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
  • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K9/0031—Rectum, anus
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
• • 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
  • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
  • C08L1/08—Cellulose derivatives
  • C08L1/26—Cellulose ethers
  • C08L1/28—Alkyl ethers
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
  • C08L1/08—Cellulose derivatives
  • C08L1/26—Cellulose ethers
  • C08L1/28—Alkyl ethers
  • C08L1/286—Alkyl ethers substituted with acid radicals, e.g. carboxymethyl cellulose [CMC]
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
  • C08L5/04—Alginic acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
  • C08L5/06—Pectin; Derivatives thereof

Definitions

• This invention relates to new and novel pharmaceutical compositions which are suitable for use as a suppository base and which may be formed into suppositories for rectal insertion, as well as used as a carrier for pharmacologically active substances to be administered by suppository route.
• this invention relates to hydrogen-bonded compounds comprising polymeric poloxyethylene glycol, having a molecular weight of from 200 to 6000, which are hydrogen-bonded to polymeric vegetable polycyclohexose compounds, as for example, gum guar, algin, pectin and carboxymethylcellulose.
• This hydrogen-bonded compound provides an advantageous carrier for pharmacologically active substances, or it may be formed into suppositories which may be used directly for insertion into the rectum.
• Suppositories are conical or elliptical medicated solids intended for insertion into one of the several orifices of the body, excluding the mouth. Insertion into the body should be simple and easy, without incidental tissue trauma or pain. After insertion, the suppository should disintegrate readily, that is, either melt, dissolve or disperse, thereby distributing the active therapeutic substances and/or the suppository base within the body cavity. Suppositories should be of a shape to permit the easy insertion into the particular body cavity for which they are intended and be of suflicient weight to provide an indicated therapeutic dose of the drug, when serving as a pharmaceutical carrier.
• a suppository may be utilized to obtain either a local or systemic effect.
• the action of a drug administered by suppository, but which is not absorbed through the mucous membrane lining the orifice of insertion, is considered to be a local effect in contrast to the effect resulting after the use of a suppository from which the active ingredients are absorbed into the systemic circulation.
• Emollients, astringents, antibiotics and certain anti-inflammatory agents are examples of classes of compound which may be utilized in combination with a suppository base to achieve a local effect, whereas a Wide variety of drugs, such as hormones, analgesics, sedatives, alkaloids, certain soluble inorganic and organic synthetic therapeutic compounds, have been successfully administered by the suppository route fortheir systemic effect.
• drugs such as hormones, analgesics, sedatives, alkaloids, certain soluble inorganic and organic synthetic therapeutic compounds
• the rich blood supply of the tissues of the rectum and vagina provide a suitable means for obtaining a systemic blood level of a drug, thereby avoiding the upper gastrointestinal tract which is not desirable in those instances where individual patient intolerance to a drug, or destruction of the drug by the digestive juices, prevents its oral administration.
• the sytemic onset of action of drugs administered my the suppository route may be more prompt than when the same drug is administered orally.
• the difference in time is usually ascribed to the longer period that such drugs remain in the stomach after oral administration.
• the pharmacologic response is observed within 3 to 5 minutes after introduction into the rectum by suppository medication, an effect which is much more rapid than that observed after the oral use if the same substance.
• Suppositores may be prepared from either water-immiscible fatty substances or water-miscible hydrophilic substances.
• fatty substances which have been suggested as bases for suppositories are lard, theobroma oil, resins and fats.
• this group of suppository compounds are included such substances as white wax, spermacetic, oleic acid and stearic acid mixtures, and hydrogenated vegetable oils.
• the aqueous immiscibility of the fatty suppository substance is a general limitation of this class of compounds being used as carriers for certain pharmacologically active polar compounds.
• the hydrophobic character of the lipid material causes pooling in the essentially aqueous character of the rectum, and thereby inhibits the release and transfer of the active material.
• This nonuniform distribution of medicament results in both poor absorption and an uneven rate of absorption.
• Some fatty components, such as white wax and spermaceti do not melt at body temperature and require other additives to provide a composition which will permit disintegration of the suppository mass at body temperature.
• the vegetable oils and waxes have still another disadvantage in that rancidity will occur unless suitable preservatives are added, while the use of oleic and stearic acid mixtures is limited for those medicaments which do not react with these acid components.
