MX2008009090A - Foam-forming composition - Google Patents

Abstract

The present invention relates to a novel foam-forming composition suitable for rectal administration of locally-acting pharmaceutically active ingredients, and the product adapted to administer said foam-forming composition. Also, the present invention relates to a method for its preparation. According to the present invention a foam-forming composition is provided which exhibits a high expansion ratio and at the same time conferring optimal appearance of the formed foam to allow sufficient contact time of the active to the target site in the intestine in order to obtain optimal local effect. The composition according to the present inventions provides superior properties for the treatment of rectal diseases.

Description

FOAM FORMING COMPOSITION Field of the Invention The present invention relates to a new foam-forming composition suitable for the rectal administration of prednisolone and to a product adapted to administer the foam-forming composition. Also, the present invention relates to a method for its preparation. Background of the Invention Ulcerative colitis of the left side (distal) and ulcerative proctitis are subtypes of ulcerative colitis diseases with multiple treatment options. In addition to the oral formulations used in patients with extensive colitis or pancolitis, those with diseases limited to 60 cm distal to the anal edge also have the option of topical therapies with formulations of aminosalicylates or glucocorticoids [R.D. Cohen et al. The American Journal of Gastroenterology: Vol. 95, No. 5 2000; p. 1263]. Dosage forms suitable for rectal delivery include suppositories, foams and liquid enemas, which differ with respect to their physicochemical properties and the potential for proximal diffusion. A prospective randomized comparison of the foams against liquid enemas reported that patients preferred foam because of greater comfort, the Ref.194702 ease of retention and minimal interference with your daily routine. The disadvantage of using foams instead of liquid enemas is the reduced proximal diffusion of the foam. Although liquid enemas have been shown to extend reliably with respect to splenic flexion, foam can only reach the proximal sigmoid colon [J.K. Marshall et al., The American Journal of Gastroenterology; vol. 95, No. 7, 2002. p. 1628]. Especially when the rectal treatment involves the use of poorly absorbed prednisolone metasulphobenzoate and consequently acting locally, the effectiveness of the therapy depends on the direct contact of this active ingredient with the inflamed mucosa. Accordingly, it is important that a highly expanded volume of the foam be obtained to provide a broad distribution throughout the diseased area. The use of aqueous foams having a highly expanded volume is already known. An example of such a foam comprising prednisolone metasulphobenzoate is already known from EP0774957. This patent teaches that an increased diffusion of the active pharmaceutical substance along the intestine can be obtained using a composition exhibiting a delayed foaming action. Such delayed foam formation can be achieved by providing a composition in a pressurized container in which the propellant is separated physically from the composition. However, the disadvantage of this single-dose, foam-forming composition is that although a highly expanded volume of the foam of up to 275 ml can be obtained, the initial volume of the non-foaming composition to be dosed is also extremely elevated (22 ml). Such a high initial volume is disadvantageous since it requires the use of a large can, especially when multiple doses are to be contained in the can. The packaging and distribution of large cans is an economic disadvantage. In addition, such a large can is very impractical to handle for the patient. From the prior art compositions it appears that aerosol foams are complicated physicochemical structures that are not formed under arbitrary circumstances. In particular, a special balance between the foam forming components is important. The slight shifts in the composition can already lead to a collapse of the foam or alternatively the foam is not formed at all, especially when the administration will occur by means of an applicator nozzle with a small diameter. Thus, a given formulation simply can not be adapted without additional provisions to lead to the desired foam. Especially, the problem with the highly expandable foam forming compositions according to the prior art which is due to their appearance, the expulsion preliminary of said formed foam is easily induced. This leads to insufficient retention of the active ingredient with respect to the mucosa of the inflamed area that is necessary to obtain optimal results in combating the disease. Thus, it is an object of the present invention to provide a foam-forming composition for prednisolone and its derivatives, which solves the problems identified above. Surprisingly, it has now been found that an expansion ratio of the increased foam volume has a greater effect on the appearance of the foam formed and therefore provides an advantageous and clinically improved composition that can serve as an alternative for the few compositions that are currently available in the market. Brief Description of the Invention The present invention provides a foam-forming composition that exhibits a volume of highly expanded foam and that at the same time confers an appearance that allows a sufficient contact time of the active substance with respect to the target site in the intestine. such that an optimum local effect of the active pharmaceutical ingredient present in the foam is obtained. Therefore, in a first modality, provides an aqueous foaming composition suitable for rectal administration of a therapeutically effective amount of prednisolone or its pharmaceutically acceptable derivatives, characterized in that the composition has a volume expansion ratio in the range of 26 to 70. In a preferred embodiment of the present invention, the volume expansion ratio is at least 26, preferably at least 28, more preferably at least 30. The volume expansion ratio is less than 70, more preferably less than 60, even more preferably less than 50. The volume expansion ratio (VER) is defined here as the ratio between the expanded volume of the foam (Vf in ml) and the initial volume of the non-foamy raw material (Vi in ml) according to the equation VER = Vf / Vj .. The expanded volume of the foam (Vf) can be determined by the emission of a dose of a predetermined volume or weight of the foamed raw material in a vertical tube with the radius (R) and the subsequent measurement of the length (D) in the tube filled with the foam , provides the volume of the expansion according to the equation: Vf = D xpx R2. The initial volume Vi can be determined from the weight of the emitted dose divided by its density at 37 SC (in general, for aqueous compositions, the density is 1).

