PHARMACEUTICAL COMPOSITIONS COMPRISING CO-DRIED SUCRALFATE GEL AND POLYALCOHOL

Abstract: A process for the preparation of sucralfate gel, in the dry state, that does not lose its colloidal properties is disclosed. Moreover, taking into consideration the particular tropism of sucralfate gel towards the gastric mucosa and its properties of bioadhesion, the claim is extended to the use of dry sucralfate gel as a carrier for medicaments intended for the treatment of Helicobacter pylori infections as antibiotics, antibacterials, antiinflammatories, or in order to maintain for as long as possible antisecretory drugs, such as cimetidine, ranitidine, prostaglandins and omeprazol, in the gastric environment.

Description: PHARMACEUTICAL COMPOSITIONS COMPRISING CO-DRIED SUCRALFATE GEL AND POLYALCOHOL State of the art Sucralfate is an anti-ulcer drug for which a non- systemic action mechanism has been proposed. In fact, its properties depend on its ability to bind itself to 5 the ulcerated sites of the gastric mucosa thereby creating a physical barrier able to protect the mucosa itself from the aggression of acids and enzymes. This behaviour has stimulated researchers in pharmaceuticals to improve those characteristics of the product which ° have a direct influence on the ability of the same to carry out a "protective covering" action of the gastro¬ intestinal wall. Particular attention has been directed towards the granulometric characteristics and the specific surface area of the preparation, to its 5 physical structure (crystalline form, water bound structure etc. ) or to its reactivity with acids. Afterwards, this "classic" action mechanism became enriched as result of new experimental evidences which, without eliminating the necessity that sucralfate 0 interact with the gastro-intestinal mucosa, showed that mechanisms connected with PGE2 activity, or with the Epidermal Growth Factor must also be taken into account. More recently, significant light was thrown upon 5 the knowledge of the role that a microorganism, Helicobacter pylori, plays in the development of gastric pathologies. Many researchers are convinced that the reason why the bacterium is able to implant itself in a decisively hostile environment due to the high gastric acidity levels, is to be searched for in the ability of the same to attach itself to the epithelial cells of the stomach which are in a position to provide at least two linkage points: one represented by sialic acid, a monosaccharide present on some surface glycoproteins of the gastric epithelial cells, to which the germ specifically links itself, and the other represented by the Lewis B antigens, which are also to be located on the surface of epithelial cells and having branched glycosidic chains with terminal monosaccharides. It is by now certain that the bond between the bacterium and the epithelial cells represents one of the determinant pathways towards the process of ulceration. In fact, the bacterium has a form which is generally described as being like a cork screw and a particular mobility, thanks to which it is able to penetrate through the mucosa layer which protects the epithelium and then stably bind with the two sites mentioned above. From this point onwards, the process is still not clear, even though it seems that the intervention of the immune system against the unwelcome guest is more damaging than helpful, since it can cause damage to the epithelium itself, favouring the germ taking root. The result is that the lesion can lead to an ulcer or becoming chronic in an inflammatory gastric process. This sequence of events makes it immediately evident as to why it is important to be able to intervene before the bacterium is able to take root, by identifying a therapeutic means able to compete with it for the bond-sites or to attack it in a specific manner, as, for example, by means of a localized antibiotic therapy. In order to achieve this, a therapeutic instrument able to anchor itself to the mucosa is required, able to compete for the binding sites of the germ, to transport and maintain in situ an antibacterial agent to which the germ is sensitive. Sucralfate could possess these qualities if it were endowed with an optimized physical form in terms of bioadhesion with the mucosa. The recent EP-A- 0,286,978 discloses a physical form of sucralfate denominated a gel due to its particular characteristics. Sucralfate gel could take on the role of an agent especially designed to counteract Helicobacter pylori and its undesirable consequences. In fact, this new form of sucralfate has proved to possess