MXPA97000521A - Acu foam composition - Google Patents

Abstract

The present invention relates to a pharmaceutical product comprising a pressurized container containing an aqueous composition that is foamed, rectally or vaginally administrable, and a separate propellant, said composition being characterized in that it comprises: a) a majority amount by weight of water b) 0.5 to 3.5 by weight of a foaming agent in the form of a liquid-immiscible gas, c) at least one foam-stabilizing surfactant and emulsifier, and d) a water-soluble polymer; of delayed foaming after ejection from the pressurized container, whereby expansion of the composition to its final volume of foam is completed in more than one second after said expulsion

Description

AQUEOUS FOAMABLE COMPOSITION DESCRIPTION OF THE INVENTION The present invention relates to an aqueous foamable composition, suitable for dosing or distribution using known aerosol dispensing systems. - More particularly, the invention relates to foamable compositions having a delayed foaming action after distribution, and - »< 3 which are especially suitable for the distribution or rectal or vaginal administration of pharmaceutically active ingredients. It is known to use aqueous foams for the rectal administration of pharmaceutical substances.

Examples of such foams are described in European patent EP-A-0468555 (Giuliani S.p.A.), EP-A-0395329 (Smith Kline &French) and French patent FR-A-2647344 (Physiopharm). The compositions shown in these prior art documents are thus formulated so that the same substance or mixture of substances (namely one or more chlorofluorocarbons) is used as a foaming agent and a propellant for the expulsion of the composition out of a conventional aerosol can. These compositions Known show immediate foaming after REF: 23930 ejection from the aerosol container. Intravaginal contraceptive compositions are also known in the art. US Patent No. 4,588,581 (Schmolka) discloses a liquid contraceptive composition for spraying from a pressurized aerosol container, which is said to form a gel on contact with living tissue. The composition comprises in certain proportions water, propellant, a volatile non-propellant solvent, an inhibitor of sperm function, and a polyoxyethylene-polyoxybutylene copolymer as a surfactant. An object of the present invention is to provide an aqueous foamable composition which exhibits a foaming or delayed foaming action after ejection from a pressurized container. Pharmaceutical compositions exhibiting a delayed foaming action are particularly suitable for rectal or vaginal administration. The two main advantages associated with a foaming action that is delayed rather than immediate are 1) the likelihood of inducing a defecation or rejection reflex after administration of the composition is much less; and 2) a better diffusion effect is obtained, which leads to increased bioavailability of the active substance. By "immediate foaming" herein is meant the expansion of the foam to its final volume in less than one second after ejection from the container in question. "Delayed foam" is obtained when the expansion of the foam to its final volume is achieved after more than one second. Delayed foaming can, however, take place in several minutes. The initial foaming action is partial or negligible. Non-aqueous foamable compositions with a delayed foaming action are known from WO-A-991/11991 (Kabi Pharmacia). This document teaches the person skilled in the art to exclude water from compositions with a delayed foaming action. Of course, this suggests that a delayed foaming action can not be achieved with aqueous foams. The foamable compositions described in this prior art document contain a mixture of polyol or a liquid polar polyol, as a carrier, particularly low molecular weight polyethylene glycols (300 to 800). These polyethylene glycols are easily adsorbed and rapidly excreted. However, although these are considered to be of low toxicity (see Donovan et al., Pharma ceu ti cal Research 7 (8), 863-868 (1990)), these may contain undesirable residual amounts of monoethylene glycol, diethylene glycol and 5-oxide. of ethylene. Water is advantageous since this is a safer vehicle, and it is also much cheaper. The other essential components of the non-aqueous foamable compositions described in WO-A- * - 91/11991 are at least one stabilizing surfactant of foam and emulsifier, a pharmaceutically active ingredient and an active propellant. It has surprisingly been found that by employing an appropriate combination of materials, it is possible to produce a composition foamable aqueous having a delayed foaming action. According to one aspect of the invention, there is thus provided an aqueous foamable composition having a delayed foaming action after ejection from a pressurized container, the composition comprising: a) a majority amount by weight of water; b) a foaming agent in the form of a liquid gas immiscible with water; C) at least one foam stabilizing surfactant and emulsifier; and d) a water soluble polymer. As mentioned above, this composition is of particular use for rectal or vaginal administration of pharmaceutical products. For medical use, the composition will also contain a pharmaceutically active ingredient. If desired, a mucoadhesive ingredient can also be included. The additives • Conventional agents for pharmaceutical compositions are also optionally present. The aqueous foamable compositions of the present invention show significant advantages over the known non-aqueous compositions, which have a delayed foaming action. First, when they are used for administration , rectal or vaginal pharmaceutical products, an aqueous foam allows the use in compositions of mucoadhesive polymers, which are usually soluble in water or dispersible in water. These mucoadhesive polymers can substantially increase the rectal / vaginal retention time, thus leading to increased topical action of the foam, and hence of the drug, and increasing the bioavailability of the pharmaceutical product. Examples of such mucoadhesive polymers are carboxymethylcellulose and carbomers. It is well known that the mucoadhesive strength of polyethylene glycol (used in the known compositions described in WO-A-91/11991) is much lower. In addition, neither carboxymethylcellulose nor carbomer are soluble in polyethylene glycols; in fact, the carbomer reacts with the polyethylene glycols to give hard and rigid complexes. In addition, the manufacturing process is simpler for the foamable compositions, since the mixture of the vehicle and the surfactant need not be heated and subsequently cooled, as it is in the preparation of non-aqueous foamable compositions exhibiting a delayed foaming action. In the foamable compositions of the invention, water is the vehicle for the other components. The compositions of the invention preferably comprise 57 to 97 weight percent water, more preferably 65 to 95 weight percent. The presence of another polar liquid (for example a mixture of water-soluble or water-miscible liquid of polar liquids) in admixture with water is acceptable provided that the desired foaming properties of the compositions are not destroyed. Examples of polar liquids that can be mixed with water are glycerol, propylene glycol and polyethylene glycols. The foaming agent of the composition is preferably a so-called liquefied gas, for example a gas which can be liquefied at a relatively low pressure at room temperature. Suitable blowing agents are propane, butane, isobutane, pentane and mixtures of these alkanes. These foaming agents are immiscible with water and liquefy when pressurized in the compositions of the invention. As can be seen from Table I, these also have a relatively high boiling point, and a relatively low vapor pressure compared to other gases commonly used as foaming agents, for example oxygen, nitrogen, carbon dioxide and nitrous oxide. For environmental reasons, it is preferred not to use chlorofluorocarbons as foaming agents. However, recently developed environmentally benign propellants such as 1,1,1,2-tetrafluoroethane (134a / P) and 1,1,1,3,3,3-hepta-fluoropropane (HFA 227) are appropriate for use as foaming agents of the present invention.