• the mixture of organic acids may cause a local issue irritant elfect in some individuals.
• hydrophilic aqueous miscible substances such as the polyoxyethylene glycols, glycerinated gelatin and polymerized ethylene oxide derivatives of glycols.
• these compounds possess disadvantages which detract from their use and are unsuitable for use with a number of drugs because of pharmaceutical incompatability. This is especially important when considering drugs which undergo hydrolytic decomposition in the presence of water and the glycols.
• the aqueous miscible suppository bases are prepared to contain a certain amount of water and also since these bases are hygroscopic, special packaging techniques must be used to maintain their stability under storage conditions.
• Suppositories are manufactured by two basic processes-the hot pour technique and the compressionextrusion technique.
• the hot pour technique involves the pouring of the molten suppository composition into a suitable mold, which is then cooled below the melting point of the suppository base. Upon hardening, it assumes the desired form and shape.
• the compression-extrusion technique involves the packing of the mold with the suppository base under pressure. This method has the advantage that the base is solid at all times and therefore the dispersed materials do not sediment as they would when liquid compositions are utilized during the hot pour m9 technique.
• the high speed production of suppositir-ies required by commerce makes the extrusion technique a preferred method.
• the hard suppository is more apt to cause tissue trauma to the sensitive ano-rectal tissues of the infant as well as in those patients presenting ano-rectal disease, such as hemorrhoids, ano-rectal fistula and fissure, or during the immediate post-operative period following proctologic surgery.
• a polycyclohexose compound as for example, guar gum, algin, carboxymethylcellulose, and pectin
• polyoxyethylene glycol having a molecular weight of from 200 to 6000 which are known in commerce as Carbowaxes
• a hydrogen bonded chelation compound is formed.
• the new suppository compound is a homogeneous substance, having no reproducible physical and chemical properties and which is capable of being shaped and formed into suppositories which have new desirable and advantageous properties.
• the new suppository compound is compatible with pharmacologically active substances and disintegrates, both rapidly and uniformly, after insertion into the body.
• the resistance determined for gum guar at 1 percent concentration and at pH 5.55 is 1225 ohms and the conductance value is 808 mhos X 10
• the conductance determined for polyoxyethylene glycol, having an average molecular weight of 400, and which is known in the trade as Carbowax 400, at 1 percent concentration and pH 6.15 has a resistance of 17,300 ohms and a conductance of 57.5 mhos
• the hydrogen-bonded chelation compound formed by guam guar and polyoxyethylene glycol-400 at the same concentration has a pH of 5.95, has an average resistance of 1420: 130 ohms and an average conductance of 705 mhos 10
• the values determined are reproducitale and characteristic for the particuluar hydrogen-bonded chelation compound formed.
• polyoxyethylene glycol 4,000 When larger molecular weight polyoxyethylene glycol compounds are used as reagents, such as polyoxyethylene glycol 4,000, the degree of hydrogen-bonded formation is lessened, so that, for example, the conductance for the chelation compound of gum guar-polyoxyethylene glycol 4,000 has a conductance of 795 mhos 10 If hydrogen-bond chelation compound formation has not occurred, then the conductance for the mixture would be 865.5 n1h0s 10 When a suppository prepared with this new compound is inserted into the body, the hydrophilic character of the base causes it to absorb moisture, producing a uniform disintegration and dispersion of the suppository.
• the resultant increases surface area of the dispersed hydrophilic materials coats the hydrophilic ano-rectal mucosa to provide intimate contact with the tissue barrier, thereby facilitating absorption for those substances that tended to enter the systemic circulation or, to permit the full therapeutic activity for those agents intended to exert a local effect.
• This unique effect is achieved because of the desirable coefficient of expansion of the hydrogen-bonded chelation compound which results in a surface shearing action which produces a rapid disintegration of the suppository.
• the unique physical characteristics of the hydrogen-bonded chelation suppository compound permits high pressure rapid molding without surface liquifaction and does not require additive stabilizers or lubricants to facilitate the ejection of the formed suppository from the mold.
• the hot pour technique is used, the high viscosity of the suppository mass retards sedimentation so that a uniform dispersion is maintained even in the liquid state.