It has surprisingly been found that by employing a foam-forming composition with an increased volume expansion ratio, a foam is generated with an advantageous appearance, i.e., that it sinks rather quickly but a thin layer of foam components which include prednisolone remains on the surface of the intestine. This advantageous appearance allows a sufficient contact time between the active pharmaceutical ingredient of the mucosa and the inflamed area, while a preliminary expulsion reflex is minimized at the same time. The optimal reabsorption of prednisolone from the foam to the inflamed mucosa is established accordingly. Detailed Description of the Invention The composition of the present invention is an aqueous composition. For the present invention, an aqueous composition means that a majority of the weighted volume of the composition is composed of water, also referred to as the aqueous carrier, preferably, the composition of the present invention comprises 57-97 weight percent of water, more preferably 65-95 weight percent. This aqueous carrier obviously also covers any aqueous buffer solution such as, for example, a phosphate buffer which, apart from water, also contains potassium phosphate and amounts of sodium hydroxide. sodium and hydrochloric acid to obtain the desired pH. In a preferred embodiment of the present invention, the aqueous composition does not include emulsifying waxes and / or mineral oils. The disadvantage of these components is that they could further irritate already inflamed areas of the intestine. In still another aspect, the composition of the present invention comprises at least one surfactant, a thickening agent and a propellant. Depending on the combination of the surfactants and the thickening agents, a person skilled in the art can first verify the compatibility of the ingredients with the active ingredient. The thickening agent in the composition of the present invention can be chosen from any water-soluble polymer. Preferably, the thickening agent is a water soluble cellulose polymer. Without being limited, the following polymers can be included in the composition, for example carboxymethyl cellulose, polyoxyethylene-polyoxypropylene copolymers covered under the generic term poloxamer, xanthan gum, agar, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose. More preferably, hydroxypropyl cellulose is used. Typically, the weight percentage of the thickening agent is between 0.01 to 1% (w / w). In the present invention, the amount is at most 1.0%, preferably when a lot of 0.5%, more preferably it is when much of 0.3% (p / p) of the composition. In the present invention, the minimum content is at least 0.01%, preferably at least 0.05%, more preferably at least 0.1%, (w / w) of the composition. The precise identity of the surfactant present in the composition of the present invention is not critical and may be chosen from those having an effective emulsifying action in combination with water and the foaming agent. Preferably, a mixture of two or more different surfactants is used. In the mixture, at least one surfactant can provide the emulsifying action, while the other can provide a foam stabilizing action. The known anionic and nonionic surfactants can be used. In the composition of the present invention, the surfactant can be a mixture of at least two nonionic surfactants since they are less irritating. Nonionic surfactants can include esters of glycerol fatty acids such as glycerol monostearate, esters of glycol fatty acids such as propylene glycol monostearate, fatty acid esters of polyhydric alcohol such as propylene glycol monooleate, esters of polyoxyethylene fatty acids such as polyoxyethylene stearate, alcohol esters of fatty acids of polyoxyethylene such as polyoxyethylene stearyl ether, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monoolate, sorbitan esters such as sorbitan monostearate, caprylocaproyl macrogolglycerides such as Labrasol®. Preferably, nonionic surfactants that increase the viscosity of the foam forming composition should be avoided. In a preferred embodiment, a mixture of the macrogolglycerides of caprylocaproyl and polyoxyethylene monooleate sorbitan is used. Suitably, the total amount of the surfactant present in