[go: up one dir, main page]

WO1999065435A1 - Corps hydrogel - Google Patents

Corps hydrogel Download PDF

Info

Publication number
WO1999065435A1
WO1999065435A1 PCT/GB1999/001721 GB9901721W WO9965435A1 WO 1999065435 A1 WO1999065435 A1 WO 1999065435A1 GB 9901721 W GB9901721 W GB 9901721W WO 9965435 A1 WO9965435 A1 WO 9965435A1
Authority
WO
WIPO (PCT)
Prior art keywords
body according
treatment
hydrogel
infection
vaginal
Prior art date
Application number
PCT/GB1999/001721
Other languages
English (en)
Inventor
David Monteith
John Francis Porter
Original Assignee
Cenes Drug Delivery Limited
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 Cenes Drug Delivery Limited filed Critical Cenes Drug Delivery Limited
Priority to AU43779/99A priority Critical patent/AU4377999A/en
Publication of WO1999065435A1 publication Critical patent/WO1999065435A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
    • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
    • C08G18/6666—Compounds of group C08G18/48 or C08G18/52
    • C08G18/667—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38
    • C08G18/6674—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3203
    • C08G18/6677—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3203 having at least three hydroxy groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/00051—Accessories for dressings
    • A61F13/00063—Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00655—Plasters adhesive
    • A61F2013/00676—Plasters adhesive hydrogel
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2210/00—Compositions for preparing hydrogels