• the new suppository compound does not turn rancid and is stable under the ordinary conditions of storage.
• the new suppository base is non-irritating to the anorectal mucosa and may be introduced even in the immediate post-operative period.
• the selected polycyclohexose compound is mixed with the polyoxyethylene glycol and the mixtured warmed to a temperature of between 50 C. and C., for a period of at least 15 minutes. While the lower temperature range of 40 C. may be used for the lower molecular weight polyoxyethylene glycols, as for example, those polyoxyethylene glycols having a molecular weight of from 200 to 600, the upper temperature range of 65 C. is utilized for those members of the polyoxyethylene glycols series having a molecuular weight of from 1000 to 6000. During the warming phase, the mixture is stirred so that a uniform distribution of the polycyclohexose compound in the polyoxyethylene glycol is achieved.
• the ratio of polycyclohexose compound to polyoxyethylene compound required to form the desired hydrogenbonded chelation compound ranges from 5 parts by weight of the polycyclohexose and 95 parts by weight of the polyoxyethylene glycol, to 40 parts by weight of the polycyclohexose to 60 parts by weight of the polyoxyethylene glycol.
• a preferred range of ratio concentration of the components is between 10 parts to 25 parts by weight of the polycyclohexose to 90 parts to parts by weight of the polyoxyethylene glycol.
• the exact ratio of components selected to form the new hydrogen-bonded chelation compound suppository base depends upon the particular intended use of the suppository and its manufacturing technique to be employed.
• a suppository intended to be manufactured by high speed compression apparatus will require a higher degree of hydrogenbonding to withstand the increased pressures and stresses and consequently the upper limits of range of the ratio of concentration of components will be used.
• the upper concentrations will be preferred because of the increased viscosity of the molten new suppository compound.
• the lower ranges of the ratio of concentration of components are more desirable to derive a more pliable suppository mass.
• this new suppository base material When it is desired to utilize this new suppository base material for the manufacture of pharmaceutically acceptable suppositories, the appropriate quantity of prepared new suppository compound is placed in a suitable container and melted over a water bath. Should it be preferred to utilize the dry composition, then the solid suppository compound is subdivided into coarse granular particles, either by passing through a comminuting apparatus or by trituration. The pharmacologically active material is then added to the suppository base whether molten or shredded and is uniformly dispersed. The suppositories are then manufactured either by compressionextrusion or through molding by the hot pour technique.
• drugs which may be incorporated with the suppository base and then shaped into suppositories of suitable size for therapeutic administration are, antibiotics, as for example, tetracycline, penicillin, chlortetracycline, neomycin, bacitracin, polymyxin and the sulfa drugs; antiseptic agents; germicides; contraceptive agents; hormones, such as testosterone, estrone, hexesterol, stilbestrol, thyroid hormone, thyroid substance, thyroxin; the steroids, such as hydrocortisone, cortisone-alcohol, prednisolone; analeptic agents, such as caffeine, theophyllin and metrazole; diuretic compounds such as chlorthiazine, hydrochlorthiazine, fiuoromethiazine; sedative agents, such as barbituric acid derivatives, hydantoin derivatives, central nervous system stimulants, such as amphetamine; analgesic medication such as aspirin,
• Example 1 In a suitable container is placed 400 gms. of polyoxyethylene glycol-400 and 600 grams of polyoxyethylene glycol-1000. The mixture is warmed to about 50 C., until complete soiution is achieved and then 1 kilogram of polyoxyethylene glycol-6000 is added in small increments to the warm solution. When all of the polyoxyethylene glycol-6000 has been added, the mixture is stirred while 200 gms. of gum guar is added in small increments with stirring. After all of the gum guar has been added, the stirring is continued while the reaction mixture is warmed at a temperature of between 55 and 65 C. for one-half hour, after which time it is allowed to cool to room temperature.
• a cream colored waxy solid which has a melting point of 57-59 C.
• a 2 gm. sample is completely dispersed in ml. of water Within 20 minutes, at 37 C.
• the melting point of the compound is between 57 and 59 C., it may be molded at a temperature of C.
• the new base assumes a rigid form within one minute.
• the new compound may be worked with at temperature range of from room temperature to as high as C. It will be found that the suppositories are ejected rapidly and smoothly, and without sticking to the die.
