan mono-oleate, and has an HLB value of 15.
  • the polysorbate surfactant may be from 2.0% to 7.0% by weight, for example from 3.0% to 6.0%, for example 4.5% to 5.5% by weight of the total weight of the pharmaceutical composition.
  • the thickening agent may be carboxymethyl cellulose, for example one of the sodium or calcium salts of carmellose, or a mixture thereof, and has for example from 0.5 to 1.0 cellulose derivatives per monomer unit.
  • the thickening agent may be sodium carmellose and may be from 0.05% to 1.00% by weight, for example 0.1% to 0.5%, and for example 0.3% to 0.4%, of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition may further comprise a preservative.
  • a preservative that may be used are benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, cresol, dehydroacetic acid, phenol, phenylethyl alcohol, phenylmercuric acetate or nitrate, potassium sorbate, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol and parabens .
  • Parabens refers to a group consisting of esters of p-hydroxybenzoic acid, such as methylparaben (Methylparahydroxybenzoate) , ethylparaben (ethylparahydroxybenzoate) , p- hydroxybenzoic acid, propylparaben (propylparahydroxybenzoate) or butylparaben (butylparahydroxybenzoate) .
  • the preservative may be one or more of methylparaben, propylparaben and sodium benzoate .
  • the preservative or mixture thereof may be from 0.01% to 1.0% by weight, for example from 3.0% to 6.0%, for example 4.5% to 5.5% by weight of the total weight of the pharmaceutical composition.
  • the buffer may be a sodium or potassium salt of dihydrogen phosphate, for example potassium dihydrogen phosphate, dissolved in purified water with a pH 4.5.
  • dihydrogen phosphate for example potassium dihydrogen phosphate
  • the propellant may be one or more of a group comprising n-butane, isobutane and propane, and a mixture thereof.
  • a mixture of n-butane, isobutane and propane may also be referred to as BIP.
  • the BIP mixture may comprise from 75 to 85% by weight of n-butane and iso-butane and from 15 to 25% by weight of propane.
  • the propellant may be from 5% to 15% by weight, for example from 6% to 12%, for example 8% to 9% by weight of the total weight of the pharmaceutical composition.
  • the pressurisation agent may be nitrogen.
  • the pressurisation agent is added to the container to obtain for example 4 to 6 bar, for example 4.5 to 5.5 bar, for example 5 bar of the internal pressure of the container having therein the pharmaceutical composition.
  • an administration device comprising a glass container, for example a plasticised type III container according to the Ph. Eur. Section 3.2.1, having therein a pressurised pharmaceutical composition comprising 5 -ASA or pharmaceutically acceptable salt thereof, and a silicone oil.
  • the 'container' may be a vial.
  • the device has a smooth internal surface and may be sealed by a plastic valve comprising polypropylene and/or polyethylene (without dipping tube), a girdle and a 3.3 ml dosing head. Upon actuation of the valve the pharmaceutical composition is expelled from the container via the dosing head in a dose (and expansion volume) proportional to the length of time the valve is actuated.
  • a foam is formed.
  • a disposable cannula is fitted to the valve to enable the delivery of the foam to the rectum upon actuation of the valve.
  • a 1 g dose of active principle will be administered from the same device and pharmaceutical composition therein for 14 consecutive days .
  • the foam may comprise from 80 to 95 parts of the pharmaceutical composition and/or from 5 to 25 parts of a propellant and/or pressurisation agent.
  • the propellant and/or pressurisation agent may be from for example 10 to 20 parts, for example 10 to 15 parts, by weight of the total weight of the foam.
  • Step (a) may comprise providing an aqueous solution of a buffer and silicone oil and optionally a surfactant, a stabilising agent, a thickening agent and a preservative; and dispersing 5 -ASA therein.
  • Step (a) may comprise the steps of: I. preparing a buffer
  • F68 ® carmellose sodium and polysorbate 80; IV. adding and mixing Labrasol ® ; V. adding and mixing dimeticone; and
  • Such mixing methods are those that are available by the man skilled in the art, and can be achieved with an efficient hotnogenizer such as a "Gann Emulgor" type. According to the present description the terms dispersion, homogenization and mixing are equivalent.
  • a process for filling a container followed by increasing the pressure within the container wherein a glass container, as described above, is filled with the pharmaceutical composition comprising 5-ASA or pharmaceutically acceptable salt thereof and a silicone oil, as described above, before the pressure within the internal cavity of the container is increased.
  • a process for dispensing a foam comprising the pharmaceutical composition from the device.
  • the foam is for use as an intra-rectal foam.
  • Table 1 Pre-pressurised Pharmaceutical Composition according to the present invention.
  • a typical 100 g batch of the pharmaceutical composition according to the above proportions would comprise a mixture of butane, isopropane and propane (BIP) (8.33 g) and nitrogen (5 bar) .
  • An opaque plasticised type III glass container (vial) was filled with the pharmaceutical composition (54 g) prepared according to example 1, and further filled with the propellant mixture butane, iso-butane and propane
  • the container contains 14 administrations of a 1 g dose of active principle.
  • Tables 2, 3 and 4 describe comparative tests between the pharmaceutical composition of the present invention prepared according to examples 1 and 2 , with a pharmaceutical composition prepared according to examples 1 and 2 excluding Labrasol ® and dimeticone 80.
  • the pharmaceutical compositions are compared once the composition has been actuated and is in foam form.
  • Expansion volume was measured according to the Ph. Eur. Monograph of foams.
  • An aluminium container comprising the composition according to examples 1 and 2 above was agitated for at least 30 seconds.
  • the container was placed in an upside down position (at 180 °) and connected to a calibrated 1 m long column [15 mm internal diameter, 100 ml volume] via a small nalgene 6 mm diameter pipe.
  • the head was pressed for at least 2 seconds and then released; a single dose was emitted from the container.
  • the ' cannula was changed between each dose and the above steps were followed for each measurement .
  • Method 2 Method of Measuring sample weight
  • Table 3 Pharmaceutical Composition of the Present Invention according to examples 1 and 2.
  • Table 4 (comparative example) : Comparison between an aluminium container and the glass container containing the pharmaceutical composition of the current invention after storage at 3 months and 25 0 C.
  • Theoretical yield of 5-ASA is 1 g per 3 g dose of foam.
  • the amount of 5-ASA present in the delivered foam was measured by UV spectroscopy.