the composition makes up from 1% to 15% (w / w) of the composition, preferably makes less than 10% (w / w) of the total weight of the composition. In a preferred embodiment of the present invention, the composition contains a lubricant. Preferably, the lubricant is silicone. In this preferred embodiment, the silicone further stabilizes the foam-forming composition. More preferably, the silicone is polydimethylsiloxane. The amount of the lubricant is at least 0.1%, preferably at least 0.5%, more preferably at least 1% (w / w) of the composition and at most 10%, preferably at much 5%, more preferably when much of 3% (p / p) of the composition. The propellant according to the present invention is used to achieve the effect of foam formation. The propellant can be chosen in accordance with known principles for the preparation of a composition that can form a foam of the aerosol type packaged in a pressurized container and suitable for rectal application. The propellant can be any suitable gas such as a low molecular weight hydrocarbon, for example isobutane, N-butane, propane, pentane, CFC, HFC, or air. Preferably, the propellant comprises a mixture of butane, isobutane, propane (B.I.P.). Suitably, the propellant can have a vapor pressure within the range of 0.5 to 2.5 bar (at room temperature). The propellant may be present in an amount of 4 to 12% (w / w) of the composition. Preferably, the amount is between 6 to 10%, more preferably between 7 to 9% (w / w) of the composition. Additionally, liquid nitrogen may be present as the pressurizing agent to obtain the required number of doses. In a preferred embodiment, the pressure in a multiple dose container is in the range of 5 to 12, more preferably 7 to 11 bar, and even more preferably 6 to 8 bar. The composition of the present invention is suitable for rectal administration of an amount therapeutically of prednisolone or its pharmaceutically acceptable derivative. Particularly, the pharmaceutically acceptable derivative of prednisolone may be the locally acting forms of prednisolone. Preferably, it is the prednisolone metasulphobenzoate. The pharmaceutically acceptable salt is preferably a sodium salt. Suitably, other locally active pharmaceutically active ingredients may also be used in the foam-forming composition of the present invention. Preferably, they can be selected from the group consisting of tixocortol pivalate, fluticasone propionate, beclomethasone dipropionate, mesalazine, budesonide and the pharmaceutically acceptable salts thereof. The pharmaceutically active ingredient may be present in any effective amount that causes a therapeutic effect in the patient. The therapeutically active ingredient is preferably present in amounts of about 0.005% by weight to about 10% by weight, more preferably about 0.05% by weight to about 2% by weight, based on the total weight of the foam-forming composition. The foam-forming composition may also contain other ingredients such as preservatives, lubricants and chelating agents. The typical conservatives they include sodium benzoate, sorbic acid, phenylethyl alcohol and parahydroxybenzoate. The chelating agent may include EDTA. In yet another embodiment of the present invention a pressurized multi-dose aerosol container is provided, comprising the foam-forming composition according to the invention. The problem with foam forming compositions comprised in a multi-dose aerosol container is the insufficient ability to repeat the doses of the foam emitted. It appears that the amount of the active ingredient present in a single dose and the volume of expansion of a dose emitted can fluctuate between the first and the last dose in a range that is outside the target range. Since it is a prerequisite for the development of an advantageous multi-dose rectal formulation that all the doses provided are within the specified narrow range with respect to both the amount of the active substance and the final volume reached of the dose, such repeatability The high dose is critical for the development of a commercially advantageous product. It has now surprisingly been found that by employing a low viscosity of the foam-forming composition, it is possible to produce foam with a repeatability of sufficient dose.