• the hardness of the suppository is determined by the extent of hydrogen-bond formation between the polycyclohexose compound and the polyoxyethylene glycol.
• the range in concentration for the different molecular weight polyoxyethylene glycol compounds may vary with the desired texture of the suppository, while the hardness will depend directly upon the degree of hydrogen-bonded chelation linkage present.
• Example 2 In a suitable container is placed l600 gms. of polyoxyethylene glycol-400 and to this is added 600 gms. of gum guar. The mixture is warmed to about 50 C. and stirred for a period of one-half hour, after which time it is allowed to cool to room temperature. Upon cooling the compound becomes a creamy, waxy, solid having a melting point of 5 0 C. to 53 C. It has a complete dispersion in water at 37 C. within 20 minutes. The conductance of a 1 percent concentration at pH 5.95, is 705215 mhos X 10 This conductance value establishes that hydrogen-bonding occurs since the conductance for the new compound is less than the sum of the conductance values for the separate, individual components.
• Gum guar has a conductance of 808 mhos 10 and polyoxyethylene glycol-400 has a conductance of 46.5 mhos 10
• Example 3 In a suitable container is placed 700 gms. of polyoxyethylene glycol-4000 and 300 gms. of gum guar. The mixture is warmed to a temperature of 60 C. which is maintained over a period of 1 hour, with constant stirring. At the end of this time, the heating is stopped and the molten material is allowed to cool to room temperature. While cooling a hard, solid mass results which has a melting point of from 6l-63 C. A 2 gram sample shows complete dispersion in 20 ml. of water, at 37 C. within 20 minutes.
• Example 4 The pH of a 1 percent dispersion is 6.02 and it shows a conductance of 795 mhos 10
• Example 4 In place of the gum guar described in Examples 1 through 3 above, there may be substituted in equal quantities, algin, pectin and carboxymethylcellulose. The remainder of the steps being the same.
• Example 5 In place of the polyoxyethylene glycol400, polyoxyethylene glycol-1000, and polyoxyethylene glycol-6000 described in Examples 1 through 4 above, there may be substituted wholly, or in part, a polyoxyethylene glycol having a molecular weight range within 200 and 6000.
• the particular polyoxyethylene glycol to be used depends upon the desired texture in the finishedsuppository. When larger amounts of a lower molecular weight polyoxyethylene glycol are used, then the texture of the finished suppository will be more wax-like. Such a suppository will be less friable and may be prepared in long, narrow, rodlike shapes.
• the exact amount of each of the particular polyoxyethylene glycol to be used will depend upon the particular purpose and method of manufacture for the suppository.
• the formation of the hydrogen-bonded chelation compound occurs more readily with the lower molecular weight polyoxyethylene glycol compounds than with the higher molecular weight compounds. However, in all instances, hydrogen-bonded chelation compound formation may be shown through the measurement of the conductance value for the new compound formed.
• the hydrogen bonding bet-ween the gum guar and the polyoxyethylene glycol is clearly established by the unexpected finding of a conductance which is less than the sum of the separate conductance of the individual components. The remainder of the steps being the same.
• Example 6 To gms. of a compound prepared according to the method described in Examples 1 through 5 above, and which has been melted on a water-bath, at a temperature below 65 C., is added 15 gms. of powdered aspirin, U.S.P. The aspirin should be subdivided to at least standard mesh particle size, prior to adding to the molten base. The mixture is stirred to achieve uniform distribution of the aspirin and then removed from the water-bath to cool to room temperature. When the whole has solidified, the mixture is chilled and passed through a number 8 standard mesh screen. The powdered suppository material is then filled into a compression-extrusion apparatus fitted with a suitable mold, so that suppositories weighing 2 gm.
• each may be prepared. Should it be desired to use a hot pour molding technique, for the preparation of suppositories, then the molten mass is poured directly into the mold and allowed to cool therein. A mold of sufficient size and shape to prepare a 2 gm. suppository is utilized. The suppositories are administered from 1 to six times daily, depending upon the needs of the patient.
• Example 7 In place of aspirin used in Example 6 above, there may be substituted any of the following therapeutic compounds, or mixtures of these, as well as other compatible active therapeutic compounds, so that the concentration of the therapeutic agent, per suppository, will be within the active therapeutic range, as for example the range described for each of the compounds noted below.
