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WO1994027579A1 - Composition pour le traitement d'ulceres - Google Patents

Composition pour le traitement d'ulceres Download PDF

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Publication number
WO1994027579A1
WO1994027579A1 PCT/US1994/005748 US9405748W WO9427579A1 WO 1994027579 A1 WO1994027579 A1 WO 1994027579A1 US 9405748 W US9405748 W US 9405748W WO 9427579 A1 WO9427579 A1 WO 9427579A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
polysulfate
ulcer
sucralfate
antibiotic
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.)
Ceased
Application number
PCT/US1994/005748
Other languages
English (en)
Inventor
Arthur H. Golberg
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.)
Ribogene Inc
Original Assignee
Ribogene Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ribogene Inc filed Critical Ribogene Inc
Priority to AU70427/94A priority Critical patent/AU7042794A/en
Publication of WO1994027579A1 publication Critical patent/WO1994027579A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • This invention relates to a method and medication for the treatment of an ulcer.
  • a composition comprising an antibiotic adsorbed onto a disaccharide polysulfate-aluminum compound is contacted with the ulcer site.
  • the composition adherently coats the ulcer, protecting it while imparting an antibiotic activity which accelerates healing.
  • this method is utilized for treatment of an internal ulcer.
  • the disaccharide polysulfate-aluminum compound with adsorbed antibiotic preferentially binds to the ulcer.
  • its protective and healing properties are enhanced.
  • Disaccharide polysulfate-aluminum compounds are accepted medications for the treatment for peptic ulcers. Such compounds are disclosed in U.S. Patent 3,432,489 to Nitta et al (Nitta), which is incorporated herein by reference. Typical compounds are sucrose polysulfate-aluminum compounds, lactose polysulfate-aluminum compounds and maltose polysulfate-aluminum compounds.
  • Nitta discloses the internal use of these compounds in the treatment of peptic ulcers by oral administration. Such ulcers have a pathology characterized by erosion of the mucosa of the alimentary canal.
  • the major areas where mucosa occurs include the mouth, the esophagus, the stomach (gastric mucosa) and the duodenum (duodenal mucosa) .
  • the mucosa is located anatomically in areas bathed by acid and which normally have a pH ranging from about 1.0 to 4.0.
  • sucrose polysulfate aluminum compound referred to in The Merck Index, Merck & Co., Inc., Rahway, NJ, 10th Edition, 1983 at number 8755 as sucralfate.
  • This compound is currently marketed as an anti-ulcerative agent.
  • Disaccharide polysulfate-aluminum complexes are frequently referred to herein for the purposes of simplicity as sucralfate.
  • Sucralfate is now also recognized by those skilled in the art as being useful in the treatment of peptic ulcer disease (Barrers et al, Am. J. Surg. , 148 (1984) pp 809-12) and in short term duodenal and gastric ulcer healing (Halter, S.
  • composition may further contain any number of pharmacological agents including anesthetics, vaso- constructors, protectants, counterirritants, astringents, wound healing agents, antiseptics, keratolytics and anticholinergics. These agents may also include antibiotics.
  • these compounds may be applied to topical or external ulcers. This includes scrapes or other injuries of the skin. Indeed, they may be employed to treat virtually any such tissue wound, wherever situated on the body.
  • Another object of the instant invention to provide a preparation which forms a protective barrier over an ulcer and also acts as a carrier which enhances antibiotic activity at the wound site.
  • This invention provides a method for treating ulcers through contact with a composition which is safe, effective and comprises an antibiotic adsorbed onto a disaccharide polysulfate-aluminum compound.
  • This invention provides a composition and a method for treating ulcers. These ulcers may be situated anywhere on or within the body.
  • composition of the instant invention comprises an antibiotic adsorbed (or complexed) onto a disaccharide polysulfate-aluminum compound such as sucralfate.
  • This composition may be used in the same manner as sucralfate alone. It may be applied to an external ulcer in powdered form or, more typically, in a pharmaceutically acceptable dispersant. With internal ulcers, these compositions are normally ingested so as to reach the involved area. They may simply be taken orally or injected into the area of the body where the ulcer is located.
  • ulcer wounds Treatment of ulcer wounds is often complicated by infection. Infection presents a particular problem when the ulcer being treated is" internal to the body. A localized application is difficult to achieve.
  • antibiotic must be one which adsorbs onto (or complexes with) the disaccharide polysulfate-aluminum compound. This interaction ensures that the antibiotic is selectively carried to the ulcer site, and is held there by the compound. This increases its effective concentration and pharmacological effect.
  • antibiotics have no affinity towards a disaccharide polysulfate-aluminum compound. They do no more than mix with a sucralfate. Consequently, in an aqueous environment such as that in the alimentary canal of the body, they are rapidly diluted. They are also eluded from the sucralfate and/or wound site, and their effectiveness is rapidly lost.
  • antibiotics adsorb onto sucralfate.
  • the resultant combination or complex is stable and permits targeting of the location of antibiotic.
  • Representative adsorbable antibiotics include nalidixic acid, , doxycycline hyclate and tetracycline. Others may readily be determined.
  • the absorbability or affinity of an antibiotic to complex with a disaccharide polysulfate-aluminum compound may be determined by dissolving an antibiotic in an aqueous slurry of sucralfate. The concentration of dissolved antibiotic can be monitored by spectroscopic analysis or other technique. If adsorbable, the concentration of dissolved antibiotic will drop, only to stabilize when the sucralfate- antibiotic complex reaches equilibrium or saturation.
