EP2685967A1 - Use of type a2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms e - Google Patents

Use of type a2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms e

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Publication number
EP2685967A1
EP2685967A1 EP12717059.5A EP12717059A EP2685967A1 EP 2685967 A1 EP2685967 A1 EP 2685967A1 EP 12717059 A EP12717059 A EP 12717059A EP 2685967 A1 EP2685967 A1 EP 2685967A1
Authority
EP
European Patent Office
Prior art keywords
coli
proanthocyanidins
sterile
type
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12717059.5A
Other languages
German (de)
French (fr)
Inventor
Francesco Di Pierro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Velleja Research SRL
Original Assignee
Velleja Research SRL
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Filing date
Publication date
Application filed by Velleja Research SRL filed Critical Velleja Research SRL
Publication of EP2685967A1 publication Critical patent/EP2685967A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats

Definitions

  • the present invention relates to oral compositions containing type A2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms.
  • Recurrent cystitis together with acute cystitis (also known as simple or uncomplicated cystitis), interstitial cystitis, bacterial prostatitis and pyelonephritis, belongs to the UTI (Urinary Tract Infection) group.
  • UTI User Tract Infection
  • Vaccinium macrocarpon derivatives effectively counteracts the symptoms, even in the absence of antibiotic treatment.
  • the use of the derivative obviously applies to patients who have negative urine cultures but are expected to become positive again within 4-8 weeks.
  • the monographs of the plant in question still cite the presence of molecules such as benzoic acid and fructose, the first of which is converted to hippuric acid, causing acidification of the urine with a consequent antibacterial effect, while the second performs a direct action on E. coli strains with type 1 filamentous structures which are consequently mannose- sensitive; however, these two substances are unlikely to 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).
  • Vaccinium macrocarpon extract is characterised by type A proanthocyanidins (PAC), and their presence and characterisation, in terms of the dose administered, has been strongly correlated with the claimed activity against recurrent cystitis (Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L et al. BMC Infect Dis. 2010, 14; 10-94).
  • PAC proanthocyanidins
  • Acute cystitis in this context means all non-recurrent forms of cystitis, including interstitial cystitis, pyelonephritis and bacterial prostatitis when induced by fimbriated bacterial forms.
  • PACs are polyphenolic structures with strongly antioxidant properties. Like all antioxidants they are rather unstable, and industrial and formulation management which fails to take account of this characteristic tends to reduce their content (Pappas E, Schaich KM Crit Rev Food Sci Nutr. 2009 Oct; 49(9):741-781). PACs are also substances able to interact with bacteria which are typical gastric colonisers, like H. pilori (Matsushima M, Suzuki T, Masui A, Kasai K, Kouchi T et al J Gastroenterol Hepatol. 2008 Dec; 23(Suppl 2) S 175-S 180). The presence of the latter in a patient's stomach obviously reduces the quantity of PAC available to counteract the action of E. coli.
  • proanthocyanidin A2 forms complexes, via proline residues, with the proteins of the salivary mucosa and the oesophageal, gastric and intestinal fluids.
  • the increased molecular weight of the proanthocyanidin A2-protein limits the possibility of molecular motion of the PACs along the enterocyte line. In this form, the PACs are less active and their bioavailability is lower, which reduces their presence in the urine.
  • the invention therefore relates to pharmaceutical forms of PAC such as tablets, powders, granulates and capsules coated with natural or synthetic film-forming substances permitted for dietary use (e.g. shellac) and non-dietary use (hydroxypropyl methylcellulose).
  • PAC pharmaceutical forms of PAC such as tablets, powders, granulates and capsules coated with natural or synthetic film-forming substances permitted for dietary use (e.g. shellac) and non-dietary use (hydroxypropyl methylcellulose).
  • compositions will contain at least 18 mg of PAC assayed by the DMAC analysis method (Ocean Spray, Maryland, USA) or 54 mg assayed by a method validated according to the European Pharmacopoeia.
  • the gastroprotected product allows patients to be treated during the acute stage of cystitis. In this case, the positive urine culture becomes negative. It has been found that if the gastroprotected product is administered at the acute cystitis stage by recruiting patients who have no fever, with symptoms (dysuria, nocturia, urinary urgency, etc.) which are not severe, but with a positive urine culture (> 100,000 CFU/mL), the symptoms disappear and the urine culture becomes negative.
  • 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.
  • the treatment lasted for 5 days in all cases.
  • Tables 1-3 show the bioburden and tolerability trends in each patient.
  • the formulations according to the invention are clearly clinically effective in the treatment of acute cystitis.
  • formulations according to the invention are set out below.
  • the quantities are expressed as mg/tablet.
  • Vaccinium macrocarpon (30% Eur. Ph.) 200,000

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are oral compositions containing Type A2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms.