remarkable bioadhesion towards gastric mucosa, far more important than that possessed by sucralfate in the physical powder form. This biophysical superiority has brought about a more efficient anti-ulcer activity, so much so that the new form of sucralfate gel has led to the halving of the therapeutic dose of the product from 5 g per day to 2 g per day, with indisputable advantages with respect to the patient's compliance. From the technical point of view, this sucralfate gel of an enhanced quality has been obtained thanks to a novel production process of the starting materials. The active ingredient sucralfate is a complex salt of saccharose octasulfate with aluminium hydroxide and the manufacturing process is concluded with the precipitation of the salt from an aqueous solution of the two counter-ions, with a successive drying step which results in an amorphous powder. The innovation obtained with sucralfate gel consists in changing the precipitation procedure so as to obtain a colloidal form. This gel form is proved, not only by its granulometric properties, but above all by the thixotropic rheological characteristics of its aqueous suspension, which give confirmation of its ability to interact with the mucosa of the gastro-intestinal tract. Such characteristics are lost when the precipitated gel is brought to the dry state through the common heat or vacuum drying techniques. Consequently, the sucralfate gel starting material used in the preparation of pharmaceutical forms consists of a moist solid which is nothing but the filtered precipitate containing a large amount of water bound to the sucralfate colloidal particles. It is both necessary and obligatory to maintain the starting material in a moist state in order to conserve the enhanced activity of the sucralfate gel. However, this fact imposes strict limits on the pharmaceutical arsenal of sucralfate gel therapy in that it does not allow for the preparation of solid pharmaceutical forms such as tablets, capsules, lozenges or powders. In fact, the present form of administration of sucralfate gel is necessarily an aqueous suspension which, although more than adapted to the type of pathology and the mechanism which the product has to perform, involves problems such as the high volumes to be transported, the possibility of bacterial pollution and the poor practical use. The problem to overcome is, therefore, how to maintain the characteristics of sucralfate gel while having, at the same time, a solid dry product. Detailed description of the invention Now it has been found, and it is the main object of the invention, the way of obtaining a solid form of moist sucralfate gel which keeps, once redispersed in water, the particular properties of the gel. In fact, this new solid form denominated dry sucralfate gel, is a fine powder, highly smooth-flowing which, when in contact with water and with simple shaking, gives rise to a homogeneous sucralfate gel suspension with the same thixotropic properties as the moist sucralfate gel suspension. The drying process of the invention allows for the transformation of a sucralfate gel suspension into the powder of the same, keeping unaltered the physical properties that give the sucralfate gel its improved qualities. The process of the invention consists in mixing the sucralfate aqueous suspension with a suitable amount of a solid substance having hydroxy groups and drying the mixture obtained by means of the spray- drying process. The resulting solid compound, again dispersed in water, gives rise to a suspension which possesses the same characteristics as those of the starting one, i.e. it shows the properties of the gel. In practice, the rheology, the bioadhesion, the size distribution of the particles of the reconstituted suspension do not turn out to be changed with respect to those of the starting suspension prepared with moist sucralfate gel. As a consequence of this, the dry product obtained can be defined as dry sucralfate gel. The substances suitable to act as gel protectors in this particular transformation from a liquid to a solid were identified amongst the classes of the sugars or of the solid polyalcohols, a particular effect being given by compounds such as sorbitol, mannitol, xylitol, lactose, cyclodextrin and similars. Of particular significance is the fact that the added amount of these substances added is critical to the outcome. It has been found that the ratio of the sucralfate amount to the protective agent amount must be kept at a level higher than 1:1. When that ratio goes below the level indicated, the reconstituted