  • Antibiotics having an affinity toward sucralfate are desirably incorporated into the present compositions in from 0.2% to 5% by weight of compound. These antibiotics may be concentrated on an 7 ulcer through their linkage to sucralfate and its property of preferentially binding to a wound site. This ensures that a therapeutically effective amount of antibiotic is present to combat infection and to facilitate healing of the ulcer.
  • the complex of antibiotic and disaccharide polysulfate-aluminum compound Once the complex of antibiotic and disaccharide polysulfate-aluminum compound has been formed as described above, it can be separated from the aqueous dispersant and dried. It remains stable in this form and can be administered directly as a powder or mixed with a pharmaceutically acceptable dispersant to permit formation of a tablet or another slurry.
  • the composition is normally administered from 1 to 4 times over the course of a single day. The administration is continued for as many days as are necessary to relieve the condition being treated.
  • sucralfate composition administered in accordance with the invention need not be great.
  • Sucralfate has been found to bind preferentially to a wound site as opposed to normal tissue.
  • the present compositions concentrate on and adhere to an ulcer. This significantly reduces the amount(s) of disaccharide polysulfate-aluminum compound and/or antibiotic which would otherwise be needed for optimum therapeutic effect.
  • a very light coating may be applied directly to the ulcer site. As little as 10 milligrams per square centimeter, more desirably at least 25 mg/cm 2 of particulate composition may be applied. This may be performed by dusting the ulcer with a free flowing, powder form of the present composition.
  • the composition may also be diluted with a pharmaceutically acceptable dispersant and then applied directly to the ulcer.
  • the dispersant may be any conventional material for topical application. It may conveniently be an ointment composed, for example, of petroleum jelly or lanolin or other suitable carriers. Other representative dispersants which may be used are disclosed in U.S. Patent No. 4,626,433 of Gros, the disclosure of which is incorporated herein by reference.
  • the composition may be ingested in any dispersed form.
  • the composition may be compacted into a tablet with a solid such as lactose or starch or other conventional binder.
  • a solid such as lactose or starch or other conventional binder.
  • it may be mixed with an organic liquid such as alcohol or glycol and then encapsulated.
  • An aqueous slurry may also be employed.
  • Such a slurry normally comprises at least 70% liquid by total weight.
  • the normal dosage for internal application will range from 2 to 8 grams of composition in a twenty-four hour period.
  • any of these forms of the present composition may be used to treat internal ulcers.
  • the tablets After ingestion, , the tablets readily disintegrate forming an aqueous slurry within the alimentary canal.
  • This or one of the other slurries of the present invention constitutes a preferred means of transmitting the composition to an ulcer site.
  • the composition is maintained at the ulcer site for a sufficient time to ensure that a desirable amount of the composition will bind to the ulcer. In most cases, this occurs inherently during administration because as little as 15 seconds, more desirably 30 seconds, is usually enough only in rare cases is any special effort necessary. Thus, for example, where an oral ulcer is being treated, the slurry should be held temporarily in the mouth and then may be expectorated or swallowed.
  • Each antibiotic was placed in water and stirred at a temperature of 37°C until equilibrium was reached. An aliquot was then removed and the concentration of dissolved antibiotic was determined by uv spectroscopic analysis.
  • EXAMPLE 2 The effectiveness of the present antibiotic- sucralfate complexes was measured in the treatment of gastric ulcers artificially induced in rabbits. Six antral stomach wall injuries were produced by pinch biopsy in each of ten anesthetized rabbits weighing about 2.5 kg. This was performed by laparotomy. The rabbits then received 800 cGy irradiation and appropriate post-operative care.
  • the antimicrobial activity of a doxycycline hyclate-sucralfate complex having a weight ratio of 1:70 was determined using a modified U.S.P. turbidimetric method.
  • a control sample of a dilute culture of staphylococcus aureus in U.S.P. medium 3 was analyzed at 530 nm for percent transmission. This control and samples additionally containing varying concentrations of the antibiotic alone, sucralfate alone and the complex were incubated in a 37°C. water bath. After four (4) hours, the samples were removed and their transmissions were measured as previously described. The results were as follows:
  • sucralfate alone exhibits no antimicrobial activity.
  • complexed antibiotic has only a slightly lessened activity as compared to the uncomplexed, antibiotic control. Therefore, this example shows that a targeted medication of desired therapeutic activity is readily obtained.
  • Example 4 The procedure of Example 3 is repeated substituting tetracycline and tetracycline-sucralfate complex having a weight ratio of 1:160. The results were as follows:
  • antibiotic-sucralfate complex exhibits a significant anti-microbial activity, only slightly lessened from that of the antibiotic control.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition pharmaceutique comportant un antibiotique adsorbé sur un composé de polysulfate disaccharide d'aluminium, tel que le sucralfate, s'avérant efficace dans le traitement des ulcères. La composition recouvre l'ulcère et le protége tout en exerçant une activité antibiotique qui accélère la guérison.
PCT/US1994/005748 1993-05-24 1994-05-23 Composition pour le traitement d'ulceres Ceased WO1994027579A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU70427/94A AU7042794A (en) 1993-05-24 1994-05-23 Ulcer treating composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6492093A 1993-05-24 1993-05-24
US064,920 1993-05-24

