ITMI20110409A1 - USE OF PROANTOCYANIDINES TYPE A2 IN THE GASTROPROTECT SHAPE FOR THE TREATMENT OF THE CISTITES IN THE ACUTE PHASE SUPPORTED BY FIMBRIED BACTERIAL FORMS - Google Patents

Description

â € œ USE OF TYPE A2 PROANTHOCYANIDINS IN GASTROPROTED FORM FOR THE TREATMENT OF CYSTITIS IN ACUTE PHASE SUPPORTED BY FIMBRATED BACTERIAL FORMSâ €

The present invention relates to oral compositions comprising proanthocyanidins of type A2 in gastroprotected form for the treatment of acute phase cystitis sustained by fimbriate bacterial forms.

State of the art

Recurrent cystitis, together with acute cystitis (also called simple or incidental cystitis), interstitial cystitis, bacterial prostatitis and pyelonephritis, is ascribed to the UTI group (from the English Urinary Tract Infection). These are pathologies caused by uropathogenetic strains of E. coli, very often of intestinal derivation and capable of proliferating up to exceeding the threshold of 100,000 bacteria per ml of urine, a fundamental parameter for a correct diagnosis of cystitis. As in any other pathology sustained by bacterial infection, these diseases require antibiotic therapy.

In reality, as reported by many authors, when the disorder is characterized by recurring phenomena (recurrent cystitis), the use of derivatives of Vaccinium macrocarpon is able to effectively counteract the symptoms even in the absence of antibiotic therapy. Obviously, the use of the derivative is applied to culture-negative patients for whom, however, the new positivity is expected over the next 4-8 weeks. This phenomenon, different from recurrence where to expand is obviously a residual bacterial clone not eliminated by antibiotic therapy, is called recurrence and in the great majority of cases it would be determined by a phenomenon of bacterial transmigration which, linked to the anatomical proximity existing between the intestine and bladder, allows some fimbriated strains to cross the septa delimiting the two organs (Rossi R, Porta S, Canovi B. J Clin Gastroenterol. 2010 Sep; 44, Suppl 1; S61-S62).

The use, in recurrent cystitis, of the juice of the berries of the American cranberry obtained by pressing the Vaccinium macrocarpon (Ericacea) has been known since 1923 (Blatherwick J 1923 J Biol Chem 57: 815-818) . In recent times, in relation to the low palatability of the product, the use of the juice as it is reduced, if not abandoned and, first through the production of products obtained by dehydration of the juice itself and then through the normal extraction procedures, extracts with titres ranging from 0.5 to 80% in type A proanthocyanidins (PAC) have been obtained and used. Today the preparations at 30% are the most used, especially for issues related to the cost-quality ratio.

Although in the monographs of the plant in question we continue to mention the presence of molecules such as benzoic acid and fructose capable, the first, of transforming into hippuric acid, causing acidification of the urine with consequent anti-bacterial effect and, the second, of a direct action on E. coli strains with type 1 hair-like structures and therefore mannose-sensitive, it is very difficult that these two substances can explain the action of the preparation in the urological field (Pappas E, Schaich KM Crit Rev Food Sci Nutr. 2009 Oct; 49 (9): 741-781). The extract of Vaccinium macrocarpon is instead characterized by the proanthocyanidins of type A (PAC) and, on the contrary, their presence and their characterization, in terms of administered dosage, has been put in strong correlation with the claimed activity recurrent anti-cystitis (Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L et al. BMC Infect Dis. 2010, 14; 10-94). These, interacting directly with the type P fimbriacee structures present on the uropathogenetic strains of E. coli, would prevent the linkage between the fimbriae themselves and the receptor glycoprotein placed on the uro-bladder epithelium. This impediment would limit the adhesion, and therefore proliferative, capacity of E. coli which would no longer be able to determine effective colonization and disease (Pinzón-Arango PA, Liu Y, Camesano TA. J Med Food. 2009 Apr; 12 ( 2): 259-70).

Description of the invention

It has now been found that the gastroprotection of a formulation containing the extract of Vaccinium macrocarpon optimizes its pharmaco-clinical performance and makes it possible to use it even in acute (non-recurrent) cystitis.