TABLE I Steam Pressure Agent Foam Point at 21 ° C (kPa) Boiling (° C) propane 855 -43.0 isobutane 317 -12.7 butane 221 -0.5 pentane 56 +36.1 134a / P 590 -26.0 HFA 227 403 -16.0 The compositions of the invention typically contain up to 10 percent by weight of foaming agent, preferably 0.5 to 7.0 percent by weight, more preferably 1.0 to 3.5 percent by weight. The surfactant or mixture of surfactants incorporated in the compositions of the invention can be chosen from those having an effective emulsifying action in relation to water and the foaming agent. Preferred surfactants are anionic and nonionic, for example, polyoxyethylene sorbitan esters, polyoxyethylene fatty esters, alkyl phenoxy ethanols, fatty acid esters, alkanolamides and alkyl sulfates such as sodium lauryl sulfate. More preferred are the polyoxyethylene sorbitan esters, which are liquid nonionic surfactants, for example polysorbate 80 (polyoxyethylene-20-sorbitan monooleate, CAS 9005-65-6) and polysorbate 20 (polyoxyethylene-20-sorbitan monolaurate, CAS-9005-64-5). The compositions of the invention typically contain up to 3 weight percent surfactant, preferably 0.1 to 2 weight percent. The precise identity of the water-soluble polymer in the compositions of the invention is not critical, but it has been found that water-soluble polysaccharides that do not have or have very few polar groups (such as carboxylates, sulfates and phosphates) are appropriate . The water-soluble polymers are preferably selected from xanthan gum, agar, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Xanthan gum is the most preferred. The compositions of the invention typically contain up to 5 weight percent water soluble polymer, preferably 0.1 to 3 weight percent. As mentioned above, the compositions of the invention can be used to distribute pharmaceutically active ingredients. Since the compositions are aqueous, such active ingredients must be insensitive to water. According to yet another aspect of the invention, there is thus provided a foamable or foamable, aqueous pharmaceutical composition having a delayed foaming action after ejection from a pressurized container, the composition comprising the following pharmaceutically acceptable components. a) a principal amount by weight of water; b) a foaming agent in the form of a liquid gas immiscible with water; c) at least one foam stabilizing surfactant and emulsifier; d) a water soluble polymer; e) an effective amount of active substance; and f) if desired, an adhesive agent and / or one or more conventional pharmaceutical additives. According to a further aspect of the invention, there is provided a composition of the invention as defined hereinabove for use in therapy.