Publications (1)

Publication Number Publication Date
WO1994027579A1 true WO1994027579A1 (fr) 1994-12-08

Family

ID=22059142

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/005748 Ceased WO1994027579A1 (fr) 1993-05-24 1994-05-23 Composition pour le traitement d'ulceres

Country Status (3)

Country Link
AU (1) AU7042794A (fr)
IL (1) IL109758A0 (fr)
WO (1) WO1994027579A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001019362A3 (fr) * 1999-09-14 2001-12-13 Orapharma Inc Formulations permettant de traiter out de prevenir l'inflammation d'une muqueuse
FR2824474A1 (fr) * 2001-05-11 2002-11-15 Fabre Pierre Dermo Cosmetique Composition cosmetique a base de sucralfate et de sulfates de cuivre et de zinc
US6893665B2 (en) 1999-09-14 2005-05-17 Orapharma, Inc. Formulations for treating or preventing mucositis
EP1829546A1 (fr) * 1999-09-14 2007-09-05 Mucosal Therapeutics LLC Formulations pour traiter ou prévenir la mucosite

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403048A2 (fr) * 1989-06-14 1990-12-19 Warner-Lambert Company Un modèle de structure de système craniomandibulaire humain
EP0402933A2 (fr) * 1989-06-16 1990-12-19 Laboratorio Italiano Biochimico Farmaceutico Lisapharma S.P.A. Utilisation du gel humide de sucralfate comme véhicule pour médicaments à activité topique et pour des produits cosmétiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403048A2 (fr) * 1989-06-14 1990-12-19 Warner-Lambert Company Un modèle de structure de système craniomandibulaire humain
EP0402933A2 (fr) * 1989-06-16 1990-12-19 Laboratorio Italiano Biochimico Farmaceutico Lisapharma S.P.A. Utilisation du gel humide de sucralfate comme véhicule pour médicaments à activité topique et pour des produits cosmétiques

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001019362A3 (fr) * 1999-09-14 2001-12-13 Orapharma Inc Formulations permettant de traiter out de prevenir l'inflammation d'une muqueuse
US6893665B2 (en) 1999-09-14 2005-05-17 Orapharma, Inc. Formulations for treating or preventing mucositis
US6946118B1 (en) 1999-09-14 2005-09-20 Orapharma, Inc. Formulations for treating or preventing mucositis
EP1829546A1 (fr) * 1999-09-14 2007-09-05 Mucosal Therapeutics LLC Formulations pour traiter ou prévenir la mucosite
FR2824474A1 (fr) * 2001-05-11 2002-11-15 Fabre Pierre Dermo Cosmetique Composition cosmetique a base de sucralfate et de sulfates de cuivre et de zinc
WO2002092045A1 (fr) * 2001-05-11 2002-11-21 Pierre Fabre Dermo-Cosmetique Composition cosmetique a base de sucralfate et de sulfates de cuivre et de zinc

Also Published As

Publication number Publication date
AU7042794A (en) 1994-12-20
IL109758A0 (en) 1994-08-26

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