Abstract

La présente invention porte sur de nouvelles compositions pharmaceutiques appropriées pour une utilisation en tant que mousses, notamment en tant que mousses rectales. Selon la présente invention, il est proposé une composition pharmaceutique appropriée pour être utilisée en tant que mousse, renfermant 5-ASA ou un sel pharmaceutiquement acceptable correspondant et une huile de silicone. La composition pharmaceutique peut rester sensiblement liquide lors d'une mise en pression, évitant, par exemple, une cristallisation significative du principe actif. La composition pharmaceutique fournit également d'autres avantages physiques, tels qu'une reproductibilité de dose du principe actif et, si une cristallisation se produit, une facilité de remise en suspension. L'invention fournit en outre un dispositif d'administration complémentaire et/ou des propriétés améliorées de formation de mousse de la composition pharmaceutique.
PCT/IB2009/006005 2008-06-11 2009-06-10 Nouvelle composition de mousse WO2009150530A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08252010.7 2008-06-11
EP08252010 2008-06-11

Publications (2)

Publication Number Publication Date
WO2009150530A2 true WO2009150530A2 (fr) 2009-12-17
WO2009150530A3 WO2009150530A3 (fr) 2010-10-28

Family

ID=39876579

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/006005 WO2009150530A2 (fr) 2008-06-11 2009-06-10 Nouvelle composition de mousse

Country Status (1)

Country Link
WO (1) WO2009150530A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8580302B2 (en) 2000-11-20 2013-11-12 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
WO2018109717A1 (fr) * 2016-12-16 2018-06-21 Ferring B.V. Formulations de mousse rectale

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4933330A (en) * 1987-04-01 1990-06-12 Dak-Laboratoriet Benzoic acid derivatives and use thereof
US5378470A (en) * 1989-07-25 1995-01-03 Henning Berlin Gmbh Rectally administered pharmaceutical preparation
US5725872A (en) * 1993-12-14 1998-03-10 Ferring Bv Composition for foams, notably rectal foams, and foams thus obtained
WO2007082698A1 (fr) * 2006-01-19 2007-07-26 Disphar International B.V. Composition moussante

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4933330A (en) * 1987-04-01 1990-06-12 Dak-Laboratoriet Benzoic acid derivatives and use thereof
US5378470A (en) * 1989-07-25 1995-01-03 Henning Berlin Gmbh Rectally administered pharmaceutical preparation
US5725872A (en) * 1993-12-14 1998-03-10 Ferring Bv Composition for foams, notably rectal foams, and foams thus obtained
WO2007082698A1 (fr) * 2006-01-19 2007-07-26 Disphar International B.V. Composition moussante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOU KARAM M ET AL: "First approach to the development of a colonic stimuli-sensitive delivery system for rectal administration of 5-aminosalicylic acid" S.T.P. PHARMA SCIENCES 1995 FR, vol. 5, no. 1, 1995, pages 89-92, XP008098257 ISSN: 1157-1489 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8580302B2 (en) 2000-11-20 2013-11-12 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
WO2018109717A1 (fr) * 2016-12-16 2018-06-21 Ferring B.V. Formulations de mousse rectale
CN110430869A (zh) * 2016-12-16 2019-11-08 费灵有限公司 直肠泡沫配制物
RU2757275C2 (ru) * 2016-12-16 2021-10-12 Ферринг Б.В. Композиции ректальной пены

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