The compositions of the invention are especially suitable for the rectal or vaginal administration of pharmaceutically active substances. Examples of clinical conditions that may benefit from treatment by rectal administration of pharmaceutical substances are constipation, bowel evacuation, inflammatory bowel diseases (ulcerative colitis, Crohn's disease), irritable bowel syndrome and anorectal disorders. The unwanted gastrointestinal side effects, for example those that may be caused by the administration of analgesics to children, may also be prevented by rectal administration of the appropriate pharmaceutical products. According to a further aspect of the invention, there is provided a method of treating conditions of the colon or lower gastrointestinal tract of the human or animal body, comprising rectal administration of a pharmaceutical composition of the invention, as defined above in the present. Examples of clinical conditions that can benefit from the treatment / prophylaxis by vaginal administration of pharmaceutical substances are sexually transmitted diseases (STD's), for example the sexual transmission of fungal, protozoal, bacterial and viral diseases. The invention can also be used as a contraceptive, by the use of spermicides as a component of the foamable composition. According to a further aspect of the invention, there is provided a method for combating the transmission of sexually transmitted diseases, comprising vaginal administration of a pharmaceutical composition of the invention as defined hereinbefore. The delayed foaming effect shown by the compositions of the invention gives rise to a better diffusion effect which can be obtained with known aqueous foamable compositions. This is particularly important in the treatment of distal localized colonic diseases, or for intravaginal use to prevent STD's. According to a further aspect of the invention, there is provided the use of a composition of the invention for the manufacture of a medicament for fighting diseases of the colon or lower gastrointestinal tract.

According to a further aspect of the invention, there is provided the use of a composition of the invention for the manufacture of a medicament for combating the sexual transmission of fungal, protozoal, bacterial and viral diseases. Some active substances must be distributed or administered rectally, either because they tend to act directly on the colon, or because they are metabolized in the liver or break down as a result of the acidity of the gastric juice or by the action of gastrointestinal enzymes. Other active substances are advantageously administered rectally. Among the active ingredients for the treatment of gastrointestinal conditions which may be mentioned by way of example only, are: a water-soluble complex of bismuth and a polyacrylate, for example a bismuth-carbomer complex (as described in WO-A -92/01457); laxatives, for example, bulk laxatives such as methylcellulose and psyllium, stimulant laxatives such as NaVK'-ATPase blocker, castor oil, anthraquinone, bisacodyl and sodium picosulfate, or osmotic laxatives such as magnesium sulfate, magnesium citrate, lactulose, lactose and sorbitol; antidiarrheal agents, for example, codeine, diphenoxylate and loperamide; anti-inflammatory agents, for example, 4- and 5-aminosalicylic acid (known as 4-ASA and 5-ASA), prednisolone-sodium etasulphobenzoate, hydrocortisone, budesonide, cyclosporine, beclomethasone dipropionate, fish oils, azathioprine and 6-mercaptopurine; local and synergistic analgesics, for example, morphine, and substances for systemic effect, such as insulin, peptides and enzymes, which are etabolized to a greater degree in the first derivation in the liver, or which are decomposed by gastrointestinal enzymes. Among the active ingredients for the prophylactic treatment of the STD's that can be mentioned, by way of example only, are: polysulfated polysaccharides including carrageenans and modified heparin without anticoagulant activity, which have been shown to block herpes-virus and HIV infections in vi tro; bile acid derivatives, which have shown activity against enveloped viruses and chlamydia; spermicides such as nonoxynol-9 (which have been associated with increased transmission of HIV when used in moderate amounts) and benzalkonium chloride; methyl esters of short-chain fatty acids, which break the membranes of gram-negative bacteria and enveloped viruses; peptide antibiotics such as defensins and protegrins, which are known to attack enveloped viruses, as well as protozoa and bacteria; and haloperoxidase, which is known to selectively inhibit the pathogenic microbes present in sexually transmitted fluids. The precise amount of the active ingredient used will depend inter alia on the identity of the active ingredient and the condition against which it is directed. In general, however, the active ingredient will comprise from 0.001 to 25 weight percent of the composition. When it is desired to include a mucoadhesive ingredient in the compositions of the invention, known mucoadhesive polymers such as sodium carboxymethylcellulose, poly (acrylic acid) such as carbomer, tragacanth, poly (ethylene oxide), sodium alginate, soluble starch are suitable. , gelatin, pectin, poly (vinylpyrrolidone), poly (ethylene glycol) and poly (vinyl alcohol). The preferred mucoadhesive is carbomer, for example, which is available under the name Carbopol 934P.

The amount of mucoadhesive agent that can be used in the compositions of the invention is typically up to 3 weight percent, preferably 0.1 to 1.5 weight percent. Other additives that may also optionally be present in the compositions of the invention include those additives conventionally employed in the pharmaceutical compositions or in foam formulations, for example suspending agents, dispersing agents, antioxidants, preservatives and anti-grinding agents. These are typically present in an amount of up to 5 weight percent of the composition, preferably 0 to 2 weight percent. The manufacture of the foamable compositions of the invention is carried out according to the usual techniques used for the manufacture of formulations to be introduced into pressurized containers. By way of example only, the fabrication can be carried out as follows. The water-soluble polymer is first dispersed in water by means of a high-speed homogenizer. The mucoadhesive agent, if required, is also dispersed in the same manner. Optional additives (for example foam stiffening agents, suspending agents, dispersing agents, antioxidants, preservatives, etc.) may be added at this stage. The pH of the dispersion can then be adjusted to the ded value using an appropriate acid or alkali. For pharmaceutical use, neutral pH of around 7.0 ± 0.2 is required. Thus, for example, if the pH of the dispersion resulting from the above steps of the process is too low, the neutralization can be carried out by the use of an aqueous solution of 10% sodium hydroxide (by weight ). In some cases, an acidic or alkaline pH is required for the effectiveness of the active ingredient, or to decrease its systemic absorption. For example, 5-ASA requires a pH of 4 to 5. The pharmaceutically active ingredient and the surfactant can then also be dispersed in the mixture. The concentrate obtained in this way is then transferred into a pressurized mixing tank, where it is mixed with the foaming agent. The resulting mixture is transferred to a metering and filling tank, where it is used to fill the final container, for example, a pressurized aerosol can.