sucralfate suspension progressively loses its gel properties that characterized it before drying. The new physical form of dry sucralfate gel also opens therapeutic prospects which were not practicable with the liquid suspension form. For example, it would be unthinkable to suspend together with the sucralfate an antibiotic agent of the beta-lactam class without the risk of compromising the efficacy of the preparation due to the known limited stability of these antibiotics in aqueous solutions. Instead, this therapeutic combination would represent an answer to the problem determined by the action of the microorganism Helicobacter pylori in ulcerous pathology. Now that the possibility of successfully drying a suspension of sucralfate gel has been found, also allows for the provision of a combination of sucralfate gel with an antibiotic of the class of the beta-lactams. This technological solution to the problem of stability also allows for the solution to another problem connected with the therapeutic scheme necessary in the fight against Helicobacter infection: in the case of a sucralfate/antibiotic co-dried product, sucralfate becomes a carrier for the antibiotic itself, since, due to the known tropism towards the mucosa wall, it can be carried along with itself, and therefore bring into close proximity of the interested sites where the bacterium is rooted, an antibacterial agent which in this way can carry out localized action with obvious advantages with regard to possible side effects of these substances. A further object of this invention is, therefore, the use of dry sucralfate gel as a carrier for the transportation to the mucosa wall of the gastro¬ intestinal tract of specific substances that give the advantage of being able to carry out a locally aimed activity. In particular, though not limiting in any way this capacity possessed by dry sucralfate gel, the possibility of preparing a sucralfate gel/antibiotic co-dried product in order to obtain a dry product to be used as an active composition in the treatment of the rooting taking place of Helicobacter pylori in the gastro-intestinal wall, is claimed. The antibiotics to be employed in this combination include all of those towards which the microorganism has shown sensitivity. In particular, they belong to the class of the penicillins, cephalosporins, tetracyclines, aminoglycosides, azitro ycins, clarithromycins. The form of sucralfate according to the invention, can also be used as a carrier for other antibacterial agents commonly used in the therapy against Helicobacter pylori such as methronidazol, furazolidone, or nitrofurantoine or the more recent agents such as aspirin, ibuprofene, ketoprofene, naproxene, piroxicam. Finally, with regard to the tropism of sucralfate gel towards the gastroduodenal mucosa and to its proven long-term permanence in the stomach, the co-dried products of the invention can be used to maintain a therapeutic agent in the stomach for as long as possible for the treatment of gastric disorders, for example an anti-secretory agent such as cimetidine, ranitidine, omeprazol or prostaglandin derivatives such as rosaprostol, miraprostol. The following are some examples of the dry sucralfate gel preparations. Example 1 Preparation of sucralfate dry gel by spray-drying. Sucralfate (as moist gel according to EP 0,286,978) 20 g Mannitol 40 g Depurated water 360 g The ingredient mixture is subjected to stirring with turbine to finely disperse the sucralfate gel. The resulting suspension is loaded into the feeding tank of a spray-drying apparatus (Biichi) and kept under magnetic stirring. The following operative conditions are used: inlet temperature of the drying air 120*- 130*C, outlet temperature 60 * -70 * C, loading pump speed 20-30%, nozzle diameter 1 mm. Under the described conditions, 35 g of a dry powder are obtained with a water content below 5%. 30 g of powder are weighed and dispersed in about 40 ml of depurated water by simple stirring with a glass rod. A 20% w/v sucralfate gel suspension is obtained, showing an evident thixotropy due to the restoration of the structure possessed by sucralfate gel before drying. Comparative example 1 Sucralfate (as a moist gel) 20 g Depurated water 360 g Once the moist sucralfate gel dispersion has been prepared in the same operative conditions as in the previous example, drying is carried out in exactly the same way as described above. 15 g of sucralfate dry powder are obtained with a water content lower than 3%. 