Description

USE OF TYPE A2 PRQANTHQCYANIDINS IN GASTRQPRQTECTED FORM FOR THE TREATMENT OF ACUTE CYSTITIS INDUCED BY FIMBRIATED BACTERIAL FORMS E
The present invention relates to oral compositions containing type A2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms.
Prior art
Recurrent cystitis, together with acute cystitis (also known as simple or uncomplicated cystitis), interstitial cystitis, bacterial prostatitis and pyelonephritis, belongs to the UTI (Urinary Tract Infection) group. These disorders are caused by uropathogenic strains of E. coli, very often of intestinal origin, which are able to proliferate until they exceed the threshold of 100,000 bacteria per ml of urine, the fundamental parameter for a correct diagnosis of cystitis. Like all disorders caused by bacterial infection, they require antibiotic treatment.
However, as reported by many authors, when the disorder recurs frequently (recurrent cystitis), the use of Vaccinium macrocarpon derivatives effectively counteracts the symptoms, even in the absence of antibiotic treatment. The use of the derivative obviously applies to patients who have negative urine cultures but are expected to become positive again within 4-8 weeks. This phenomenon (which differs from relapses, where the microbe that expands is obviously a residual bacterial clone that was not eliminated by the antibiotic treatment) is called "recurrence", and in the vast majority of cases appears to be caused by bacterial migration, associated with the anatomical proximity between the intestine and the urinary bladder, which allows some fimbriated strains to cross the septa forming the boundary between the two organs (Rossi R, Porta S, Canovi B. J Clin Gastroenterol. 2010 Sep;44, Suppl 1 ; S61-S62).
The use of cranberry juice obtained by crushing Vaccinium macrocarpon (Ericacea) to treat recurrent cystitis has been known since 1923 (Blatherwick J 1923 J Biol Chem 57: 815-818). Nowadays, the juice is rarely if ever used "as is", due to the unpalatability of the product. Instead, extracts with a type A proanthocyanidin (PAC) content of 0.5 to 80% have been obtained and used, first by producing products obtained by dehydrating the juice, and subsequently by normal extraction procedures. 30% preparations are now the most widely used, mainly due to their value for money.
The monographs of the plant in question still cite the presence of molecules such as benzoic acid and fructose, the first of which is converted to hippuric acid, causing acidification of the urine with a consequent antibacterial effect, while the second performs a direct action on E. coli strains with type 1 filamentous structures which are consequently mannose- sensitive; however, these two substances are unlikely to 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). Conversely, Vaccinium macrocarpon extract is characterised by type A proanthocyanidins (PAC), and their presence and characterisation, in terms of the dose administered, has been strongly correlated with the claimed activity against recurrent cystitis (Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L et al. BMC Infect Dis. 2010, 14; 10-94). By interacting directly with the type P fimbriated structures present on the uropathogenic strains of E. coli, these PACs, appear to prevent between the fimbriae from attaching to the receptor glycoprotein on the epithelium of the urinary bladder. This impediment seems to limit the adherence, and consequently the proliferative capacity, of E. coli, which is no longer capable of effective colonisation and causing disease (Pinzon-Arango PA, Liu Y, Camesano TA. J Med Food. 2009 Apr; 12(2):259-70). Description of the invention
It has now been discovered that gastroprotection of a formulation containing Vaccinium macrocarpon extract optimises its pharmacoclinical yield and makes its use in acute (non-recurrent) cystitis possible.
"Acute cystitis" in this context means all non-recurrent forms of cystitis, including interstitial cystitis, pyelonephritis and bacterial prostatitis when induced by fimbriated bacterial forms.
PACs are polyphenolic structures with strongly antioxidant properties. Like all antioxidants they are rather unstable, and industrial and formulation management which fails to take account of this characteristic tends to reduce their content (Pappas E, Schaich KM Crit Rev Food Sci Nutr. 2009 Oct; 49(9):741-781). PACs are also substances able to interact with bacteria which are typical gastric colonisers, like H. pilori (Matsushima M, Suzuki T, Masui A, Kasai K, Kouchi T et al J Gastroenterol Hepatol. 2008 Dec; 23(Suppl 2) S 175-S 180). The presence of the latter in a patient's stomach obviously reduces the quantity of PAC available to counteract the action of E. coli. Finally, proanthocyanidin A2 forms complexes, via proline residues, with the proteins of the salivary mucosa and the oesophageal, gastric and intestinal fluids. The increased molecular weight of the proanthocyanidin A2-protein limits the possibility of molecular motion of the PACs along the enterocyte line. In this form, the PACs are less active and their bioavailability is lower, which reduces their presence in the urine.