Three types of aerosol containers are known for rectal applications of foams, and are suitable for use in conjunction with the present invention. The three types of container are the conventional "monobloc" system; the "canned bag" system and the "can with piston" system. These generally require the use of a propellant gas. In connection with the present invention, a system of,. "can bag" or "can with piston" requires a separate propellant. For a single block or monobloc system, the addition of a small amount of propellant in the can with the foamable composition is recommended. Nitrogen is an appropriate propellant. The aggregate propellant weight is in Generally, between 2 and 10 weight percent of the composition, for example, for 20 grams of the composition, between 0.4 and 2 grams of nitrogen may be added to the aerosol can. A further aspect of the invention is provides for an article for dispensing a pharmaceutical composition of the invention, comprising a pressurized aerosol container containing the pharmaceutical composition and, optionally, a propellant. The ingredients of the compositions discussed above are all pharmaceutically acceptable. As mentioned, the components are mixed in such proportions that a delayed foaming action is obtained, for example a stream of liquid is initially released from the aerosol container, which liquid is able to flow easily to the first, but then expands to a controlled speed to form a foam, the proportion of the expansion depends on the proportions of the basic components (a), (b), (c) and (d) defined above. In the preferred compositions of the invention, the final volume of the foam is 10 to 20 times the volume of the initial liquid, for example the composition has an expansion ratio of 10 to 20. For a better understanding of the invention, they are described the following non-limiting examples. For a number of different formulations, a variety of different properties were investigated: foaming speed; the initial volume of the composition (liquid); the initial volume of the foam; the expansion ratio; and the time required for the expansion of the composition to 50% of the final foam volume. All these properties were measured at 37 ° C. N-Butane was used as the foaming agent. The foaming speed was determined by distributing the foamable composition in a graduated cylinder, preheated and maintained at 37 ° C. The proportion of foaming is defined as the ratio between 50% of the final volume of foam (in millimeters) and the time (in seconds) required for the composition to reach that volume of 50% after ejection from the container. The units of the foaming speed are therefore ml / sec. The initial volume of the foamable compositions can be determined from the weight thereof, divided by its density at 37 ° C. (In general, the density of the formulations is close to unity). The rate of expansion is defined as the velocity between the final volume of the foam and the initial volume of the corresponding foamable composition. The viscosities were measured by means of a Brookfield Viscometer Model DV-II, using needles 64 at 1.5 rpm and 20 ° c.

Example 1 2 g of xanthan gum (water soluble polymer) were dispersed in 98 g of water. Then 1 g of polysorbate 80 (surfactant) was dispersed in the viscous mixture. In a pressurized tank, 2.5 g of n-butane was mixed with the dispersion, and the resulting mixture was introduced into a pressurized can (can bag). After the release of the foamable composition from the container or can, a white foam was obtained which had a foaming rate of 5.2 ml / sec. 22.5 g of the formulation gave 290 ml of foam at 37 ° C at the end. The expansion speed was therefore 12.9. 50% of the final foam volume was achieved after 28 seconds. For comparison purposes, five other compositions were made according to the previous example, but omitting one of the components. The water soluble polymer was excluded from the comparative formulation A; the foaming agent (liquefied gas) was excluded from the comparative formulation B; in comparative formulation C, the liquefied gas was replaced by a chlorofluorocarbon gas, and in the comparative formulation D by nitrogen (a non-liquefied gas); and in the comparative formulation E, the surfactant was excluded. Comparative formulation A gave an immediate liquefied foam, which had no resistance. Comparative formulations C and D also gave immediate foams. The comparative formulations B and E did not give rise to a foam at all. This illustrates that all components (a) to (d) as defined herein are essential for the delayed foaming action of the compositions of the invention.

Example 2 The pharmaceutical composition was formulated with prednisolone-sodium metasulphobenzoate as the active pharmaceutical ingredient, according to the data shown in Table II below. The basic formulation according to Example 1 is also shown for comparison.

TABLE II Basic Formulation Formulation of Example 1 Active weight (g)% w / w weight (g)% w / w H20 98.0 94.70 93.85 90.70 Rubber Xantano 2.0 1.90 2.0 1.90 Polisorbate 80 1.0 0.95 1.0 0.95 Conservatives - 0.17 0.16 Soy Lecithin - 0.20 0.19 Carbopol 974P - 0.60 0.58 % NaOH - 2.55 2.40 Prednisolone-sodium methosulfobenzoate - 0.625 0.60 n-butane 2.5 2.40 2.5 2.40 Total 103.5 100.00 103.5 100.00 The active formulation was used to fill a canned bag container. When it was freed from the can, it gave a white foam with an expansion ratio of 5 ml / sec at 37 ° C. 22 g of the formulation gave 275 ml of foam. The expansion ratio was therefore 12.5. 50% of the final foam volume was achieved after 27 seconds. This Example shows that the basic components (a) to (d) exert a dominant influence on the foaming behavior of the pharmaceutical foamable compositions of the invention.

Examples 3 to 8 Six compositions were formed to investigate the influence of the proportion and type of water soluble polymer on the delayed foaming properties of the compositions. The formulations are shown in Table III below. Examples 3 to 5 contained xanthan gum as the water soluble polymer, while Examples 6 to 8 contained carbomer. As can be seen from Examples 3 to 5, the foaming speed is the same between 1% and 2% of the xanthan gum (at a viscosity of 23,000 to 49,000 centipoise). At 3% by weight (and 97,000 cps) the foaming rate is significantly decreased. The concentration of the xanthan gum of about 2% by weight appears to be optimal, since it gives a delayed foaming action (5.2 ml / sec of foaming speed) in combination with a relatively large expansion ratio (12.9) . If a slow foaming speed is required, the concentration of the xanthan gum can be increased by more than 2% by weight. However, the foaming speed would be expected to be very slow above 3% by weight. It can be seen from Examples 6 to 8 that the foaming speed is the same at 0.4 and 0.6 percent by weight of the carbomer (at whose concentrations the viscosity is 130,000 and 180,000 cps respectively). At a concentration of 0.2 weight percent, the foaming rate is slightly increased from 18.7 m / sec to 25 ml / sec. A concentration of 0.2 percent by weight may be preferred, since it gives the highest rate or rate of expansion of these three Examples. The xanthan gum can be classified as a "neutral" water soluble polymer, while the carbomer is a "polyelectrolyte" water soluble polymer. At similar viscosities of the compositions of Examples 5 and 8, it can be seen that the first (with 1 percent by weight xanthan gum) shows a slower foaming rate than the second (containing 0.2 percent by weight of carbomer). Xanthan gum therefore seems to be more effective in retarding the action of foaming.

TABLE III Ex. 3 Ex. 4 Ex. 5 Ex 6 Ex. 7 Ex. 8 Composition (content% by weight) Xanthan gum 3 2 1 - - - Carbomer (sodium salt) - - - 0.6 0.4 0.2 Surfactant (Polysorbate 80) 1 1 1 1 1 1 Foaming Agent 2.5 2.5 2.5 2.5 2.5 2.5 H20 93.5 94.5 95.5 95.9 96.1 96.3 Viscosity (cps) 97 x 10J 49 x 10J 23 x 10J 180 x C) J 130 x 10 '28 x 10 ( Foaming speed (ml / sec) 1.4 5.2 5.2 18.7 18.7 25.0 Expansion ratio 9.4 12.9 9.6 10.0 10.0 10.7 Time taken to reach 50% of the 72 28 22 6 5.3 4.7 final foam volume (sec) Examples 9 to 14 It is intended that these Examples illustrate the effect of variation of cor. introduction of the surfactant of the compositions of the invention. Polysorbate 80 is the surfactant used in these Examples. Examples 9 to 11 employ xanthan gum as the water soluble polymer, while Examples 12 to 14 employ carbomer (sodium salt). The compositions and properties of the Examples are shown in Table IV below. It can be seen from Examples 9 to 11 that the foaming speed of a basic formulation can be reduced by decreasing the content of the surfactant. The rate of expansion also decreases to some degree, although the expansion ratio of about 10 in the range of 1 to 2 weight percent xanthan gum is acceptable. When the carbomer is used as the water-soluble polymer, the decrease in the surfactant content has a relatively smaller influence on the foaming rate, as can be seen from Examples 12 to 14. Also, the expansion ratio shows only a small variation in the 0.5 to 3 weight percent range of surfactant. Accordingly, a level of about 0.5 weight percent of the surfactant will generally be prred in such a formulation, for cost reasons.