Although foam forming compositions with both low and high viscosities have been described in EP 0735860 for mesalazine, this document does not teach that the viscosity of the foam-forming composition has a positive influence on the repeatability of the foam dose . The composition of the present invention preferably has a viscosity in the range of 2.0 to 20.0 mPa.s. The viscosity of the composition is at least 2.0 mPa.s, preferably it is at least 4.0 mPa.s, more preferably at least 6.0 mPa.s and even more preferably at least 7.0 mPa.s. The viscosity of the composition is at most 20.0 mPa.s, preferably less than 16.0 mPa.s, more preferably less than 12.0 mPa.s, and even more preferably less than 9.0 mPa.s. For the present invention, with the viscosity of the foam-forming composition is meant the viscosity of the non-foaming composition comprising all the components that make up the foam-forming composition except the foam-forming agent (s) . The viscosity of the emulsion can be determined using any suitable viscometer operated in accordance with standard procedures. For the present invention, the viscosities were measured by means of a Brookfield RVT apparatus with a CP 42 mobile conical plate for which The rotation speed of the emulsion during the measurement is correlated with a standard coefficient. For the present invention, the viscosity (in cP or mPa.s) is determined at 25 SC and 100 rpm. In another embodiment, the multiple dose container comprises a metering valve. Dosing valves are valves that distribute a predetermined and constant dose of the foam. Suitably, a metering valve adapted to distribute volumes from about 1 to 5 cm 3 can be used (provided by Lablabo, France). The container can be a coated aluminum can. In addition, the container can be adjusted or supplied together with an application device for insertion into the rectum, to ensure more efficient administration of the foam. In still another aspect of the present invention, there is provided a method for the preparation of the foam-forming composition. The foam-forming composition according to the present invention is prepared according to a method comprising the steps of mixing an aqueous carrier, a lubricant, a thickening agent, at least one surfactant and the pharmaceutically active ingredient to form a volumetric emulsion homogeneous Preferably, the method comprises the steps of: a) mixing an aqueous carrier, a lubricant, at less a surfactant, and a pharmaceutically active ingredient acting locally or its pharmaceutically acceptable derivative to obtain a homogeneous emulsion having a viscosity in the range from 2 to 20 mPa.s., and b) adding to the emulsion obtained in step a ) at least one propellant to form a foam forming composition. Typically, preservatives and chelating agents are first mixed with the aqueous carrier by means of a homogenizer. Then, the thickening agent is mixed in the same way. Subsequently, the surfactant (s) and the lubricant are mixed and the mixture can be solubilized and / or heated before the active ingredient is added. Alternatively, the active ingredient is mixed at the start. The cans can be filled with the volumetric emulsion and subsequently after sealing, a propellant is added to form the foam-forming composition. The foam forming composition according to the present invention will usually be packaged in a suitable pressurized dispensing can of the aerosol type well known in the art such as an aluminum can. Each can is sealed with a foam distribution valve adequate Any valve or nozzle / valve assembly that provides a means for releasing the foaming emulsion from the container and providing a foam is usable for use in the present invention. The foam that is formed from the composition of the present invention has superior properties. The advantages associated with the highly expanded foam according to the present invention is that better results are obtained to combat the disease and either a lower dose of the active ingredient or fewer dosages per day are necessary to obtain similar results when compared to the compositions of prior art. For example, in patients using the composition of the present invention, the probability of inducing a defecation or ejection reflex during the administration of the foam is lower than what can normally be expected from the foam having an expansion volume. high. In addition, increased diffusion of the foam together with a longer exposure time with respect to the active substance will lead to an optimal local effect at the target site. Also, the foam of the present invention does not cause further irritation of the inflamed target mucosa due to the absence of emulsifying waxes and / or technical oils as are present in prior art compositions. Because of these properties Superior of the foam, the current invention represents a valuable alternative to the previously known medicines used for the treatment of rectal diseases. The present invention is further illustrated by the following examples that should not be construed as limiting the scope of the invention. EXAMPLE 1 Preparation of a volumetric emulsion A pharmaceutical foam forming composition was formulated with sodium metasulfobenzoate prednisolone as the active ingredient according to the formula shown in Table I. Table I: Composition of the volumetric emulsion The volumetric emulsion is prepared by introducing sorbic acid (E200), phenylethyl alcohol (CAS 60-12- 8) and edetic acid (CAS 6381-92-6) into the aqueous carrier while mixing in a Chabaud® mixer during 10 minutes at 1500 rpm. Subsequently, the hydroxypropyl methylcellulose was added under rapid stirring at 3000 rpm for 10 minutes, and further agitation for 60 minutes at 1000 rpm. Next, polysorbate 80 (Montanox®, Seppic SA), the macrogolglycerides of caprylocaproyl (Labrasol®, Gattefose Corporation) and polydimethylsiloxane (Dow Corning® Q7-9120 silicone fluid, 100 CST, 425G, Dow Corning) were added under stirring for 15 minutes at 1500 rpm. Finally, the sodium salt of the prednisolone metasulphobenzoate (CAS 630-67-1) was incorporated into the emulsion under rapid stirring at 3000 rpm for 15 minutes. The homogeneous emulsion formed has a pH of 4.15. The viscosity was measured using a Brookfield viscometer (mobile RTV with a cone and the CP 42 plate). The viscometer is a torque meter that is driven at discrete rotational speeds. The amount of torque that is indicated must be converted to the units of absolute centipoises (CP) or in mPa.s from the graphs of the pre-calculated intervals (Brookfield). The viscosity measured at 25 SC and 100 rpm was 7.6 mPa. s.

Example 2 Preparation of the foam-forming composition A can of monoblocks (110 ml) was filled with 90 grams of the volumetric emulsion according to experiment 1 and is further filled with the B.I.P. propellants. (Novospray nbu / p25 Avantec-dehon; 8,110 g) and as the pressurizing agent, nitrogen (0.09 g) is added using a pressurization unit and leading to a pressure of 12 bar. The can was closed with a 3 ml metering valve (Lablabo S.A.). The can contains the material for 14 dosages (and 20% overdose) and the capacity for repetition of the dose and the volume of expansion were stabilized by the measurement respectively of the volumetric mass (g / ml) and the expansion volumes (ml ) of 1 / a. and the 14 / a. dose (Table II). Table II: Characteristics of the foam SD: standard deviation The expansion volume was determined by issuing a single dose (3 ml) at the descending limb of a plastic tube that remains in a vertical position that has an internal diameter (D.I.) of 1.2 cm and a length of 100 cm and that has an indication of the scale in centimeters. The maximum length of the tube filled with the volume of the foam is recorded (D) and subsequently, the volume of expansion is calculated by the equation Vexp = Dxpxr2 where r is the tube radius (ie 0.6 cm). The volumetric expansion ratio was found to be 30. The volumetric mass (g / ml) of a single dose is calculated by dividing the weight of the dose (g) by the volume of expansion (ml). The weight of the dose is determined by the measurement on a balance (Mettler PR 802, 0.01 mg of precision) of the difference of the weight of the can before and after the emission of the dose. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (13)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. An aqueous foaming composition for rectal administration of a therapeutically effective amount of prednisolone or its pharmaceutically acceptable derivatives, characterized in that it has a of volumetric expansion of at least 26. The composition according to claim 1, characterized in that the volumetric expansion ratio is at least 28, preferably at least 30. 3. The composition according to claim 1 or 2. , characterized in that the volumetric expansion ratio is less than 70, preferably less than 60, more preferably less than 50. 4. The composition according to any of the preceding claims, characterized in that the pharmaceutically acceptable derivative of prednisolone is a salt, preferably the metasulfobenz sodium oate of prednisolone. 5. The composition according to any of the preceding claims, characterized in that it comprises a surfactant, a thickening agent and a propeller. 6. The composition according to claim 5, characterized in that the thickening agent is a water-soluble cellulose polymer, preferably hydroxypropyl methylcellulose in an amount of at least 0.01%, preferably at least 0.05%, more preferably at least 0.1% (w / w) of the composition and at most 1%, preferably when much 0.5%, more preferably when much 0.3% (w / w) of the composition. The composition according to claims 5 or 6, characterized in that the surfactant is a mixture of at least two nonionic surfactants, preferably it is a mixture of macrogolglycerides of caprylocaproyl and polyoxyethylene monooleate 80 sorbitan. The composition according to any of claims 5 to 7, characterized in that the propellant comprises a mixture of butane, isobutane, propan in an amount of 4 to 12%, 6 to 10% and more preferably 7 to 9% (p. / p) of the composition. The composition according to any of the preceding claims, characterized in that it also comprises a lubricant, preferably the lubricant is silicone, more preferably the lubricant is polydimethylsiloxane in an amount of at least 0.1%, preferably at least 0.5%, more preferably at least 1% (w / w) of the composition and at most 10%, preferably at much 5%, more preferably at much 3% (w / w) of the composition. 10. A multi-dose pressurized aerosol container, characterized in that it comprises the foam-forming composition according to any of the preceding claims. The multi-dose container according to claim 10, characterized in that the viscosity of the foam-forming composition is in the range of 2.0 to 20.0 mPa.s, preferably the viscosity of the composition is at least 2.0 mPa.s , preferably of at least 4.0 mPa.s, more preferably of at least 6.0 mPa.s and even more preferably of 7.0 mPa.s and at most of 20.0 mPa.s, preferably less than 16.0 mPa.s, more preferably less than 10.0 mPa. s, even more preferably less than 9.0 mPa. s. 12. The multiple dose container according to any of claims 10 or 11, characterized in that it comprises a metering valve. 13. A method of preparing a foam-forming composition according to any of the preceding claims, characterized in that it comprises the steps of: a) mixing an aqueous carrier, a lubricant, at least one surfactant, and a pharmaceutically active ingredient acting locally or its pharmaceutically acceptable derivative to obtain a homogeneous emulsion having a viscosity in the range from 2 to 20 mPa.s; and b) adding to the emulsion obtained in step a) at least one propellant to form a foam-forming composition.