Definitions

  • the present invention relates to the use of a solid hydrogel body for the treatment of infection in mammals such as humans and animals.
  • the solid hydrogel body is unmedicated in the sense that it contains no active agent effective in the treatment of the infection. It is particularly useful in the treatment of infection or infectious disease in body cavities such as the vagina or rectum, and also in the mouth, for example, for treating gum disease.
  • the hydrogel body may also be used as a vehicle for removal of a sample for testing from a body cavity.
  • Hydrogels in solid form as delivery vehicles for pharmaceutically active agents are disclosed, for example, in patent specification EP0016652.
  • the crystalline cross- linked polyurethane hydrogels disclosed therein have the ability to swell by uptake of water without losing their solid form. They are also able to absorb quantities of active agent which can subsequently be released in a controlled manner during swelling. Such hydrogels have therefore been proposed as vehicles for the sustained release over extended periods of time of pharmacologically active substances.
  • Solid hydrogel pessaries adapted for the sustained release of prostaglandins are commercially available for intra vaginal treatments during childbirth.
  • US Patent 3,953,406 describes the use of solid hydrogel bodies to absorb lipids, such as cholesterol, lecithin and sodium cholate from bile.
  • the present invention provides a solid hydrogel body for use as a medicament for the treatment of infection; the hydrogel body containing no active agent effective in said treatment of said infection.
  • the solid hydrogel body is effective by a number of possible modes of action.
  • One mode of action involves absorption of toxins or other molecules produced as a direct result of the infection, leading to an alleviation of symptoms.
  • a second possible mode of action is the removal of low molecular weight amino acids and other growth-supporting factors such as carbon and nitrogen sources required for biosynthesis.
  • a third potential mode of action is by dehydration and disruption of opportunistic infections, so as to allow the natural equilibrium to return.
  • a fourth possible factor is the provision of a surface for macrophagous activity to clear the infection.
  • the solid hydrogel body is particularly applicable for administration by insertion into a body cavity, such as vaginal, rectal or oral administration. It may also be used as a wound packing for infected wounds.
  • the solid hydrogel body may be shaped according to the shape of the body cavity into which it is to be inserted. Particularly preferred shapes include cylinders, flat strips, lozenge- shaped, kydney-shaped etc. It may also be in the form of beads or granules. Generally, the body will have rounded leading and/or trailing ends to facilitate insertion and removal.
  • the hydrogel body of the present invention differs from conventional suppositories which generally melt or otherwise disintegrate once inside the body cavity.
  • the solid hydrogel body of the present invention retains its solid integrity during the swelling process and is removed at a convenient point, either before or after full swelling has been achieved.
  • the hydrogel body may be shaped such as to maximise its surface to volume ratio thereby enhancing uptake, e.g. by providing surface corrugations.
  • cylindrical bodies may be provided with longitudinal flutes or crenellations .
  • the hydrogel body also offers an attractive route to the acquisition of fluid samples from a body cavity (particularly, the vagina or rectum) for diagnosis purposes. This is particularly valuable for diagnosis based on the detection of toxins present. There are instances where it is necessary to take a sample for diagnosis of putative vaginal infection, but where the woman is reluctant to undergo medical examination in which direct visualisation of the vagina is necessary in order to take a swab.
  • retrieval means such as a net bag and retrieval cord, e.g. as disclosed in patent application EP92306296.2.
  • the hydrogel body may in principal be formed from any water-swellable hydrogel material which retains its solid integrity (i.e. does not dissolve or disperse) on uptake of water.
  • Preferred materials include polyurethanes and other swellable materials such as polyacrylates and polymethacry lates (for example polyhydroxyethyl ethacrylate) . Generally, these materials will be at least partially cross-linked so as to maintain their structural integrity when swollen.
  • a particularly preferred material is disclosed in patent specification
  • EP0016652 which is a polyurethane formed by reacting a polyethylene oxide, metnane diphenyl di-isocyanate and trimethylol propane.
  • the solid hydrogel body containing no active agent has been found to be surprisingly effective in the treatment of infection, particularly in the vagina.
  • Many infections are toxin-mediated.
  • Micro-organisms present may include bacterial, protozoal and fungal infections.
  • Particular infections include vaginal trichomoniasis, bacterial vaginosis (e.g. Gardnerella vaginalis) and vaginal candidiasis (e.g. Candida albicans) .
  • Other infections, including viral infections may also be treated.
  • the anti-infection effect of the hydrogel body may operate by the absorption of low molecular weight compounds from the local microenvironment.
  • Compounds of molecular weight less than 2000 Daltons, particularly less than 1000 Daltons appear to be preferentially absorbed from the local microenvironment by the hydrogel used in the tests.
  • the hydrogel formulation and structure e.g. degree of cross-linking
  • the hydrogel formulation and structure can be optimised for a wide range of molecular weights according to known techniques. Charged or polar molecules in particular are absorbed well. Therefore, as a hypothesis, it appears that the solid hydrogel body may be effective by absorbing toxins produced as a result of the infection and/or by removing low molecular weight growth- supporting factors.