TABLE IV Ex. 9 Ex. 10 Ex. 11 E. 12 Ex. 13 Ex. 14 Composition (content% by weight) Xanthan gum 3 3 3 - - - Carbomer (sodium salt) - 0.6 0.6 0.6 Surfactant 2 1 0.5 2 1 0.5 Foaming agent 2.5 2.5 2.5 2.5 2.5 2.5 H20 92.5 93.5 94 94.9 95.9 96.4 t \ > Viscosity (cps) 97 x 97 x 10"97 x 10 '180 x 10 - 180 x 10 180 x 10 me Foaming speed (ml / sec) 3.8 1.4 1.1 18.7 18.7 12.5 Expansion ratio 11 9.4 8.5 9.7 10 10 Time taken to reach 50% of the 35 72 75 6 6 5 final foam volume (sec) Examples 15 to 20 Six compositions were formulated in order to investigate the influence of the amount of foaming agent on the foaming properties of the composition, using either xanthan gum or carbomer (sodium salt) as the water soluble polymer. The compositions and properties of these Examples are shown in Table V below. It can be seen from the Examples to 17 that the decrease in the amount of the foaming agent from 3.5 to 1.5 weight percent decreases the foaming rate and the expansion rate. Examples 18 to 20 show a corresponding trend. Using either 3 percent by weight of xanthan gum or 0.6 percent by weight of carbomer (sodium salt) as the water-soluble polymer, it is observed that a content of foaming agent of 2.5 to 3.5 weight percent gives a satisfactory expansion ratio for the compositions.

TABLE V Ex. 1 5 Ex. 1 6 Ex. 17 E. 1 8 Ex. 1 9 Ex. 20 Composition (content% by weight) Xanthan gum 3 3 3 - Carbonate (sodium salt) - 0.6 0.6 0.6 Surfactant (Polysorbate 80) 1 1 1 1 1 1 Foaming agent 3.5 2.5 1.5 3.5 2.5 1.5 H20 92.5 93.5 94.5 94.9 95.9 96.9 - » Viscosity (cps) 97 x ÍO3 97 x 10 '97 x 10 * 180 x 10 (180 x 10' 180 x 10 'Foaming speed (ml / sec) 4.3 1.4 0.6 30 18.7 2 Expansion ratio 14 9.4 6.7 14.3 10 5.5 Time taken to reach 50% of the 41 72 125 5 6.4 26.5 final foam volume (sec) Example 21 In this Example, xanthan gum and carbomer (sodium salt) were used in combination as the water soluble polymer. The details of the formulation are shown in Table VI below, together with the details of Examples 5 and 8 for comparison.

TABLE VI Ex. 5 Ex. 8 Ex. 21 (mixture) Composition (content% by weight) Xanthan gum 1 - 1 Carbomer (sodium salt) - 0.2 0.2 Surfactant (polysorbate 80) 1 1 1 Foaming agent 2.5 2.5 2.5 H20 95.5 96.3 95.3 Viscosity (cps) 23 x 103 28 x 103 28 x 10 Foaming speed (ml / sec) 5.2 25 5.8 Expansion ratio 9.6 10.7 9.9 TABLE VI (continued! Ex.5 Ex.8 Ex. 21 (mixture) Composition (content% by weight) Time taken to reach 50% of the 22 4.7 17.4 final foam volume (sec) As noted above in relation to Examples 3 to 8, xanthan gum produces a more pronounced delayed foaming effect than carbomer. When the two polymers are mixed, the viscosity remains essentially unchanged, but the more pronounced delayed foaming effect of the xanthan gum is maintained in the mixture. As can be seen from • Table VI, the expansion ratio of the three Examples is very similar, but the foaming speed of Example 21, which contains the polymer mixture, is similar to that of Example 5. In In contrast, the composition of Example 8, which has similar viscosity and expansion ratios to the other two mixtures, shows a foaming rate almost five times greater. As noted hereinabove, the carbomer may act as a mucoadhesive. Accordingly, when a foamable composition of the invention contains carbomer as a mucoadhesive, the presence of appropriate amounts of xanthan gum allows adjustment of the foaming speed, as desired. This can also be observed from Example 2 above.

Examples 22 to 25 Four compositions were formulated in order to investigate the effect of varying the nature and amount of the surfactant. The details of the compositions and their properties are given in Table VII below. Sodium lauryl sulfate is an anionic surfactant, ... and polysorbate 80 is a non-ionic surfactant. At a weight content of 2%, the two types of surfactant have an equivalent effect, the anionic surfactant driving at a slightly slower foaming rate (Example 22). When the level of ionic sodium lauryl sulfate is reduced from 2 to 0.5 weight percent, the rate of foaming decreases, but the rate of expansion is similar (Example 24). A corresponding trend is shown between Examples 23 and 25. When a 50:50 mixture of anionic and nonionic surfactants is used (Example 25), it is found that the foaming rate is slightly higher than the foaming rate of a composition that it contains 1% by weight only of non-ionic surfactant (Example 5). However, using the aforementioned mixture, the expansion ratio is slightly higher than the expansion ratio of the composition of Example 5. Accordingly, an anionic surfactant can be used instead of a non-ionic surfactant in the compositions of the invention . Anionic surfactants are widely used in known foam formulations, although nonionic surfactants are frequently preferred because, by remaining unchanged, they may be less likely to be incompatible with the other components.