By acute cystitis we mean all forms of non-recurrent cystitis, therefore also including forms of interstitial cystitis, pyelonephritis and bacterial prostatitis when sustained by fimbriate bacterial forms.

PACs are polyphenolic structures with strong antioxidant properties. Like all antioxidants, they are rather unstable and their industrial and formulation management that does not take this characteristic into account tends to reduce their content (Pappas E, Schaich KM Crit Rev Food Sci Nutr. 2009 Oct; 49 (9): 741- 781). PACs are also substances capable of interacting with bacteria, typical gastric colonizers, such as H. pylori (Matsushima M, Suzuki T, Masui A, Kasai K, Kouchi T et al J Gastroenterol Hepatol. 2008 Dec; 23 (Suppl 2) S175 -S180). The possible presence of the latter in the stomach of a patient obviously reduces the amount of PAC available to counteract the action of E. coli. Finally, proanthocyanidins A2 form complexes with proteins, via proline residues, salivary mucous membranes, and esophageal, gastric and intestinal fluids. The increase in molecular weight, proanthocyanidin A2-protein, limits the possibility of molecular passage of PACs along the enterocyte line. In this form, PACs are less active and have reduced bioavailability, which limits their presence in the urine.

These problems are solved by formulating the PACs in the form of gastroprotected tablets. Gastroprotection prevents the breakdown of active ingredients in the stomach and allows their release only at pH 6.0-6.8 approximately, a typical value of the duodenum.

The invention therefore relates to pharmaceutical forms of PAC such as tablets, powders, granulates and capsules coated with natural or synthetic film-forming agents, allowed for food use (eg shellac) and not (hydroxypropylmethylcellulose).

The compositions will contain at least 18 mg of PAC detected with the DMAC analytical method (Ocean Spray, Maryland, USA) or 54 mg detected as a validated method according to the European Pharmacopoeia.

The administration of the gastroprotected product allows the therapy in the patient in the phase of acute cystitis. In this case, the positive urine culture becomes negative. It has in fact been noted that the administration of the gastroprotected product in acute cystitis by enrolling patients without fever, with

symptomatology (dysuria, nocturia, urge urination, etc.) not burdensome but

with a positive urine culture (> 100,000 CFU / mL), cancels symptoms e

negativizes urine culture.

Clinical trial

The patients were divided into 3 treatment groups: 600 mg / day

in the evening, 600 mg every 12 hours and 1200 mg / day in the evening. For all the treatment

lasted 5 days. Urine cultures were performed at enrollment, after 5

days of therapy and after a further 5 days of wash-out (t = 10).

Tables 1-3 show the trend of the microbial load

and tolerability in each individual patient.