  • Infection can thus be an abnormal proliferation of one or more micro-organisms with respect to the normal state. This may be the result of a change in physiological conditions within the patient as a whole or in a specific region of the patient's body (e.g. a vaginal pH change).
  • the absence of active agent in the hydrogel body of the present invention may be positively beneficial in maximising the number of absorptive sites available for absorption of low molecular weight species from the local microenvironment.
  • the objective of this study was to assess the absorption potential of the hydrogel polymer.
  • This example presents data from in-vitro studies to investigate the absorption of a toxin, gliotoxin (mol.wt. 326) and three amino acids, tryptophan, tyrosine, and phenyl-analine. Gliotoxin is recognised as the agent causing reddening and swelling of "Che epithelial tissue during candidiasis infection. The amino acids are utilised for growth by fungi and bacteria, including opportunistic and pathogenic agents.
  • the in-vitro system consisted of aqueous preparations of medium with known concentrations of solute. The hydrogel bodies were added and the concentrations of solutes in the medium measured over time.
  • the concentration in the surrounding solution would decrease as the hydrogel swelled. However, if there was no preferential uptake the concentration of solute would remain constant. If preferential exclusion occurred the concentration of the solute would increase accordingly in the surrounding medium.
  • Solutions of aqueous media were prepared in triplicate with gliotoxin (at pH 4 and 7) and in duplicate with individual amino acids. Hydrogel bodies were added and the solution concentrations measured with time.
  • Solution concentrations were measured at times 3 , 6 12, and 24 hours (gliotoxin) and 2, 4, 6, 8 and 24 hours (amino acids) .
  • the concentration of gliotoxin was measured by an HPLC method.
  • the sample was applied onto a Supelcosil C-18 (150mm x 4.6mm i.d.) column employing a mobile phase which was a phosphate buffer (pH4) in methanol (35/65 v/v) at a flow rate of lml/min.
  • the pump was a Hitachi 655 and injection was via a Reodyne manual injection device with 20 ⁇ l loop. Detection was carried out at 254nm using a linear UV106 detector.
  • the standard preparation comprised 600 ⁇ g/ml of gliotoxin in methanol.
  • Amino acids were detected by UV absoption at 280nm.
  • the data indicate that gliotoxin concentration decreases with hydrogel present and without (control) .
  • the decrease in concentration is more rapid at lower pH values.
  • the decrease in concentration is more rapid with hydrogel present.
  • Gliotoxin is produced during candidiasis (Thrush) by the yeast Candida albicans.
  • the presence of gliotoxin in vaginal fluid has been associated with a number of clinical manifestations such as reddening and swelling of the epithelial tissue in the vaginal canal.
  • the absorption of gliotoxin from the vaginal fluid as the hydrogel swells may reduce its concentration in the local environment and therefore reduce the clinical symptoms and/or manifestations .
  • the hydrogel has also been demonstrated to preferentially imbibe the low molecular weight amino acids.
  • the removal of amino acids from the vaginal fluid during the disease states may affect the nutrient availability within the local microenvironment and resultantly affect the growth and survival of the disease-causing microorganism(s) . This may provide an opportunity for the normal vaginal microflora to re-colonise and aid a return to the non-diversified state.
  • EXAMPLE 2 Treatment of Va ⁇ inal Candidiasis in-vivo ⁇
  • Table 2 shows primary efficacy data in the per- protocol group.
  • the primary efficacy variables were the clinical and global assessments of vaginal candidiasis after three days of double-blind treatment. The global assessment was based on a patient questionaire and the appearance of the perineum. The outcome was recorded as cured, improved or not improved. Analyses were conducted on the per-protocol group and the intent-to-treat group. The clinical assessment was based on the clinician's examination.
  • the clinical assessment on day 28 was the patient's own assessment of itching, discharge and redness. Analyses were conducted on the per-protocol group and the intent-to- treat group. It can be seen that on day 3 by microbiological assessment, 60% of the patients considered their condition to be better and 40% no better. On day 7, 80% were better by global and clinical assessment and 55.6% were better by microbiological assessment. At day 28, 80% were better by clinical assessment.
  • Table 4 shows culture results from vaginal swabs in the per-protocol group. Vaginal swabs were taken at baseline, day 3 and day 7 of the study. It shows that at day 3, 50% of patients were cured (60% were cured or improved). At day 7, 57.1% were cured (71.4% cured or improved) .
  • Figure 5 shows a summary of primary efficacy and secondary efficacy results in the intent to treat group (including all vaginal infections) . It can be seen that there are significant rates of cure or improvement in all assessments.
  • Brown D. Jr. et al. J Reprod Med 31(11)1045-1048 (1986) reported studies using butoconazole vaginal cream in the treatment of vulvovaginal candidiasis in comparison to miconazole and a placebo.
  • the cure rate at 8 days and 30 days judged by mycological and clinical evaluation was 23% (placebo) , and 43 to 58% for butoconazole treatment at various treatment times and application rates.
  • a cure rate of 54% was reported for miconazole treatment.
  • the cure and improvement rates of the present invention are substantially greater than the placebo effect in Brown et al.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un corps hydrogel solide qui ne renferme aucun agent pharmaceutiquement actif. Ce corps s'utilise en tant que tel pour le traitement d'infections bactériennes ou virales. Il se prête à l'administration par voie vaginale, rectale ou orale. Il convient également comme pansement pour blessures. Ce corps convient aussi au prélèvement d'échantillons à des fins de diagnostic.
PCT/GB1999/001721 1998-06-17 1999-06-16 Corps hydrogel WO1999065435A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43779/99A AU4377999A (en) 1998-06-17 1999-06-16 Hydrogel body