TABLE VII Ex .22 Ex. 23 Ex. 24 Ex .25 Ex .5 Composition (content% by weight) Xanthan gum 1 1 1 1 1 Sodium lauryl sulfate 2 - 0.5 0.5 - Polysorbate 80 - 2 - 0.5 1 Foaming agent 2.5 2.5 2.5 2.5 2.5 H20 94.5. 94.5 96.0 95.5 95.5 Viscosity (cps) 23 x 10 '23 x 10' 23 x 10 '23 x 10' 23 x 10 ' Foaming speed (ml / sec) 9.5 10.0 5.0 7.0 5.2 Expansion ratio 11.6 11.5 11.6 11.3 9.6 Time taken to reach 50% of the 13.0 11.5 25.0 17.0 22.0 final foam volume (sec) Example 26 A composition was formulated which had a relatively low viscosity. The details of the composition and its properties are given below.

Ex. 26 Composition (content% by weight) / -O Xanthan Gum 0.5 Polysorbate 80 1.0 n-butane 2.5 H.-0 96.0 Viscosity (cps) 10 x 103 Foaming speed (ml / sec) 13.6 Expansion ratio. 10.9 Time taken to reach 50% of the final foam volume (sec) 10 20 This Example illustrates that a delayed foaming action can be obtained even with compositions having relatively low viscosity.

E mplo 27 The compositions of Examples 1 to 26 all give rise to foams having a satisfactory degree of stiffness, for example, the foams coalesce only after a couple of hours at 37 ° C. However, in some circumstances it may be desirable to produce a stiffer foam. Accordingly, a composition was formulated which included a stiffening agent.

Ex. 27 Composition (content% by weight) Xanthan gum 0.5 Polysorbate 80 1.0 n-butane 3.0 Emulsifying wax (stiffening agent) 0.5 H0 96.0 Viscosity (cps) 10 x 103 Foaming speed (ml / sec) 25 Expansion ratio 13 Time taken to reach 50% of the final foam volume (sec) 6 The foam produced by this composition does not coalesce even after ten hours at 37 ° C Example 28 The compositions of Examples 1 to 27 are all formulations for hydrophilic foams. It can happen that some pharmaceutically active ingredients are more easily dispersed in a hydrophobic formulation. An example of such formulation having a delayed foaming action is given below.

Ex.28 Composition (content% by weight) Xanthan gum 0.2 Carbomer (sodium salt) 0.5 Fat Dura NF (hydrophobic agent) 4.5 Emulsifying wax 2.0 Polysorbate 80 1.0 n-butane 2.0 H20 89.8 Viscosity (cps) 41 x 103 Foaming speed (ml / sec) 5.0 Expansion ratio 8.0 Time taken to reach 50% of the final foam volume (sec) 20.0 Examples 29 (Comparative) and 30 These Examples illustrate the comparative behavior in vi tro of a formulation having a delayed foaming action with one having an instant foaming action. For this purpose, a model colon was used. The model colon was constructed using a soft, extended dialysis tubing, 29 mm in diameter and 1 m in length, placed inside a transparent plastic liner 80 mm in diameter and 1 m in length. The entire system was submerged in a 37 ° C water bath. The dialysis tubing was attached at one end to the plastic liner through a circular plastic adapter, and both were hermetically connected to an opening in the wall of the water bath. The opening hole had a plastic stopper that allowed the system to be closed to the surroundings, after application of the foamable composition. The other end of the dialysis tubing was also attached to the plastic liner through a circular plastic adapter, and then connected to the atmosphere by means of a flexible tube. The water was gently circulated (by means of a small circulation pump) between the soft flexible dialysis tubing (representing the colon) and the plastic liner, thereby simulating the peristaltic movements of the colon. Foamable formulations were applied to the dialysis tubing through its inlet connected to the opening in the wall of the water bath. The degree of diffusion of the foam inside the dialysis tubing was measured at different periods of time. The diffusion of the various foams in this colon model was found to correlate well with the in vitro diffusion of the same foam formulations in volunteers, as determined by gamma scintigraphy. The formulations of Examples 29 and 30 were as follows: Ex.29 Ex.30 Composition (content% by weight) Xanthan gum Carbomer (sodium salt) 0.2 - Emulsifying wax 0.5 0.5 Surfactant Polysorbate 80 2.0 2.0 Foaming agent 2.5 (CFC's) 2.5 (n-butane) HO 94.8 92.0 Viscosity (cps) 30 x 103 100 x 103 Instantaneous foam speed 1.4 ml / sec Expansion ratio 10.0 10.0 23 g of each of the above foam formulations were applied to the colon model, in both cases corresponding to 230 ml of foam volume, as measured by the cylinder method graduated at 37 ° C, described herein. With the formulation of Example 29, an instant foam was obtained, the dialysis pipe being filled over a length of 35 cm immediately. The foam eventually diffused to a length of 48 cm after 90 minutes, and did not diffuse subsequently. With the formulation of Example 30, only a 10 cm length of the dialysis pipe was initially filled, by the formulation appearing as a gel). The gel began to foam and the foam slowly expanded to a length of 35 cm from the pipe (reached 8 minutes after application). The foam continued to diffuse subsequently and reached 55 cm along the length of the dialysis pipe after 90 minutes. These two Examples illustrate the benefit of the delayed foaming action on the present foaming action, since the former occupies a smaller volume initially as a gel, expands slowly to a foam which then occupies the same volume as the foam " instantaneous "corresponding, but then it is further disseminated that what is disseminated the latter.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Having described the invention as above, property is claimed as contained in the following:

