WO2009150530A2

WO2009150530A2 - Novel foam composition

Info

Publication number: WO2009150530A2
Application number: PCT/IB2009/006005
Authority: WO
Inventors: Jean Marc Aiache
Original assignee: Ferring International Center Sa
Priority date: 2008-06-11
Filing date: 2009-06-10
Publication date: 2009-12-17
Also published as: WO2009150530A3

Abstract

The present invention relates to novel pharmaceutical compositions suitable for use as foams, notably rectal foams. According to the present invention there is provided 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. 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.

Description

NOVEL FOAM COMPOSITION

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutical compositions suitable for use as foams, notably rectal foams.

BACKGROUND OF THE INVENTION

Diseases that occur on or close to an accessible surface, such as the skin or the gastrointestinal tract, may be treated with topically administered medicaments. 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. Such 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.

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.

Examples of commercially available rectal foams for use in the treatment of, for example inflammatory bowel disease include: Colifoam^®, active ingredient hydrocortisone; and Salofalk Rectal Foam, active ingredient 5 -aminosalicylic acid (5 -ASA) .

Recent research has provided foams with an increased dose of active principle per unit volume of foam, consequently lowering the expulsion reflex observed when large volumes of foam are introduced into the rectum. EP 0 395 329 discloses foams containing 15 to 25 percent by weight of 5 -ASA (particle size less than 60μm) , 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 20μm.

These new, higher dose formulations suffer from a disadvantage: it appears that the 5 -ASA particles crystallise to form a solid once the composition is pressurized in its container. This form of crystalline solid can not be re-dissolved in water, i.e. the active principle may not be re- suspended. This disadvantage reduces the dose reproducibility over time.

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.

SUMMARY OF THE INVENTION

According to the present invention there is provided 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.

The term 'silicone oil' includes polymeric silicone fluids and oils corresponding to the structural unit (CH₃) ₃Siθ [-Si (R) ₂O-]_nSi (CH₃) 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 C₁-C₆ 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 α- (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. In a further aspect 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.

The active principle, 5-ASA or pharmaceutically acceptable salt thereof, is micronized and may have a mean particle size below 20μm, for example 5-9 μm, and a bulk density of from 150 to 450 g/dm³, for example from 200 to 250 g/dm³. In a further aspect 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.

According to the present invention there is provided 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 . In a further aspect of the invention the 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 (C₂H₄O) _a (-C₃H₆O)₁₃(C₂H₄O) _aH, 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 . In a further aspect of the invention 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. In a further aspect of the invention 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. In a further aspect of the invention 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. Examples of 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 . In a further aspect of the invention 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. Further examples of conventional buffers and excipients that may be considered by a person skilled in the art can be found in ^Handbook of Pharmaceutical Excipients' ; Ed. A. H. Kibbe, 3^rd Ed., American Pharmaceutical Association, USA and Pharmaceutical Press UK, 2000, the teachings of which are incorporated herein by reference. 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. In a further aspect of the invention 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. In a further aspect of the invention 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.

According to the present invention there is provided 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. Upon expulsion of the pharmaceutical composition from the container the composition experiences a pressure lower to that of the internal pressure of the container and a foam is formed. To facilitate the use of the foam a disposable cannula is fitted to the valve to enable the delivery of the foam to the rectum upon actuation of the valve. Typically, 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. In a further aspect of the present invention 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.

According to the present invention there is provided a process for the preparation of a pharmaceutical composition comprising the steps of : a) Providing an aqueous suspension comprising 5 -ASA and silicone oil; and b) Optionally pressurising the suspension. 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;

II. adding and mixing at least one preservative; III. adding and mixing at least one excipient, for example Lutrol

F68^®, carmellose sodium and polysorbate 80; IV. adding and mixing Labrasol^®; V. adding and mixing dimeticone; and

VI. dispersing the active principle therein.

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.

In a further aspect there is provided 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.

In a further aspect there is provided a process for dispensing a foam comprising the pharmaceutical composition from the device. In a further aspect of the invention the foam is for use as an intra-rectal foam.

In a further aspect there is provided the use of a pharmaceutical composition as described therein administered in the form of a foam in the treatment and/or prevention of Inflammatory Bowel Diseases, including Crohn's disease and ulcerative colitis, and/or colorectal cancer. The following examples are illustrative of several aspects of the present invention and should not be construed as limiting the scope of the invention. EXAMPLE 1: Preparation of the pre-pressurised Pharmaceutical Composition [100 g batch] .

A stirred solution [turbine sylverson 2000 rpm] of potassium hydrogen phosphate (0.37g) in purified water (53.59 ml) [pH 4.5] was heated in a glass container to 80 ⁰C. Methyl parahydroxybenzoate (0.32 g) , propyl parahydroxbenzoate (0.08 g) and sodium benzoate (0.20 g) were added to the solution. The solution was removed from the heat, and upon cooling to room temperature Poloxamer 188 (Lutrol^®_ F68, BASF) (1.55 g) [turbine Sylverson 2500 rpm] , sodium carboxymethylcellulose (Carmellose sodium) (0.33 g) [turbine Sylverson 3000 rpm] , polysorbate 80 (4.62 g) [turbine Sylverson 3000 rpm] , caprylocaproyl macrogolglyceride (Labrasol^®, Gattefosse Inc.) (4.62 g) [turbine Sylverson 3000 rpm], and polydimethylsiloxane (Dimeticone, Dow Corning Q7-9120 silicone fluid) (0.50 g) [turbine Sylverson 3000 rpm] were added sequentially as rain, ensuring that the solution was fully homogeneous after addition of each excipient . The mixture was transferred to a planetary mixer (Kenwood, 112 rpm) and the micronized 5-ASA (33.33 g) was added slowly as rain.