Table 1 Trend (CFU / mL) in patients diagnosed with cystitis

acute treatment for 5 days with 600 mg of gastroprotected preparation

Paz S t = 0 t = 5 t = 10 T * FM F Enterococcus E.coli E.coli B ;;> 100,000 <50,000 <50,000; GD F E.coli E. coli Sterile O;> 100,000 <50,000; GB F Proteus E. coli E. coli O ;;> 100,000 <50,000 <50,000; LP F Klebsiella Enterococcus E. coli O ;;> 100,000> 100,000 <50,000; FP M E. coli Sterile Sterile O;> 100,000; PS F Candida E . coli Sterile O;> 100,000> 100,000; GS M Enterococcus Enterococcus E. coli O ;;> 100,000 <50,000 <50,000 ;; Paz = patient; S = sex; T = tolerability; B = good; O = excellent Table 2 Trend (CFU / mL) in patients diagnosed with acute cystitis treated for 5 days with 600 mg of gastroprotected preparation every 12 hours ;; Patient S t = 0 t = 5 t = 10 T ;; VF M E. coli Sterile Sterile O;> 100,000; DW F Klebsiella E. coli Sterile O;> 100,000> 100,000; RP F Enterococcus E. coli E. coli B ;;> 100,000> 100,000> 100,000; GS F Candida E. coli Sterile O;> 100,000> 100,000; RP M Proteus E. coli Sterile O;> 100,000 <50,000; PG M Candida Candida E. coli B ;;> 100,000 <50,000 <50,000; RP F E. coli E. coli Sterile O; > 100,000 <50,000; LG F Enterococcus Sterile Sterile O;> 100,000 ;; Paz = patient; S = sex; T = tolerability; B = good; O = excellent Table 3 Trend (CFU / mL) in patients diagnosed with acute cystitis treated for 5 days with 1200 mg of gastroprotected preparation ;; Paz S t = 0 t = 5 t = 10 T ;; GM M Enterococcus Sterile Sterile B;> 100,000; FP M E. coli Sterile Sterile B;> 100,000; GB F Candida Candida E. coli B ;;> 100,000 <50,000 <50,000; MM M E. coli E. coli Sterile B;> 100,000 <50,000; MJ F Enterococcus Sterile Sterile O;> 100,000; LC F Candida Candida E. coli B ;;> 100,000 <50,000 <50,000; SL F E. coli Sterile Sterile O;> 100,000 ;; PS F E. coli Sterile Sterile B;> 100,000; RP F Enterococcus E. coli Sterile B;> 100,000 <50,000; MM M Candida Candida Sterile O;> 100,000 <50,000; RT F Candida E. coli Sterile B;> 100,000 <50,000; MF F E. coli E. coli Sterile B;> 100,000 <50,000; MR F Enterococcus E. coli Sterile O;> 100,000 <50,000; AR F E. coli Sterile Sterile B;> 100,000; GT F E. coli Sterile Sterile B;> 100,000 ;; Patient = patient ; S = sex; T = tolerability; B = good; O = excellent It is evident how the formulations of the invention are clinically effective in the therapy of acute cystitis. It has also been shown that the administration of 400 mg of non-gastroprotected extract at 30% in PAC determines a very low bladder content in PAC and no more than about 1% of the administered dose while the administration of the gastroprotected form, at the same dosage, allows the delivery in the bladder area of about 60-70% of the administered dose of PAC. Some examples of formulations of the invention are reported below. Quantities are expressed in mg / tablet. ; Example 1; Microcrystalline cellulose 228,000; Dicalcium phosphate 210,000; Vaccinium macrocarpon (30% Ph. E.) 200,000; Cross-linked sodium carboxymethylcellulose 20,000; Glycerol beenate 20,000; Shellac 15,545; Vegetable magnesium stearate 14,000; Hydroxypropyl methyl cellulose 12,947; 8,000 ;; E171 2,988; Stearic acid 1,992; Triethyl citrate 1,233; Ammonium carbonate 0,822; Polyvinylpyrrolidone 0,602; Dye E 120 0,073; Dye E 132 0,008 Example 2; Calcium phosphate 50,551 Microcrystalline cellulose 25,000 Vaccinium macrocarpon (80,000% E. Shellac 35,500 Magnesium stearate 0,900 Glycerine 0,314 Silicon dioxide 0,900 Talc 0,208 Lactose 0,208 Acetylated monoglycerides 0,219 Hydroxypropyl methyl cellulose 0,104 Polyvinyl pyrrolidone 0,073 Dye E124 0,055 Example 3; Calcium phosphate 68,932 Cellulose 30,000 microcrystalline E. 500 microcrystalline Shellac 20,200 Magnesium stearate 0,850 Glycerin 1,192 Silic io 3,500 Talc 0.792 Lactose 0.792 Acetylated monoglycerides 0.219 Hydroxypropyl methyl cellulose 0.396 Polyvinyl pyrrolidone 0.073 Dye E124 0.055 *

Claims (5)

CLAIMS 1. Oral compositions comprising type A2 proanthocyanidins in gastroprotected form for the treatment of acute phase cystitis sustained by fimbriate bacterial forms. 2. Compositions according to claim 1 in the form of capsules, tablets, powders or granules coated with natural or synthetic gastro-resistant film-forming agents. 3. Compositions according to claim 2 in which the gastro-resistant filming agents are selected from shellac and hydroxypropylmethylcellulose. 4. Compositions according to claim 1 wherein the proanthocyanidins of type A2 are present in the form of extract of Vaccinium macrocarpon. 5. Compositions according to claim 4 containing at least 18 mg of proanthocyanidins A2 detected with the analytical method DMAC (Ocean Spray, Maryland, USA) or 54 mg detected as a method validated according to the European Pharmacopoeia.