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9812965.3A GB9812965D0 (en) 1998-06-17 1998-06-17 Hydrogel body
GB9812965.3 1998-06-17

Publications (1)

Publication Number Publication Date
WO1999065435A1 true WO1999065435A1 (fr) 1999-12-23

Family

ID=10833849

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/001721 WO1999065435A1 (fr) 1998-06-17 1999-06-16 Corps hydrogel

Country Status (3)

Country Link
AU (1) AU4377999A (fr)
GB (1) GB9812965D0 (fr)
WO (1) WO1999065435A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3812856A (en) * 1972-05-17 1974-05-28 Procter & Gamble Hydro-dissociative agglomerate tampon
US3940542A (en) * 1974-06-18 1976-02-24 Union Carbide Corporation Polyurethane hydrogel fibers and tapes and composites with natural and other synthetic fibers or films
US4634672A (en) * 1983-04-08 1987-01-06 Bayer Aktiengesellschaft Immobilization of cells in polyurethane hydrogel
EP0536875A1 (fr) * 1991-08-07 1993-04-14 Paul Hartmann Aktiengesellschaft Pansement à base d'hydrogel
WO1998006364A1 (fr) * 1996-08-08 1998-02-19 The Procter & Gamble Company Macrostructure absorbante realisee a partir de melanges de differents polymeres absorbants et formant un hydrogel, aux fins de presenter un meilleur pouvoir de traitement de fluides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3812856A (en) * 1972-05-17 1974-05-28 Procter & Gamble Hydro-dissociative agglomerate tampon
US3940542A (en) * 1974-06-18 1976-02-24 Union Carbide Corporation Polyurethane hydrogel fibers and tapes and composites with natural and other synthetic fibers or films
US4634672A (en) * 1983-04-08 1987-01-06 Bayer Aktiengesellschaft Immobilization of cells in polyurethane hydrogel
EP0536875A1 (fr) * 1991-08-07 1993-04-14 Paul Hartmann Aktiengesellschaft Pansement à base d'hydrogel
WO1998006364A1 (fr) * 1996-08-08 1998-02-19 The Procter & Gamble Company Macrostructure absorbante realisee a partir de melanges de differents polymeres absorbants et formant un hydrogel, aux fins de presenter un meilleur pouvoir de traitement de fluides

Also Published As

Publication number Publication date
GB9812965D0 (en) 1998-08-12
AU4377999A (en) 2000-01-05

Similar Documents

Publication Publication Date Title
García et al. Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin
Morgado et al. Ibuprofen loaded PVA/chitosan membranes: A highly efficient strategy towards an improved skin wound healing
US4364929A (en) Germicidal colloidal lubricating gels and method of producing the same
US20210361822A1 (en) Functional wound dressing
EP2637730B1 (fr) Dispositifs intravaginaux pour l'administration régulée de lubrifiants
US8821933B2 (en) Polymers and hydrogels
CN111154149A (zh) 一种水凝胶及其制备方法与敷料
EP0742022A4 (fr) Hyrogel biocompatible
EP0918510A1 (fr) Complexes bioadhesifs de medicaments antifongiques ou antiprotozoaires du type polycarbophil et azole
EP1356831A1 (fr) Pansement à base de cellulose microbienne pour le traitement de plaies chroniques
EP3034103A1 (fr) Éponge de Collagène
EP2331086A2 (fr) Nouvelle formulation
CN103159967B (zh) 一种具有自抗炎功能的胶原基海绵伤口敷料的制备方法
CN108158995A (zh) 一种含有壳聚糖的妇科用抗菌泡沫剂及其制备方法
US4778825A (en) Macrophage stimulation by quadrol
EP0136013B1 (fr) Procédé de fabrication d'un distributeur biodégradable de médicaments et distributeur de médicaments produit par ce procédé
WO2000014155A1 (fr) Hydrogels solides utilisables pour l'administration d'agents a activite biologique
CN111973801B (zh) 一种抗炎修复的水凝胶及其制备方法
US20030203013A1 (en) Microbial cellulose wound dressing for treating chronic wounds
WO1999065435A1 (fr) Corps hydrogel
CN108354951A (zh) 一种促进创口愈合的富氧凝胶剂、制备方法及应用
KR101971834B1 (ko) 카복시메틸셀룰로오스 및 하이드록시에틸 아크릴레이트의 공중합체를 포함하는 ph 감응형 하이드로겔
Hosaka et al. In vivo evaluation of ocular inserts of hydrogel impregnated with antibiotics fop trachoma therapy
CN104274494B (zh) 一种美洲大蠊外用制剂及其制备方法
JP5788896B2 (ja) 膀胱疾患の治療のための医薬組成物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase