WO1994000112A1 - An oral formulation for gastric antibacterial treatment as well as a process thereof and the use - Google Patents
An oral formulation for gastric antibacterial treatment as well as a process thereof and the use Download PDFInfo
- Publication number
- WO1994000112A1 WO1994000112A1 PCT/SE1993/000521 SE9300521W WO9400112A1 WO 1994000112 A1 WO1994000112 A1 WO 1994000112A1 SE 9300521 W SE9300521 W SE 9300521W WO 9400112 A1 WO9400112 A1 WO 9400112A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation according
- formulation
- active
- tablet
- pylori
- Prior art date
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- 238000009472 formulation Methods 0.000 title claims abstract description 33
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- 229960005224 roxithromycin Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960004576 temafloxacin Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- VAMSVIZLXJOLHZ-QWFSEIHXSA-N tigemonam Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 VAMSVIZLXJOLHZ-QWFSEIHXSA-N 0.000 description 1
- 229950010206 tigemonam Drugs 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
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- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Definitions
- the invention relates to formulations for treatment of infections in the upper gastrointestinal tract especially infections caused by Helicobacter pylori, and a process for the manufacture of said formulations as well as the use thereof.
- Said formulations give a prolonged release of antimicrobal agent(s) in the upper gastrointestinal tract.
- H.pylori Helicobacter pylori
- H.pylori is a recently discovered bacterium, cultured for the first time in Australia 1982 [Warren JR Lancet 1983;1:1273], which has attracted much interest due to its possible aetiological role in a number of disorders in the upper gastrointestinal tract. It is considered a major cause in the development of peptic ulcer disease [Helicobacter pylori Working Party Report. World Congress in Gastroenterology, Sydney 1990] H. pylori is accepted as the aetiological agent in most cases of chronic non-specific gastritis. Chronic active gastritis is highly correlated to H. pylori -infections.
- H. pylori The pathogenic mechanism of H. pylori is not yet known in its details.
- the mode of transmission is unknown but considered to be by the faecal oral route and may be waterborne.
- H. pylori is found throughout the world but there is a higher prevalence of the organism in less developed countries and in patients with low economic status in western countries. The overall prevalence in western countries is about 52 % and increases with advancing age.
- H. pylori is a Gram-negative microaerophilic bacterium which is about 3.5 um in length and 1 ⁇ m in diameter. Due to the presence of 4-6 flagella attached to the end of its typical S- or spiral shape form, the bacterium can move rapidly in mucus. It lives closely attached to the gastric epithelial cells beneath the mucus layer and colonises the stomach, mainly the antrum, in a patchy fashion.
- the therapy is a combination of a bismuth preparation, metronidazole and amoxicillin or tetracycline.
- the dosage regimen involves many tablets and there is a need of administration several times per day. This is difficult for the patient to follow and compliance has been shown to be important to achieve the high eradication rates.
- Adverse effects, mainly due to metronidazole or bismuth are very common. About 30% of the patients have reported side effects [Axon ATR, Scand J Gastroenterol 1989;24(suppl 160):35- 38].
- Monotherapy of different antibiotics which are known to have good effect in vitro against H. pylori is insufficiently effective in vivo.
- Amoxicillin for example, eradicates H.pylori only in about 20% of treated patients.
- Combination of two drugs give higher eradication rates than monotherapy.
- Bismuth preparations bismuth subsalicyclate or colloidal bismuth subcitrate
- amoxicillin eradicated H.pylori in 44 % of treated patients
- bismuth + metronidazole, amoxicillin + tinidazole and amoxicillin + metronidazole in about 55 % of the patients, respectively [Chiba N, Rademaker JW, Rao BV et al. Gut 1991;32:A1220-1221 Abstract].
- Antibacterial agents have also been combined with acid secretion inhibitors. Combinations with histamin -blockers show no improved efiect. Proton pump inhibitors e g omeprazole, which have very little anti-H .pylori efiect on its own show a synergistic effect in combination with antibiotics. A dose of 750 mg amoxicillin twice daily with 40 mg omeprazole once daily was reported to eradicate H.pylori in 54% of the patients [Unge P, Eriksson K, Bergman B. et al. Gastroenterol
- antibiotics have relatively short duration of action and are given 3-4 times a day. Attempts to prolong the action by use of prolonged release products have generally been unsuccessful because the absorption of the antibiotic from the gastrointestinal tract is poor when administered in slow release form [Delgado Charro MB, Vila Jato JL. Int J Pharm 1992;78;35-41] Instead antibiotics are given in rapidly absorbed formulations, e g tablets or capsules. In order to achieve sufficiently long duration of action higher doses are given.
- formulations with prolonged gastric residence time are bioadhesive systems which interact with mucus or the mucosa. Another way to prolong the residence time is swelling systems which expand in contact with the gastric fluid to a size which does not allow the system to pass through the pylorus. Further examples are formulations with very high density or systems which float on the gastric contents. It has also been observed that large non-disintegrating tablets or capsules can be retained for several hours in the stomach. The retention time in the stomach is especially prolonged when the tablet or capsule is administered together with food due to the sieving function of pylorus when the stomach is in the digestive mode [Davis SS, Hardy JG, Taylor MJ et al. Int J Pharm 1984;21:331-340]. Food also retards the emptying of tablets or pellets, but the effect is less pronounced. The critical size is reported to be about 7 mm [Khosla R. Nottingham: University of Nottingham, 1987. (Diss).]
- the drug should be released within 1-24 h, preferably 1-6 h.
- the product should remain in the stomach at least 2-4 h, preferably more than 6 h.
- the major part of the drug should be released before the tablet leaves the stomach.
- the drugs suitable for the preparations according to the invention are e.g.
- the active agents could be in standard forms or used as salts, hydrates, esters etc. A combination of two or more of the above listed drugs may be preferable, for example to ininimize the risk for developing resistance.
- the antimicrobial agents can also be combined with other drugs used in the treatment of acid related diseases e.g. acid pump inhibitors or Hn-blockers, such as for example omeprazole.
- Possible formulations to be used are large non-disintegrating tablets or capsules e.g. inert matrix tablets [Hui H, Robinson JR, Lee NHL. Design and fabrication of Oral Controlled Delivery Systems. In: Robinson JR, Lee NHL, eds. Controlled Drug Delivery. Fundamentals and applications. New York: Marcel Dekker, Inc, 1987:373-432], osmotic pumps [Davis SS, Fara JW. Osmotic pumps. In: Hardy JG, Davis SS, Wilson CG, eds. Drug Delivery to the Gastrointestinal Tract. Chichester: Ellis Horwood Limited, 1989:97-109.] and membrane-coated tablets.
- inert matrix tablets Hui H, Robinson JR, Lee NHL. Design and fabrication of Oral Controlled Delivery Systems. In: Robinson JR, Lee NHL, eds. Controlled Drug Delivery. Fundamentals and applications. New York: Marcel Dekker, Inc, 1987:373-432
- osmotic pumps [Davis SS, Fara
- swelling systems [Banker, US Patent + no 261,242,] floating systems [Davis SS, Stockwell AF, Taylor MJ et al. Pharm Res 1986;3:208-213.], [Washington N, Wilson CG, Greaves JL et al. Scand J Gastroenterol 1988;23:920-924], formulations with high density [Devereux JE, Newton JM, Short MB. J Pharm Pharmacol 1990;42:500-501] and mucoadhesive systems [Junginger HE. Pharm Ind 1991;53:1056-1065] prepared from e.g. polycarbophil, polyacrylic acid, methylcellulose, polyethylene oxide, chitosan, tragacanth, sodium carboxymethyl cellulose can be used.
- an example from the above listed formulations is the inert porous matrix tablet which is obtained by mixing the drug with waxes or water insoluble polymers and with fillers and binders.
- Paraffin, polyvinylchloride, ethylcellulose, stearylic alcohol, cetylic alcohol, carnauba wax, polyethylene, polyvinyl acetate, polymethyl methacrylate could be used as suitable diffusion retarding compounds.
- Other excipients used in the preparations of such tablets are e.g. lactose, mannitol, calcium phosphates, magnesium stearate, hydroxypropyl methylcellulose, methylcellulose, polyvinylpyrrolidone, aluminium silicate, sodium carbonate, potassium phosphate or other suitable materials.
- Amoxicillin sodium was mixed in a planetary mixer for 5 minutes with paraffin. The resultant mixture was then moistened for 5 minutes with a solution of ethylcellulose in isopropanol and dried. The granulate was milled through a 1.0 mm sieve and lubricated for 2 minutes with magnesium stearate.
- the granulate was compressed to tablets on a tabletting machine fitted with 13 mm punches. Each tablet contained 415 mg amoxicillin sodium.
- the release profile of the drug is shown in Figure 1.
- Ethylcellulose 30 Magnesium stearate 14.1 The composition according to Example 2 was formed to modified release tablets containing 375 mg of amoxicillin/tablet.
- the tablet were prepared in the following way:
- Example 2 Compressed into tablets after granulation and drying as in Example 1.
- the tablets were coated with a porous membrane coating consisting of polyvinyl chloride in acetone according to [Kallstrand G, Ekman B. J Pharm Sci 1983;72(7):772-775].
- Micronized sucrose (particle size less than 10 um) was suspended in the polymer solution. Coating was achieved by spraying the suspension on a moving bed of tablets with an airless sprayer. Coating was continued until the weight if the coat on each tablet was 50 mg.
- Example 4 g
- the bioadhesive pellets were manufactured using conventional fluid-bed coating technology. Amoxicilhn trihydrate was successively coated with solutions containing chitosan and ethylcellulose, respectively.
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Abstract
An oral formulation with extended release for treatment of infections in the upper gastrointestinal tract as well as processes for the preparation and the use thereof.
Description
AN ORAL FORMULATION FOR GASTRIC ANTIBACTERIAL TREATMENT AS WELL AS A PROCESS THEREOF AND THE USE
Technical field
The invention relates to formulations for treatment of infections in the upper gastrointestinal tract especially infections caused by Helicobacter pylori, and a process for the manufacture of said formulations as well as the use thereof.
Said formulations give a prolonged release of antimicrobal agent(s) in the upper gastrointestinal tract.
Background of the invention Helicobacter pylori (H.pylori) is a recently discovered bacterium, cultured for the first time in Australia 1982 [Warren JR Lancet 1983;1:1273], which has attracted much interest due to its possible aetiological role in a number of disorders in the upper gastrointestinal tract. It is considered a major cause in the development of peptic ulcer disease [Helicobacter pylori Working Party Report. World Congress in Gastroenterology, Sydney 1990] H. pylori is accepted as the aetiological agent in most cases of chronic non-specific gastritis. Chronic active gastritis is highly correlated to H. pylori -infections. The organism is found in association with chronic active gastritis in almost 100% of the cases. Further, it was concluded in a case-control study of 372 patients that infection with H. pylori is associated with an increased risk of gastric adenocarcinoma and may be a cofactor in the pathogenesis of this malignant condition [Parsonnet J, Friedman GD, Daniel MS et al. N Engl J Med 1991;325:1127-31].
The pathogenic mechanism of H. pylori is not yet known in its
details. The mode of transmission is unknown but considered to be by the faecal oral route and may be waterborne. H. pylori is found throughout the world but there is a higher prevalence of the organism in less developed countries and in patients with low economic status in western countries. The overall prevalence in western countries is about 52 % and increases with advancing age.
H. pylori is a Gram-negative microaerophilic bacterium which is about 3.5 um in length and 1 μm in diameter. Due to the presence of 4-6 flagella attached to the end of its typical S- or spiral shape form, the bacterium can move rapidly in mucus. It lives closely attached to the gastric epithelial cells beneath the mucus layer and colonises the stomach, mainly the antrum, in a patchy fashion.
In vitro studies show a high sensitivity of H. pylori to many antibiotics [McNulty CA, Dent JC. Eur J Clin Microbiol Infect Dis 1988;7:566-569], [Lambert T, Megraud F, Gerbaud G et al. Antimicrob Agents Chemother 1986;30:510-511]. However, in vivo studies have demonstrated that there is a small correlation between in vitro sensitivity for H. pylori and treatment results in vivo for antibacterial drugs. The eradication regime with best eradication results today (elimination of H. pylori in 80-90% of treated patients) is triple therapy [Axon ATR. Scand J
Gastroenterol 1989;24(suppl 160) :35-38.]. The therapy is a combination of a bismuth preparation, metronidazole and amoxicillin or tetracycline. However, the dosage regimen involves many tablets and there is a need of administration several times per day. This is difficult for the patient to follow and compliance has been shown to be important to achieve the high eradication
rates. Adverse effects, mainly due to metronidazole or bismuth are very common. About 30% of the patients have reported side effects [Axon ATR, Scand J Gastroenterol 1989;24(suppl 160):35- 38].
Monotherapy of different antibiotics which are known to have good effect in vitro against H. pylori is insufficiently effective in vivo. Amoxicillin, for example, eradicates H.pylori only in about 20% of treated patients. Combination of two drugs give higher eradication rates than monotherapy. Bismuth preparations (bismuth subsalicyclate or colloidal bismuth subcitrate) in combination with amoxicillin eradicated H.pylori in 44 % of treated patients, bismuth + metronidazole, amoxicillin + tinidazole and amoxicillin + metronidazole in about 55 % of the patients, respectively [Chiba N, Rademaker JW, Rao BV et al. Gut 1991;32:A1220-1221 Abstract].
Antibacterial agents have also been combined with acid secretion inhibitors. Combinations with histamin -blockers show no improved efiect. Proton pump inhibitors e g omeprazole, which have very little anti-H .pylori efiect on its own show a synergistic effect in combination with antibiotics. A dose of 750 mg amoxicillin twice daily with 40 mg omeprazole once daily was reported to eradicate H.pylori in 54% of the patients [Unge P, Eriksson K, Bergman B. et al. Gastroenterol
1992;102(4);A183(abstract)]. Any explanation for this synergistic effect is not yet known, according to available information.
Many antibiotics have relatively short duration of action and are given 3-4 times a day. Attempts to prolong the action by use of prolonged release products have generally been unsuccessful
because the absorption of the antibiotic from the gastrointestinal tract is poor when administered in slow release form [Delgado Charro MB, Vila Jato JL. Int J Pharm 1992;78;35-41] Instead antibiotics are given in rapidly absorbed formulations, e g tablets or capsules. In order to achieve sufficiently long duration of action higher doses are given.
In all previous studies on H.pylori eradication rapidly available dosage forms of the antibacterial agents have been used and attempts have been made to increase the success rate by using very high doses of antibacterials as well as proton pump inhibitors. For example, 82% of treated patients were eradicated after 10 days therapy of 40 mg omeprazole twice daily in combination with 1 g amoxicillin twice daily followed by 6 weeks monotherapy of 20 mg omeprazole once daily. [Bayerdδrffer E, Marines GA, Sommer A et al. Gastroenterol 1992;102(4):A38(abstract)].
Outline of the invention We have discovered that the effectiveness of the treatment can be improved in an entirely different way, namely by administration of the antibacterial agents in prolonged release formulations and administer the formulations in such a way that they stay in the stomach several hours. It is not yet known if the H.pylori bacterias are accessible for treatment by antibacterial agents in the stomach or if the drug has to be absorbed and reach the bacterias via the blood circulation. The improved effect of formulations according to this invention may indicate that a local effect in the stomach is important.
Examples of formulations with prolonged gastric residence time
are bioadhesive systems which interact with mucus or the mucosa. Another way to prolong the residence time is swelling systems which expand in contact with the gastric fluid to a size which does not allow the system to pass through the pylorus. Further examples are formulations with very high density or systems which float on the gastric contents. It has also been observed that large non-disintegrating tablets or capsules can be retained for several hours in the stomach. The retention time in the stomach is especially prolonged when the tablet or capsule is administered together with food due to the sieving function of pylorus when the stomach is in the digestive mode [Davis SS, Hardy JG, Taylor MJ et al. Int J Pharm 1984;21:331-340]. Food also retards the emptying of tablets or pellets, but the effect is less pronounced. The critical size is reported to be about 7 mm [Khosla R. Nottingham: University of Nottingham, 1987. (Diss).]
The drug should be released within 1-24 h, preferably 1-6 h. To achieve an effective treatment of H.pylori infection the product should remain in the stomach at least 2-4 h, preferably more than 6 h. The major part of the drug should be released before the tablet leaves the stomach. The drugs suitable for the preparations according to the invention are e.g. ampicillin, amoxicillin, benzylpenicillin , phenoxymethylpenicillin, bacampicillin, pivampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, methicillin, oxacillin, piperacillin, ticarcillin,flucloxacillin, cefuroxime, cefetamet, cefetrame, cefixime, cefoxitin, ceftazidime, ceftizoxime, latamoxef, cefoperazone, ceftriaxone, cefsulodin, cefotaxime, cephalexin, cefaclor, cefadroxil. cefalothin, cefazolin, cefpodoxime, ceftibuten, aztreonam, tigemonam, erythromycin, dirithromycin, roxithromycin, azithromycin, clarithromycin, clindamycin, paldimycin, lincomycin, vancomycin, spectinomycin,
tobramycin, paromomycin, metronidazole, tinidazole, ornidazole, amifloxacin, cinoxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin, norfloxacin, ofloxacin, temafloxacin, doxycycline, minocycline, tetracycline, chlortetracycline, oxytetracycline, methacycline, rolitetracyclin, nitrofurantoin, nalidixic acid, gentamicin, rifampicin, amikacin, netilmicin, imipenem, cilastatin, chloramphenicol, furazolidone, nifuroxazide, sulfadiazin, sulfametoxazol, bismuth subsalicylate, colloidal bismuth subcitrate, gramicidin, mecillinam, cloxiquine, chlorhexidine, dichlorobenzylalcohol, methyl-2-pentylphenol. The active agents could be in standard forms or used as salts, hydrates, esters etc. A combination of two or more of the above listed drugs may be preferable, for example to ininimize the risk for developing resistance. The antimicrobial agents can also be combined with other drugs used in the treatment of acid related diseases e.g. acid pump inhibitors or Hn-blockers, such as for example omeprazole.
Possible formulations to be used are large non-disintegrating tablets or capsules e.g. inert matrix tablets [Hui H, Robinson JR, Lee NHL. Design and fabrication of Oral Controlled Delivery Systems. In: Robinson JR, Lee NHL, eds. Controlled Drug Delivery. Fundamentals and applications. New York: Marcel Dekker, Inc, 1987:373-432], osmotic pumps [Davis SS, Fara JW. Osmotic pumps. In: Hardy JG, Davis SS, Wilson CG, eds. Drug Delivery to the Gastrointestinal Tract. Chichester: Ellis Horwood Limited, 1989:97-109.] and membrane-coated tablets. Further, swelling systems [Banker, US Patent + no 261,242,] floating systems [Davis SS, Stockwell AF, Taylor MJ et al. Pharm Res 1986;3:208-213.], [Washington N, Wilson CG, Greaves JL et al. Scand J Gastroenterol 1988;23:920-924], formulations with high
density [Devereux JE, Newton JM, Short MB. J Pharm Pharmacol 1990;42:500-501] and mucoadhesive systems [Junginger HE. Pharm Ind 1991;53:1056-1065] prepared from e.g. polycarbophil, polyacrylic acid, methylcellulose, polyethylene oxide, chitosan, tragacanth, sodium carboxymethyl cellulose can be used.
An example from the above listed formulations is the inert porous matrix tablet which is obtained by mixing the drug with waxes or water insoluble polymers and with fillers and binders. Paraffin, polyvinylchloride, ethylcellulose, stearylic alcohol, cetylic alcohol, carnauba wax, polyethylene, polyvinyl acetate, polymethyl methacrylate could be used as suitable diffusion retarding compounds. Other excipients used in the preparations of such tablets are e.g. lactose, mannitol, calcium phosphates, magnesium stearate, hydroxypropyl methylcellulose, methylcellulose, polyvinylpyrrolidone, aluminium silicate, sodium carbonate, potassium phosphate or other suitable materials.
Examples
It is the object of the present invention to provide an extended- release preparation with prolonged gastric residence time after oral administration, containing one or more antimicrobial agents.
Example 1: g
Amoxicillin sodium 830
Paraffin 500 Ethylcellulose 60
Magnesium stearate 28.8
Amoxicillin sodium was mixed in a planetary mixer for 5 minutes with paraffin. The resultant mixture was then moistened for 5 minutes with a solution of ethylcellulose in isopropanol and dried. The granulate was milled through a 1.0 mm sieve and lubricated for 2 minutes with magnesium stearate.
The granulate was compressed to tablets on a tabletting machine fitted with 13 mm punches. Each tablet contained 415 mg amoxicillin sodium. The release profile of the drug is shown in Figure 1.
Example 2: g
Amoxicillin trihydrate 215.6
Paraffin 250
Sodium carbonate 209
Ethylcellulose 30 Magnesium stearate 14.1
The composition according to Example 2 was formed to modified release tablets containing 375 mg of amoxicillin/tablet. The tablet were prepared in the following way:
Amoxicillin trihydrate, paraffin and sodium carbonate were mixed for 5 minutes in a planetary mixer. The remaining process was made according to Example 1. The release profile of the drug is shown in Figure 2.
Example 3 g
Amoxicillin trihydrate 215
Tripotassium phosphate 209
Polyvinylpyrrolidone 20 Magnesium stearate 20
Compressed into tablets after granulation and drying as in Example 1. The tablets were coated with a porous membrane coating consisting of polyvinyl chloride in acetone according to [Kallstrand G, Ekman B. J Pharm Sci 1983;72(7):772-775].
Micronized sucrose (particle size less than 10 um) was suspended in the polymer solution. Coating was achieved by spraying the suspension on a moving bed of tablets with an airless sprayer. Coating was continued until the weight if the coat on each tablet was 50 mg.
Example 4: g
Amoxicillin trihydrate 244
Ethylcellulose 268
Chitosan 366
Hydrochloric acid 0,13
*
Water purified q.s.
*
Ethanol q.s.
Used in the manufacture of pellets but removed during subsequent processing
The bioadhesive pellets were manufactured using conventional fluid-bed coating technology. Amoxicilhn trihydrate was successively coated with solutions containing chitosan and ethylcellulose, respectively.
Claims
1. An oral formulation containing active materials for treatment of infections in the upper gastrointestinal tract characterized in that the formulation is retained in the stomach for a prolonged time whereby the active materials are released continuously during said time.
2. A formulation according to claim 1 where the preferred retention time is at least 1 h during which period the active materials are released continuously.
3. A formulation according to claim 1, wherein the formulation contains one or more antibacterial agents.
4. A formulation according to claim 1 where the infection is caused by Helicobacter pylori.
5. A formulation according to claim 1 wherein the active substance is amoxicillin.
6. A formulation according to claim 1 comprising a combination of two or more active agents.
7. A formulation according to claim 1 where the dosage form has bioadhesive properties.
8. A formulation according to claim 1 consisting of a non- disintegrating prolonged release formulation containing antibacterial agents.
9. A formulation according to claim 8 wherein the size is not less than 7 mm.
10. A formulation according to claim 9 where the release of the active compound is controlled by a non-disintegrating membrane.
11. A formulation according to claim 9 where the formulation is an inert porous matrix.
12. A process for the manufacture of a preparation according to claim 11 wherein the active substance is mixed with polymers or materials in an amount exceeding 10% of the weight of the mixture and the resulting mixture is compressed into a tablet.
13. A process according to claim 12 wherein the tablet is heated to a temperature above the melting point of the waxy material to retard the release profile and improve the mechanical strength of the tablet.
14. Use of a formulation according to claim 1 in the preparation of an active dosage form for the treatment of infections in the upper gastrointestinal tract.
15. Use of a formulation according to claim 1 together with acid secretion inhibitors.
16. Use of a formulation according to claim 1 together with proton pump inhibitors.
17. Use according to claim 16 wherein the proton pump inhibitor is omeprazole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU45178/93A AU4517893A (en) | 1992-06-24 | 1993-06-11 | An oral formulation for gastric antibacterial treatment as well as a process thereof and the use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9201930A SE9201930D0 (en) | 1992-06-24 | 1992-06-24 | GASTRIC ANTIBACTERIAL TREATMENT |
| SE9201930-6 | 1992-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994000112A1 true WO1994000112A1 (en) | 1994-01-06 |
Family
ID=20386583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1993/000521 WO1994000112A1 (en) | 1992-06-24 | 1993-06-11 | An oral formulation for gastric antibacterial treatment as well as a process thereof and the use |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU4517893A (en) |
| IS (1) | IS4030A (en) |
| SE (1) | SE9201930D0 (en) |
| SI (1) | SI9300330A (en) |
| WO (1) | WO1994000112A1 (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0754465A4 (en) * | 1994-04-01 | 1998-05-06 | Tsumura & Co | PROCESS FOR PRODUCING EXTENDED RELEASE TABLETS AND ENTERIC TABLETS |
| WO1998040054A1 (en) * | 1997-03-12 | 1998-09-17 | Astra Aktiebolag (Publ) | An enteric coated oral dosage form comprising sodium amoxycillin |
| WO1998052547A1 (en) * | 1997-05-24 | 1998-11-26 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Gastroretentive controlled release microspheres for improved drug delivery |
| US5948773A (en) * | 1993-09-09 | 1999-09-07 | Takeda Chemical Industries, Ltd. | Formulation comprising antibacterial substance and antiulcer substance |
| US6068859A (en) * | 1994-05-06 | 2000-05-30 | Pfizer Inc. | Controlled-release dosage forms of Azithromycin |
| EP0941064A4 (en) * | 1996-11-17 | 2001-12-12 | Yissum Res Dev Co | PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED RELEASE OF beta -LACTAM ANTIBIOTICS |
| US6428813B1 (en) | 1997-03-25 | 2002-08-06 | Takeda Chemical Industries, Ltd. | Gastrointestinal mucosa-adherent pharmaceutical composition |
| US6694692B2 (en) | 1998-10-16 | 2004-02-24 | Francesco Piccone | Modular formwork elements and assembly |
| WO2004087175A1 (en) * | 2003-04-04 | 2004-10-14 | Pharmacia Corporation | Oral extended release compressed tablets of multiparticulates |
| WO2005065685A1 (en) * | 2004-01-06 | 2005-07-21 | Panacea Biotec Ltd. | Controlled release pharmaceutical composition comprising an acid-insoluble polymer and a bioadhesive polymer |
| US6984403B2 (en) | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
| WO2006031420A3 (en) * | 2004-08-27 | 2006-11-30 | Spherics Inc | Multi-layer tablets and bioadhesive dosage forms |
| WO2007110875A1 (en) * | 2006-03-24 | 2007-10-04 | Panacea Biotec Ltd. | Antibiotic compositions of modified release and process of production thereof |
| WO2008030141A1 (en) * | 2006-09-06 | 2008-03-13 | Bosnalijek, Pharmaceutical And Chemical Industry, Joint Stock Company | Use of nifuroxazide in the form of a component of a combined drug therapy for treating diseases associated with helicobacter pylori and a curing method for eradicating a causative agent |
| US7625507B2 (en) | 2003-12-04 | 2009-12-01 | Pfizer Inc. | Extrusion process for forming chemically stable drug multiparticulates |
| USRE45198E1 (en) | 1996-01-04 | 2014-10-14 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
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| EP0455475A2 (en) * | 1990-05-03 | 1991-11-06 | Reckitt And Colman Products Limited | Use of triclosan in the treatment of diseases of the gastrointestinal tract |
| WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
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-
1993
- 1993-06-09 IS IS4030A patent/IS4030A/en unknown
- 1993-06-11 WO PCT/SE1993/000521 patent/WO1994000112A1/en active Application Filing
- 1993-06-11 AU AU45178/93A patent/AU4517893A/en not_active Abandoned
- 1993-06-23 SI SI9300330A patent/SI9300330A/en unknown
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| EP0455475A2 (en) * | 1990-05-03 | 1991-11-06 | Reckitt And Colman Products Limited | Use of triclosan in the treatment of diseases of the gastrointestinal tract |
| WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
| EP0490450A1 (en) * | 1990-12-11 | 1992-06-17 | Yamanouchi Europe B.V. | Heterocyclic carboxylic esters, methods for their preparation and their use for the preparation of gastrointestinal medicines |
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| CURRENT OPINION IN GASTROENTEROLOGY, Volume 8, 1992, C.S. GOODWIN et al., "Peptic Ulcer Disease and Helicobacter Pylori Infection", page 122 - page 127. * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948773A (en) * | 1993-09-09 | 1999-09-07 | Takeda Chemical Industries, Ltd. | Formulation comprising antibacterial substance and antiulcer substance |
| EP0995447A1 (en) * | 1993-09-09 | 2000-04-26 | Takeda Chemical Industries, Ltd. | Formulation comprising antibacterial substance and antiulcer substance |
| US6319904B1 (en) | 1993-09-09 | 2001-11-20 | Takeda Chemical Industries, Ltd. | Formulation comprising antibacterial substance and antiulcer substance |
| EP0754465A4 (en) * | 1994-04-01 | 1998-05-06 | Tsumura & Co | PROCESS FOR PRODUCING EXTENDED RELEASE TABLETS AND ENTERIC TABLETS |
| EP0758244B2 (en) † | 1994-05-06 | 2008-02-13 | Pfizer Inc. | Controlled-release dosage forms of azithromycin |
| US6068859A (en) * | 1994-05-06 | 2000-05-30 | Pfizer Inc. | Controlled-release dosage forms of Azithromycin |
| US7108865B2 (en) | 1994-05-06 | 2006-09-19 | Pfizer Inc | Controlled-release dosage forms of azithromycin |
| USRE45198E1 (en) | 1996-01-04 | 2014-10-14 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6399086B1 (en) | 1996-11-17 | 2002-06-04 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Pharmaceutical preparations for the controlled release of beta-lactam antibiotics |
| EP0941064A4 (en) * | 1996-11-17 | 2001-12-12 | Yissum Res Dev Co | PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED RELEASE OF beta -LACTAM ANTIBIOTICS |
| WO1998040054A1 (en) * | 1997-03-12 | 1998-09-17 | Astra Aktiebolag (Publ) | An enteric coated oral dosage form comprising sodium amoxycillin |
| US6428813B1 (en) | 1997-03-25 | 2002-08-06 | Takeda Chemical Industries, Ltd. | Gastrointestinal mucosa-adherent pharmaceutical composition |
| WO1998052547A1 (en) * | 1997-05-24 | 1998-11-26 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Gastroretentive controlled release microspheres for improved drug delivery |
| US6207197B1 (en) | 1997-05-24 | 2001-03-27 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Gastroretentive controlled release microspheres for improved drug delivery |
| GB2341550B (en) * | 1997-05-24 | 2002-01-09 | West Pharm Serv Drug Res Ltd | Gastroretentive controlled release microspheres for improved drug delivery |
| GB2341550A (en) * | 1997-05-24 | 2000-03-22 | West Pharm Serv Drug Res Ltd | Gastroretentive controlled release microspheres for improved drug delivery |
| US6694692B2 (en) | 1998-10-16 | 2004-02-24 | Francesco Piccone | Modular formwork elements and assembly |
| WO2004087175A1 (en) * | 2003-04-04 | 2004-10-14 | Pharmacia Corporation | Oral extended release compressed tablets of multiparticulates |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US6984403B2 (en) | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
| US7625507B2 (en) | 2003-12-04 | 2009-12-01 | Pfizer Inc. | Extrusion process for forming chemically stable drug multiparticulates |
| WO2005065685A1 (en) * | 2004-01-06 | 2005-07-21 | Panacea Biotec Ltd. | Controlled release pharmaceutical composition comprising an acid-insoluble polymer and a bioadhesive polymer |
| EA012296B1 (en) * | 2004-01-06 | 2009-08-28 | Панацея Биотек Лтд. | Controlled release pharmaceutical composition comprising an acid-insoluble polymer and a bioadhesive polymer |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| WO2006031420A3 (en) * | 2004-08-27 | 2006-11-30 | Spherics Inc | Multi-layer tablets and bioadhesive dosage forms |
| WO2007110875A1 (en) * | 2006-03-24 | 2007-10-04 | Panacea Biotec Ltd. | Antibiotic compositions of modified release and process of production thereof |
| WO2008030141A1 (en) * | 2006-09-06 | 2008-03-13 | Bosnalijek, Pharmaceutical And Chemical Industry, Joint Stock Company | Use of nifuroxazide in the form of a component of a combined drug therapy for treating diseases associated with helicobacter pylori and a curing method for eradicating a causative agent |
Also Published As
| Publication number | Publication date |
|---|---|
| IS4030A (en) | 1993-12-25 |
| SI9300330A (en) | 1993-12-31 |
| SE9201930D0 (en) | 1992-06-24 |
| AU4517893A (en) | 1994-01-24 |
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