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) .

Example 2: Preparation of the Pressurised Pharmaceutical Composition.

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

(BIP) (4.5 g, 2.5 bar, AVANTEC, Prance) and, using a pressurising unit, the pressurising agent nitrogen was added until the internal pressure of the container reached 5 bar. The container was closed with a 3.3 ml metering valve (Lablabo S. A.) . 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.

Method 1: Method of Measuring Expansion volume

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

The mean change in vial mass post-actuation of a single dose as described in the method of measuring expansion volume, was measured by weighing the vial pre- and post-actuation and calculating the difference between the two masses .

The mass of a single dose, as prepared in the method of measuring expansion volume, was measured by actuating a single dose onto a tared, flat-bottomed dish. The dish was then weighed and the mass recorded. Table 2 (Comparative example) : Formulation according to examples 1 and 2 without labrasol and dimeticone .

The lack of residue of the foam after 3 months is the sign of an absence of active principle in the foam. This also explains the increase of the expansion yolume : the foam expands more as it contains a smaller percent of active principle.

Table 3 : Pharmaceutical Composition of the Present Invention according to examples 1 and 2.

Comparison between the pharmaceutical composition of the present invention and the composition excluding Labrasol^® and dimeticone illustrate the improved formulation of the current invention. The expansion volumes of the foam of the present invention were more consistent with time.

Further tests revealed that the vigorous agitation of the .pharmaceutical composition of the present invention was not necessary. The presence of the silicone oil in the formulation enables a simple shake, i.e. from an upright to an upside-down position of the container; approximately ten times, to be sufficient for correct re-suspension of the pharmaceutical composition.

It was thought that a possible uneven internal surface of the aluminium container may initiate the sedimentation and subsequent crystallisation of the active principle as seen in tables 2 and 3. In order to improve the formulation further, a comparative experiment between a conventional aluminium container and a glass container was performed. A conventional aluminium container was substituted with the glass container in example 2 above. After three months storage at 25°C, the mass of the delivered dose of foam produced from both the glass container and the aluminium container were measured. The amount of 5 -ASA obtained in each dose was also measured.

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 ⁰C.

1 Theoretical yield of 5-ASA is 1 g per 3 g dose of foam.

2 Adjusted to account for the actual mass of foam delivered

(theoretical mass of foam is 3 g) .

The amount of 5-ASA present in the delivered foam was measured by UV spectroscopy.

Claims

1. A pharmaceutical composition comprising 5 -aminosalicylic acid or a pharmaceutically acceptable salt thereof, as a therapeutically active ingredient; and silicone oil.

2. A pharmaceutical composition according to claim 1, wherein the silicone oil has a viscosity from 10 to 90 centistokes .

3. A pharmaceutical composition according to any of claims 1-2, wherein the silicone oil is selected from dimeticone 80 and dimeticone 20, and any mixture thereof .

4. A pharmaceutical composition according to any of claims 1-3, wherein the silicone oil is from 0.01% to 10^'.0%, preferably from 0.1% to 2.0%, by weight of the total weight of the composition.

5. A pharmaceutical composition according to any of claims 1-4, wherein said therapeutically active ingredient has a mean particle size below 20μm.

6. A pharmaceutical composition according to any of claims 1-5, wherein said therapeutically active ingredient has a bulk density from 150 to 450 g/dm³, preferably from 200 to 250 g/dm³.

7. A pharmaceutical composition according to any of claims 1-6, wherein said therapeutically active ingredient is from 20% to 50%, preferably from 30% to 45%, by weight of the total weight of the composition.

8. A pharmaceutical composition according to any of claims 1-7, further comprising a caprylocaproyl macrogolglyceride, preferably Labrasol^®.

9. A pharmaceutical composition according to any of claims 1-8, further comprising sodium carmellose.

10. A pharmaceutical composition according to any of claims 1-9, further comprising Lutrol FS8^®.

11. A pharmaceutical composition according to any of claims 1-10, further comprising Polysorbate 80.

12. A pharmaceutical composition according to any of claims 1-11, further comprising a preservative, wherein the preservative is selected from methylparaben, propylparaben and sodium benzoate, and any mixture thereof.

13. A pharmaceutical composition according to any of claims 1-12, further comprising a phosphate buffer.

14. A pharmaceutical composition according to any of claims 1-13, further comprising a propellant, wherein said propellant is selected from π-butane, isobutane and propane, and any mixture thereof.

15. A pharmaceutical composition according to any of claims 1-14, further comprising nitrogen.

16. A pharmaceutical composition according to any of claims 1-15, where the composition is pressurised to between 4 and 6 bar, preferably 5 bar.

17. A pharmaceutical composition according to any of claims 1-16, in the form of a foam, preferably an intra-rectal foam.

18. A pharmaceutical composition according to any of claims 1-17, which comprises said therapeutically active ingredient in an amount of from 0.5 to 1.5 g per unit of foam dosage form.

19. A multi-dose medical administration device comprising a glass container having therein a pharmaceutical composition according to any of claims 1-16.

20. A pharmaceutical composition according to any of claims 1-18 for the treatment or prevention of Inflammatory Bowel Diseases, including

Crohn's disease and ulcerative colitis, and colorectal cancer.

21. A pharmaceutical composition comprising 5-ASA, silicone oil and a propellant.

22. A pharmaceutical composition in the form of a foam comprising 5-ASA and a silicone oil.