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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants

Definitions

• the present invention relates to therapeutic combinations of (-)-(lS, 4R) -4-[2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2-eyclopentene-1-methanol (15921)89) and non- nucleoside reverse transcriptase inhibitors (NNRTIs), which have anti-HIV activity.
• NRTIs non- nucleoside reverse transcriptase inhibitors
• the present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors.
• the therapeutic agent 15921 ) 89 (European Specification EP0434450) is a promising anti- HIV ehemotherapeutic candidate (International Conference on Antiviral Research, April 23, 1995) showing potent activity against Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome (AIDS), low cytotoxicity and excellent penetration into the brain which is important for the treatment of AIDS and
• HIV linked central nervous system conditions such as AIDS dementia complex.
• RT reverse transcriptase
• the reverse transcriptase comprises polymerase and ribonuclease components which together are responsible for the transcription of viral RNA into double-stranded DNA prior to integration in the host cell genome.
• Reverse transcriptase inhibitors such as zidovudine didanosine, zalcitabine, and 1592U89 are all nucleosides which rely on cellular kinases to convert them into their triphosphates, which are competitive inhibitors of the natural substrate for RT.
• An attractive alternative strategy is the use of suitable non-nucleoside reverse transcriptase inhibitors.
• Non-nucleoside reverse transcriptase inhibitors which have been synthesized to date include HEPT, TIBO derivatives, atevirdine, L-ofloxacin, L-697,639, L-697-661 , nevirapine (BI-RG-587), loviride ( ⁇ -APA), delavuridine (BHAP), phosphonoformic acid, benzodiazepinones, dipyridodiazepinones, 2-pyridones, bis(heteroaryl)piperazines, 6- substituted pyrimidines, imidazopyridazines, 1 ,4-dihydro-2H-3,1-benzoxazin-2-ones, such as (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1- benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropy
• a further feature of the present invention is a combination comprising 1592U89, a NNRTI, and a second reverse transcriptase inhibitor, for example lamivudine.
• a second reverse transcriptase inhibitor for example lamivudine.
• a combination comprising 1592U89, a NNRTI, and a HIV protease inhibitor.
• the ratios of the components of such combinations will conveniently be the same as the ratios of the relevant compounds in the double combinations of the invention.
• protease inhibitor compounds include those disclosed in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501 , WO 95/16688, W0/US94/13085, W0/US94/12562, US 93/59038, EP 541 168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701 , WO 95/32185, and U.S. Patent No.
• Another aspect of the present invention is a combination comprising 1592U89, a second reverse transcriptase inhibitor, for example, lamivudine, a NNRTI, and a HIV protease inhibitor.
• a second reverse transcriptase inhibitor for example, lamivudine, a NNRTI, and a HIV protease inhibitor.
• the ratios of the components of such combinations will conveniently be the same as the ratios of the relevant compounds in the double or triple combinations of the invention.
• physiologically functional derivative includes any physiologically acceptable solvate, salt, ether, ester, salt of such ester, or solvates of any such salt, ether or ester, of 1592U89 or NNRTI(s); or any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
• Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, ri-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C,_ 4 alkyl, or C,_ 4 alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L- valyl or L-isoleucyl); and (4) phospho
• any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
• Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
• Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
• Preferred derivatives of 1592U89 are the mono-, di-, and tri-phosphate esters of (1 R, 4S)-9-[4-(hydroxymethyl)-2-cyclopenten-1 -yl]guanine (carbovir).
• physiologically acceptable salts of 1592U89 or NNRTI(s) and their physiologically acceptable derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 (wherein X is C,_ 4 alkyl).
• an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 (wherein X is C,_ 4 alkyl).
• Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorgainic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids.
• Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na , NH 4 and NX 4 (wherein X is a C, ⁇ alkyl group).
• salts of 1592U89 or NNRTI(s) will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
• salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
• Preferred salts of 1592U89 are the succinate salt and the hemisulphate salt.
• Combinations of 1592U89, or a physiologically functional derivative thereof, and NNRTI(s) or a physiologically functional derivative thereof, including combinations containing one or more reverse transcriptase inhibitor(s), or physiologically functional derivatives thereof, and one or more HIV protease inhibitor(s), or physiologically functional derivatives thereof, may hereinafter be referred to as combinations according to the invention.
• the present invention further provides combinations according to the invention for use in the treatment of an HIV infection including infections with HIV mutants bearing resistance to nucieoside inhibitors, particularly zidovudine, lamivudine, ddl, ddC or d4T or combinations thereof and HIV protease inhibitors.
• the combinations according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
• the present invention provides a method for the treatment of an HIV infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a combination of 1592U89, or a physiologically functional derivative thereof, and at least one NNRTI or a physiologically functional derivative thereof, or other combinations according to the invention.
• a method for the treatment of an HIV infection in an infected animal for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a combination of 1592U89, or a physiologically functional derivative thereof, and at least one NNRTI or a physiologically functional derivative thereof, or other combinations according to the invention.
• Reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
• the compounds of the combination may be administered simultaneously, either in the same or different pharmaceutical formulations or sequentially. If there is sequential administration, the delay in administering the second and any subsequent active ingredient should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. It will also be understood that the compounds of the combination or the physiologically functional derivatives of any thereof, whether presented simultaneously or sequentially, may be administered individually or in multiples or in any combination thereof. 1592U89 and NNRTI(s) are preferably administered simultaneously or sequentially in separate pharmaceutical formulations, most preferably simultaneously.
• the present invention also provides the use of 1592U89 in the manufacture of a medicament for administration simultaneously or sequentially with at least one NNRTI for the treatment and/or prophylaxis of HIV infections and associated clinical conditions hereinbefore described. It will be appreciated that 1592U89 and at least one NNRTI may be used in the manufacture of the above medicament.
• the synergistic effects of the combination of 1592U89 and a NNRTI or a physiologically functional derivative of any thereof may be seen over a ratio, for example, of 1 to 10: 1 to 20 (by weight), preferably 1 to 5: 1 to 10 (by weight), particularly 1 to 2: 1 to 3 (by weight).
• Convenient ratios of 1592U89 to a NNRTI include 1 :1 , 1 :1.5, 1 :2, 1 :3, and 1 :4.
• the synergistic effects of the combination of 1592U89, a NNRTI and a HIV protease inhibitor or a physiologically functional derivative of any thereof may be seen over a ratio, for example, of 1 to 10: 1 to 20: 1 to 20 (by weight), preferably 1 to 5: 1 to 10:1 to 10 (by weight), particularly 1 to 2:1 to 3:1 to 3 (by weight).
• Convenient ratios of 1592U89: NNRTI: HIV protease inhibitor include 1 :1 :1.5, 1 :1.5:2, 1 :2:3 and 1 :3:4.
• each compound may be employed in the combination in an amount at which it exhibits antiviral activity when used alone.
• the amount of a combination of 1592U89 and one or more NNRTIs required to be effective as an anti-HIV agent may, of course, vary and is ultimately at the discretion of the medical practitioner.
• the factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.
• a suitable dose of 1592U89 for administration to a human for treatment of an HIV injection may be in the range of 0.1 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 3 to 90 mg per kilogram body weight per day and most preferably in the range 5 to 60 mg per kilogram body weight per day.
• a suitable dose of a NNRTI for administration to a human may be in the range of 1 to 100 mg per kilogram body weight per day, advantageously in the range of 3 to 70 mg per kilogram body weight per day, preferably in the range of 5 to 60 mg per kilogram body weight per day.
• a suitable dose of a protease inhibitor for administration to a human may be in the range of 5 to 100 mg per kilogram body weight per day, advantageously in the range of 8 to 70 mg per kilogram body weight per day, preferably in the range of 8 to 50 mg per kilogram body weight per day.
• the desired dose may preferably be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
• These sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1500 mg, preferably from 5 to 1000 mg, most preferably from 10 to 700 mg of active ingredient per unit dosage form.
• the dose may be administered as a continuous infusion.
• the components of the combination which may be referred to as active ingredients may be administered for therapy to an animal e.g. a mammal including a human in a conventional manner.
• compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
• the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
• the individual components of the combination are administered separately they are generally each presented as a pharmaceutical formulation.
• the references hereinafter to formulations refer unless otherwise stated to formulations containing either the combination or a component thereof.
• a combination of 1592U89 and one or more NNRTIs, or a physiologically functional derivative of any thereof may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
• a convenient unitary dosage formulation contains the active ingredients in amounts of from 50 mg to 3 g each, for example, 100 mg to 2 g.
• a typical unitary dosage may contain 50 mg to 3 g each of 1592U89 and and one or more NNRTIs, advantageously 100 mg to 2 g each of 1592U89 and one or more NNRTIs.
• a unitary dosage form comprising at least two active ingredients selected from 1592U89 and one or more
• NNRTIs or physiologically functional derivatives of any thereof and a pharmaceutically acceptable carrier therefor are included in the NNRTIs or physiologically functional derivatives of any thereof and a pharmaceutically acceptable carrier therefor.
• compositions are often prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack.
• Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions.
• the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions and, therefore, lead generally to more successful treatment.
• a multiple, for example, double or triple, pack comprising at least one active ingredient 1592U89 and one or more NNRTI(s) of the combination of the invention and an information insert containing directions on the use of the combination of the invention.
• the invention provides a patient pack comprising in association for separate administration 1592U89 or a physiologically functional derivative thereof together with at least one NNRTI or a physiologically functional derivative thereof.
• Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
• Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
• the tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
• Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
• Topical administration may also be by means of a transdermal iontophoretic device.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
• Suitable carriers include cocoa butter and other materials commonly used in the art.
• the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
• Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
• the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Preferred unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
• formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
• the compounds of the combination of the present invention may be obtained in a conventional manner.
• 1592U89 may be prepared by the method described in European Specification EP0434450, PCT application PCT/GB/4500225, PCT/GB95/02014, U.S. Patent No.
• NNRTIs may be prepared by any method known to persons skilled in the art, for example those methods disclosed in EPA 0509398, EP429987, U.S. 5,366,972, EP482481, EP667348, U.S. 5,571 ,912, U.S. 5,532,358, WO 94/02155, EP582455, WO 95/20389, WO
• HIV protease inhibitors may be prepared by any method known to persons skilled in the art, for example those methods disclosed in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501 , WO 95/16688, WO/US94/13085, W0/US94/12562, US 93/59038, EP 541 168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701 , WO 95/32185, and U.S. 5,256,783, incorporated herein by reference hereto.
• Active ingredient denotes 1592U89, NNRTI(s), HIV protease inhibitor(s), or multiples thereof or a physiologically functional derivative of any of the aforementioned compounds.
• Example 1 Tablet Formulation
• formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
• formulations D and E are prepared by direct compression of the admixed ingredients.
• the lactose in formulation E is of the direct compression type (Dairy Crest-
• the formulation is prepared by wet granulation of the ingredients with a solution of povidone followed by the addition of magnesium stearate and compression.
• a capsule formulation is prepared by admixing the ingredients of formulation D in Example 1 above and filling into a two-part hard gelatin capsule.
• Formulation B (infra) is prepared in a similar manner.
• Capsules of formulation C are prepared by melting the Macrogel 4000 B.P., dispersing the active ingredient in the melt and filling the melt into a two-part hard gelatin capsule.
• Capsules of formulation D are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
• Vitamin E TPGS obtained from Eastman Chemical Co.
• TPGS obtained from Eastman Chemical Co.
• PEG400 polyethylene glycol 400
• the resultant solution was heated to 65 C.
• 1.5 kg of active ingredient was dissolved in the liquefied solution of Vitamin E TPGS and PEG 400.
• 0.395 kg of propylene glycol at room temperature was added and mixed until a homogenous solution was formed.
• the solution was cooled to 28-35 C. The solution was then de-gassed.
• the mixture was preferably encapsulated at 28-35 C at a fill weight equivalent to 150 mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatin capsules using a capsule filling machine.
• the capsule shells were dried to a constant fill moisture of 3-6°/o water and a shell hardness of 7-10 newtons, and placed in a suitable container.
• controlled release capsule formulation is prepared by extruding ingredients a,b, and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mq/capsule
• Active Ingredient 200 Hydro chloric Acid Solution 0.1 M or
• the active ingredient is dissolved in most of the water (35° - 40° C) and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate.
• the batch is then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.
• the active ingredient is dissolved in the glycofurol.
• the benzyl alcohol is then added and dissolved, and water added to 3 ml.
• the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml amber glass vials (type 1).
• Purified Water q.s. to 5.00 ml
• the active ingredient is dissolved in a mixture of the glycerol and most of the purified water.
• An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbital solution and finally the flavor.
• the volume is made up with purified water and mixed well.
• Witepsol H15 is melted in a steam-jacketed pan at 45 C maximum.
• the active ingredient is sifted through a 200 ⁇ m sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45 C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
• the entire suspension is passed through a 250 ⁇ m stainless steel screen and, with continuous stirring, is allowed to cool to 45 C.
• 2.02 g of the mixture is filled into suitable, 2 ml plastic molds. The suppositories are allowed to cool to room temperature.
• Example 7 Pessaries mg/pessary Active Ingredient 250

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• 1998
  • 1998-05-14 AU AU79123/98A patent/AU7912398A/en not_active Abandoned
  • 1998-05-14 BR BR9809127-1A patent/BR9809127A/pt not_active Application Discontinuation
  • 1998-05-14 AR ARP980102250A patent/AR012702A1/es unknown
  • 1998-05-14 CA CA002289655A patent/CA2289655A1/en not_active Abandoned
  • 1998-05-14 JP JP54991198A patent/JP2001525839A/ja active Pending
  • 1998-05-14 PE PE1998000375A patent/PE74799A1/es not_active Application Discontinuation
  • 1998-05-14 WO PCT/EP1998/002836 patent/WO1998052570A1/en not_active Application Discontinuation
  • 1998-05-14 EP EP98929309A patent/EP0979082A1/en not_active Withdrawn
  • 1998-05-15 CO CO98027484A patent/CO4950569A1/es unknown
  • 1998-05-15 HR HR9719883.2A patent/HRP980264A2/hr not_active Application Discontinuation
  • 1998-05-15 MA MA25076A patent/MA26496A1/fr unknown
• 1999
  • 1999-11-16 NO NO995620A patent/NO995620L/no not_active Application Discontinuation

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