• Range of concentration per Active agent suppository, mg:
• Theophyllin 5 to 30 Senna 5 to 300 Cascara 25 to 100 Isatin 5 to 15 Sodium liothyronine 5 mcg to 50 mcg.
• Suppositories prepared with these and other therapeutic agents which are pharmaceutically suitable for suppository administration, are stable and will result in the full desired therapeutic effect for the respective active ingredients.
• Such suppositories are administered from 1 to 6 times daily, depending upon the need of the patient, the pharmacologic effects of the active ingredient and the status of the disease present.
• Suppositories prepared according to the procedures described above are a desirable means of administering pharmacologically active materials. It will be found that these are completely dispersible in minimal quanties of aqueous fluid, usually within a period of 20 minutes, at
• the dispersion of the suppository is achieved through a unique action.
• the hydrophilic properties of the base adsorbs moisture, causing a unilateral swelling action.
• the expansion of the hyodrogen-bonded polycyclohexose moiety facilitates the uniform dispersion of the suppository base and the active ingredient.
• the hydrophilic character of the suppository base tends to aid adherence of the dispersed substances as a surface film on the mucosal wall of the body cavity. This intimate contact promotes the rapid transfer and absorption of pharmacologically active material. In the instances where the pharmacologically active material does not traverse the mucosal tissue, then the intimate tissue contact provided by such uniform dispersion of the suppository base and active ingredient, results in a superior local therapeutic effect.
• Example 8 Suppositories prepared from a compound obtained as a result of Examples 1 through 5 above, may be used to induce laxation or to provide an emollient coating to the ano-rectal mucosa.
• the suppository mass is shaped into suppositories, having an average weight of from 0.50 gms. to 2.0 gms. each.
• the suppositories may be manufactured by either the cold compression-extrusion technique or the hot pour method. Such suppositories may be inserted into the rectum from 1 to 4 times daily, depending upon the particular patient need.
• the use may be at morning and night.
• a protective elfect to the ano-rectal mucosa is dedesired, then a more frequent usage is indicated and the suppository may be inserted up to 4 times daily.
• a compound comprising a polymeric polycyclohexose compound selected from the group consisting of gum guar, pectin, algin, canboxymethylcellulose and mixtures of these and a polyoxyethylene glycol selected from the group consisting of polyoxyethylene glycols with a molecular weight of from 200 to 6000.
• a compound comprising from 5 to parts by weight of a polymeric polycyclohexose compound selected from the group consisting of gum guar, pectin, algin, carboxymethylcellulose and mixtures of these and from 5 to parts by weight of a polyoxyethylene glycol selected from the group consisting of polyoxyethylene glycol having a molecular weight of from 200 to 6000.
• a compound comprising 4 parts by weight of polyoxyethylene glycol-400, 6 parts by Weight of polyoxyethylene g1yco1-1000 and 10 parts by weight of polyoxyethylene glycol-6000 and 2 parts by Weight of gum guar.
• a compound comprising 16 parts by Weight of polyoxyethylene glycol-400 and 6 parts by weight of gum guar.
• a compound comprising 7 parts by Weight of polyoxyethy1ene glycol-4000 and 3 parts by Weight of gum guar.
• Carboxymethylcellulose-polyoxyethylene glycol Carboxymethylcellulose-po1yoxyethy1ene glycol- 15. Algin-polyoxyethylene glycol-400. 16. AIgin-polyoxyethylene glycol-6000.

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Citations (8)

• 1964
  • 1964-06-18 US US376260A patent/US3325472A/en not_active Expired - Lifetime
• 1965
  • 1965-06-14 BE BE665409D patent/BE665409A/xx unknown
  • 1965-06-15 DE DE19651645283 patent/DE1645283B2/de active Granted
  • 1965-06-16 LU LU48859D patent/LU48859A1/xx unknown
  • 1965-06-17 FR FR21256A patent/FR6802M/fr not_active Expired
  • 1965-06-17 NL NL6507808A patent/NL6507808A/xx unknown
• 1967
  • 1967-01-30 FR FR21263A patent/FR1472041A/fr not_active Expired

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