Claims (27)

1. A pharmaceutical product comprising a pressurized container containing an aqueous composition that is foamed, rectally or vaginally administrable, and a separate propellant, said composition comprising: (a) a majority amount by weight of water) 0.5 to 3.5 by weight of a foaming agent in the form of a liquid gas immiscible with water) at least one foam stabilizing surfactant and emulsifier; and (d) a water soluble polymer; the composition has a delayed foaming action after ejection from the pressurized container, whereby expansion of the composition to its final volume of foam is completed in more than one second after said expulsion.

2. A pharmaceutical product according to claim 1, characterized in that the pressurized container is a canned bag container.

3. A pharmaceutical product according to claim 1, characterized in that the pressurized container is a piston with a canister.

4. A pharmaceutical product according to any of the preceding claims, characterized in that it comprises 57 to 97 weight percent in water.

5. A pharmaceutical product according to claim 4, characterized in that it contains 65 to 95 weight percent in water.

6. A pharmaceutical product according to any of the preceding claims, characterized in that it comprises 1.0 to 3.5 weight percent of foaming agent.

7. A pharmaceutical product according to any of the preceding claims, characterized in that the foaming agent is propane, butane, isobutane, pentane, 1,1,1,2-tetrafluoroethane (134a / p), 1,1,1,2, 3,3,3-heptafluoropropane (HFA 227) or a mixture of any of these.

8. A pharmaceutical product according to any of the preceding claims, characterized in that it contains 0.1 to 2 weight percent surfactant foam stabilizer and emulsifier.

9. A pharmaceutical product according to any of the preceding claims, characterized in that the foam stabilizing and emulsifying surfactant is selected from polyoxyethylene sorbitan esters, polyoxyethylene fatty esters, alkyl phenoxyethanols, fatty acid esters, alkanolamides and alkyl sulfates.

10. A pharmaceutical product according to claim 9, characterized in that the foam stabilizing and emulsifying surfactant is a polyoxyethylene sorbitan ester.

11. A pharmaceutical product according to any of the preceding claims, characterized in that it contains 0.1 to 3 weight percent of water soluble polymer.

12. A pharmaceutical product according to claim 11, characterized in that the water soluble polymer is a water soluble polysaccharide.

13. A pharmaceutical product according to claim 12, characterized in that the polysaccharide is selected from xanthan gum, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose.

14. A pharmaceutical product according to claim 13, characterized in that the water-soluble polymer is xanthan gum.

15. A pharmaceutical product according to any of the preceding claims, characterized in that the composition further comprises: (a) an effective amount of a pharmaceutically active substance; and (b) if desired, a mucoadhesive agent and / or one or more conventional pharmaceutical additives.

16. A pharmaceutical product according to claim 15, characterized in that the active substance is present in an amount of 0.001 to 25 weight percent of the composition.

17. A pharmaceutical product according to claim 15 or claim 16, characterized in that the active substance is a water-soluble complex of bismuth and a polyacrylate.

18. A pharmaceutical product according to claim 17, characterized in that the active substance is a water-soluble bismuth-carbomer complex.

19. A pharmaceutical product according to claim 15 or claim 16, characterized in that the active substance is an anti-inflammatory agent.

20. A pharmaceutical product according to claim 19, characterized in that the anti-inflammatory agent is 4- or 5-aminosalicylic acid.

21. A pharmaceutical product according to claim 15, characterized in that a mucoadhesive agent is present in an amount of 0.1 to 1.5 weight percent.

22. A pharmaceutical product according to claim 21, characterized in that the mucoadhesive agent is selected from sodium carboxymethylcellulose, polyacrylic acid such as carbomer, tragacanth, polyethylene oxide, sodium alginate, soluble starch, gelatin, pectin, polyvinylpyrrolidone, polyethylene glycol and alcohol poly.

23. A pharmaceutical product according to claim 22, characterized in that the mucoadhesive agent is carbomer.

24. A pharmaceutical composition according to any of the preceding claims, characterized in that it has an expansion ratio of 10 to 20.

25. The use of a composition for use with a pressurized container according to any of claims 1 to 24, characterized in that it is for the manufacture of a rectally administrable medicament, to combat diseases of the colon or lower gastrointestinal tract.

26. The use of a composition according to claim 25, characterized in that the medicament is for the treatment of ulcerative colitis and Crohn's disease.

27. The use of a composition for use with a pressurized container according to any of claims 1 to 24, characterized in that it is for the manufacture of a rectal or vaginally administrable medicament for combating the sexual transmission of fungal, protozoan, bacterial diseases and viral.