These problems are solved by formulating the PACs as gastroprotected tablets. Gastroprotection prevents the disintegration of the active constituents in the stomach, and only allows their release at a pH of approx. 6.0-6.8, a value typical 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 substances permitted for dietary use (e.g. shellac) and non-dietary use (hydroxypropyl methylcellulose).
The compositions will contain at least 18 mg of PAC assayed by the DMAC analysis method (Ocean Spray, Maryland, USA) or 54 mg assayed by a method validated according to the European Pharmacopoeia.
Administration of the gastroprotected product allows patients to be treated during the acute stage of cystitis. In this case, the positive urine culture becomes negative. It has been found that if the gastroprotected product is administered at the acute cystitis stage by recruiting patients who have no fever, with symptoms (dysuria, nocturia, urinary urgency, etc.) which are not severe, but with a positive urine culture (> 100,000 CFU/mL), the symptoms disappear and the urine culture becomes negative.
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. The treatment lasted for 5 days in all cases. Urine cultures were performed on recruitment, after 5 days' treatment and after a further 5-day wash-out (t=10).
Tables 1-3 show the bioburden and tolerability trends in each patient.
Table 1 Trend (CFU/mL) in patients with a diagnosis of acute cystitis treated for 5 days with 600 mg of gastroprotected preparation
Pat S t=0 t=5 t=10 T
FM F Enterococcus E. coli E. coli G
> 100,000 < 50.000 < 50.000
GD F E. coli E. coli Sterile E
> 100.000 < 50.000
GB F Proteus E. coli E. coli E
> 100.000 < 50.000 < 50.000
LP F Klebsiella Enterococcus E. coli E
> 100.000 > 100.000 < 50.000
FP M E. coli Sterile Sterile E
> 100.000
PS F Candida E. coli Sterile E
> 100.000 > 100.000
GS M Enterococcus Enterococcus E. coli E
> 100,000 < 50,000 < 50.000
Pat = patient; S = sex; T = tolerability; G = good; E = excellent
Table 2 Trend (CFU/mL) in patients with a diagnosis of acute cystitis treated for 5 days with 600 mg of gastroprotected preparation every 12 hours
Pat S t=0 t=5 t=10 T
VF M E. coli Sterile Sterile E
> 100.000
DW F Klebsiella E. coli Sterile E
> 100.000 > 100.000
RP F Enterococcus E. coli E. coli G
> 100,000 > 100,000 > 100,000
GS F Candida E. coli Sterile E
> 100,000 > 100,000
RP M Proteus E. coli Sterile E
> 100.000 < 50.000
PG M Candida Candida E. coli G
> 100.000 < 50.000 < 50.000
RP F E. coli E. coli Sterile E
> 100.000 < 50.000
LG F Enterococcus Sterile Sterile E
> 100,000
Pat = patient; S = sex; T = tolerability; G = good; E = excellent Table 3 Trend (CFU/mL) in patients with a diagnosis of acute cystitis treated for 5 days with 1200 mg of gastroprotected preparation
Pat S t=0 t=5 t=10 T
GM M Enterococcus Sterile Sterile G
> 100,000
FP M E. coli Sterile Sterile G
> 100.000
GB F Candida Candida E. coli G
> 100.000 < 50.000 < 50.000
MM M E. coli E. coli Sterile G
> 100.000 < 50.000
MJ F Enterococcus Sterile Sterile E
> 100,000
LC F Candida Candida E. coli G
> 100.000 < 50.000 < 50.000
SL F E. coli Sterile Sterile E
> 100.000
PS F E. coli Sterile Sterile G
> 100.000
RP F Enterococcus E. coli Sterile G
> 100,000 < 50.000
MM M Candida Candida Sterile E
> 100.000 < 50.000
RT F Candida E. coli Sterile G
> 100.000 < 50.000
MF F E. coli E. coli Sterile G
> 100.000 < 50.000
MR F Enterococcus E. coli Sterile E
> 100,000 < 50.000
AR F E. coli Sterile Sterile G
> 100.000
GT F E. coli Sterile Sterile G
> 100.000
Pat = patient; S = sex; T = tolerability; G = good; E = excellent The formulations according to the invention are clearly clinically effective in the treatment of acute cystitis.
It has also been demonstrated that the administration of 400 mg of non- gastroprotected extract containing 30% PAC leads to a very low PAC content in the urinary bladder, not exceeding approx. 1% of the dose administered, whereas the administration of the gastroprotected form at the same dose allows delivery to the bladder area of approx. 60-70% of the dose of PAC administered.
Some examples of formulations according to the invention are set out below. The quantities are expressed as mg/tablet.
Example 1
Microcrystalline cellulose 228,000
Dicalcium phosphate 210,000
Vaccinium macrocarpon (30% Eur. Ph.) 200,000
Crosslinked sodium carboxymethylcellulose 20,000
Glyceryl behenate 20,000
Shellac 15,545
Vegetable magnesium stearate 14,000
Silicon dioxide 8,000
Hydroxypropyl methylcellulose 12,947
E171 2,988
Stearic acid 1,992
Triethyl citrate 1,233
Ammonium carbonate 0,822
Polyvinylpyrrolidone 0,602
El 20 colouring 0,073
El 32 colouring 0,008 Example 2
Calcium pho sphate 50,551
Microcrystalline cellulose 25,000
Vaccinium macrocarpon (80% Eur. Ph.) 200,000 Shellac 35,500
Magnesium stearate 0,900
Glycerin 0,314
Silicon dioxide 0,900
Talc 0,208 Lactose 0,208
Acetylated monoglycerides 0,219
Hydroxypropyl methylcellulo se 0, 104
Polyvinylpyrrolidone 0,073
E124 colouring 0,055 Example 3
Calcium phosphate 68,932
Microcrystalline cellulose 150,000
Vaccinium macrocarpon (30% Eur. Ph.) 500,000
Shellac 20,200 Magnesium stearate 0,850
Glycerin 1, 192
Silicon dioxide 3,500
Talc 0,792
Lactose 0,792 Acetylated monoglycerides 0,219
Hydroxypropyl methylcellulo se 0,396
Polyvinylpyrrolidone 0,073
E124 colouring 0,055