10 g of this powder are weighed and dispersed in 40 ml of water, being simply stirring with a glass rod: a granulous suspension is obtained which does not show any evidence of possessing thixotropy properties and the consistency of which is definitely liquid. Example 2 Sucralfate (as moist gel) 20 g Mannitol 40 g A oxycillin 4 g Depurated water 400 g The ingredient mixture is subjected to stirring with turbine to finely disperse sucralfate gel and amoxycillin. The resulting suspension is loaded into the feeding tank of a spray-drying apparatus (Bϋchi) and kept under magnetic stirring. The following operative conditions are used: inlet temperature of the drying air 120 * -130 # C, outlet temperature 60*-70'C, loading pump speed 20-30%, nozzle diameter 1 mm. Under the described conditions, about 40 g of a dry powder are obtained with a water content below 5%. 30 g of powder are weighed and dispersed in about 40 ml of depurated water by simple stirring with a glass rod. A 20% w/v sucralfate gel suspension is obtained having an evident thixotropy which gives it a creamy consistency. Example 3 Sucralfate (as moist gel) 20 g Mannitol 40 g Acetylsalicylic acid fine powder 4 g Depurated water 400 g The mixture of the ingredients is subjected to stirring with turbine to finely disperse sucralfate and acetylsalicylic acid. The suspension is loaded into the feeding tank of a spray-drying apparatus (Biichi) and kept under magnetic stirring. The following operative conditions are used: inlet temperature of the drying air lΣO'-lSO'C, outlet temperature 60'-70 * C, loading pump speed 20-30%, nozzle diameter 1 mm. Under the described conditions, about 40 g of a dry powder are obtained with a water content below 5%. 30 g of powder are weighed and dispersed in about 40 ml of depurated water by simple stirring with a glass rod. A 20% w/v sucralfate gel suspension is obtained, which is thixotropy and has creamy consistency. Example 4 Sucralfate (as moist gel) 20 g Mannitol 40 g Ranitidine 2 g Depurated water 400 g The mixture of the ingredients is subjected to stirring with turbine to finely disperse sucralfate gel and ranitidine. The resulting suspension is loaded into the feeding tank of a spray-drying apparatus (Bϋchi) and kept under magnetic stirring. The following operative conditions are used: inlet temperature of the drying air 120 * -130 * C, outlet temperature 60*-70 # C, loading pump speed 20-30%, nozzle diameter 1 mm. Under the described conditions, about 38 g of a dry powder are obtained. 30 g of powder are weighed and dispersed in about 40 ml of depurated water by simple stirring with a glass rod. A 20% w/v sucralfate gel suspension is obtained, which is thixotropy and very adhesive, and has a creamy consistency.

Claims: C AIMS 1. A co-dried product of sucralfate gel and of at least equiponderal amounts of a polyalcohol, obtained by spray-drying of a dispersion of sucralfate moist gel and of said polyalcohol, able to give rise in water to a thixotropy suspension, of creamy consistency and adhesive, at a concentration of about 20% w/v of sucralfate. 2. A co-dried product according to claim 1, wherein the polyalcohol is selected from sorbitol, xylitol, mannitol, lactose, glucose, fructose, saccharose. 3. A co-dried product according to claim 2 wherein the polyalcohol is mannitol. 4. A co-dried product according to any one of claims 1 to 3 containing one more active ingredient. 5. A co-dried product according to claim 4, wherein the active ingredient is an antibiotic agent belonging to the classes of beta-lactams, cephalosporins, tetracyclins, acrolides, aminoglycosides, azitromycin, claritromycin. 6. A co-dried product according to claim 4, wherein the active ingredient is an antibacterial agent selected from metronidazole, furazolidone or nitrofurantoine belonging to the class of quinolones. 7. A co-dried product according to claim 4, wherein the active ingredient is an antiinflammatory agent selected from aspirin, ibuprofene, ketoprofene, naproxene, piroxicam. 8. A co-dried product according to claim 4, wherein the active ingredient is an antisecretory agent against gastric acidity selected from cimetidine, ranitidine, omeprazol or a prostaglandin derivative selected from rosaprostol, iraprostol. 9. Pharmaceutical compositions containing as the active ingredient a co-dried product of claims 1-8.

Inventors: COLOMBO PAOLO, CONTOS SIMOS, ZAGNOLI GIORGIO, COLOMBO, PAOLO, CONTOS, SIMOS, ZAGNOLI, GIORGIO
Applicants: COLOMBO PAOLO, CONTOS SIMOS, ENOSYS SA, ZAGNOLI GIORGIO, COLOMBO, PAOLO, CONTOS, SIMOS, ENOSYS S.A., ZAGNOLI, GIORGIO
Application year: 1995
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47, A61P1, C07H11