Claims

1. Oral compositions containing type A2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms.
2. Compositions as claimed in claim 1 in the form of capsules, tablets, powders or granules coated with natural or synthetic gastroresistant film-forming agents.
3. Compositions as claimed in claim 2 wherein the gastroresistant film-forming agents are selected from shellac and hydroxypropyl methylcellulose.
4. Compositions as claimed in claim 1 wherein the type A2 proanthocyanidins are present in the form of Vaccinium macrocarpon extract.
5. Compositions as claimed in claim 4 containing at least 18 mg of type A2 proanthocyanidins determined by the DMAC assay method (Ocean Spray,
Maryland, USA), or 54 mg determined by a validated method according to the European Pharmacopoeia.
EP12717059.5A 2011-03-15 2012-03-14 Use of type a2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms e Withdrawn EP2685967A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000409A ITMI20110409A1 (en) 2011-03-15 2011-03-15 USE OF PROANTOCYANIDINES TYPE A2 IN THE GASTROPROTECT SHAPE FOR THE TREATMENT OF THE CISTITES IN THE ACUTE PHASE SUPPORTED BY FIMBRIED BACTERIAL FORMS
PCT/EP2012/054453 WO2012123491A1 (en) 2011-03-15 2012-03-14 Use of type a2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms e

Publications (1)

Publication Number Publication Date
EP2685967A1 true EP2685967A1 (en) 2014-01-22

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP12717059.5A Withdrawn EP2685967A1 (en) 2011-03-15 2012-03-14 Use of type a2 proanthocyanidins in gastroprotected form for the treatment of acute cystitis induced by fimbriated bacterial forms e

Country Status (3)

Country Link
EP (1) EP2685967A1 (en)
IT (1) ITMI20110409A1 (en)
WO (1) WO2012123491A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106265627A (en) * 2015-06-23 2017-01-04 香港浸会大学 A kind of method treating inflammatory diseases and proanthocyanidin compound are as the medicinal application treating inflammatory diseases
EP3320897A1 (en) 2016-11-14 2018-05-16 Dompè Primary S.r.l Process for the preparation of coated cranberry granules with stable proanthocyanidine content
IT201600122310A1 (en) * 2016-12-01 2018-06-01 Sofar Spa Composition for use in the treatment of bowel disorders
IT201600130012A1 (en) * 2016-12-22 2018-06-22 Neilos S R L Composition for use in the treatment of disorders of the urogenital system
DE102018127408A1 (en) * 2018-11-02 2020-05-07 Ruhrpharm AG Cranberry extract PAC-A composition and its use in the prevention and / or treatment of urinary tract infections

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7785640B2 (en) * 2004-01-16 2010-08-31 Amerilab Technologies, Inc. Effervescent composition including cranberry extract

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
18 December 2009 (2009-12-18), XP055212781 *
ANONYMOUS: "Urinary tract infection - Wikipedia, the free encyclopedia", 2 September 2015 (2015-09-02), XP055212751, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Urinary_tract_infection> [retrieved on 20150911] *
See also references of WO2012123491A1 *

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ITMI20110409A1 (en) 2012-09-16

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