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WO2007117173A1 - Système, méthodes et produits de distribution de fluide - Google Patents

Système, méthodes et produits de distribution de fluide Download PDF

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Publication number
WO2007117173A1
WO2007117173A1 PCT/RU2006/000173 RU2006000173W WO2007117173A1 WO 2007117173 A1 WO2007117173 A1 WO 2007117173A1 RU 2006000173 W RU2006000173 W RU 2006000173W WO 2007117173 A1 WO2007117173 A1 WO 2007117173A1
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WO
WIPO (PCT)
Prior art keywords
fluid
composition
suppository base
circuit
suppository
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/RU2006/000173
Other languages
English (en)
Inventor
Alexander Valdimirovich Grachev
Dmitry Valentinovitch Morozov
Lev Alexandrovitch Denisov
Victor Mikhailovitch Kozlov
Ramil Usmanovitch Khabriev
Artyom Andreyevitch Chumakov
Liliya Alexandrovna Saburova
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.)
Biocad JSC
Original Assignee
Biocad JSC
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 Biocad JSC filed Critical Biocad JSC
Priority to PCT/RU2006/000173 priority Critical patent/WO2007117173A1/fr
Publication of WO2007117173A1 publication Critical patent/WO2007117173A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/41—Emulsifying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/50—Circulation mixers, e.g. wherein at least part of the mixture is discharged from and reintroduced into a receptacle
    • B01F25/51—Circulation mixers, e.g. wherein at least part of the mixture is discharged from and reintroduced into a receptacle in which the mixture is circulated through a set of tubes, e.g. with gradual introduction of a component into the circulating flow
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/45—Magnetic mixers; Mixers with magnetically driven stirrers

Definitions

  • TECHNICAL FIELD This invention relates to a system and method of dispensing a fluid.
  • Suppositories are solid dosage forms of medicine intended for administration via the rectum, vagina, or urethra. They are useful drug delivery systems when a patient cannot receive medicine orally, intravenously, or by injection (such as when a patient is vomiting, experiencing seizures, or has an obstruction of the upper gastrointestinal tract); when only a local effect is needed (such as when a patient has a lower gastrointestinal malady or vaginal infection); or when the medicine is not orally effective and an alternate route of administration is necessary (such as when medicine exhibits first-pass metabolism). Suppositories are compounded so as to melt, soften, or dissolve in the body cavity (where the temperature is approximately 37 0 C) and release the medication within.
  • Suppositories are generally made by combining an active ingredient with a molten suppository base.
  • This fluid mixture is continuously stirred and pumped through a fluid circuit to prevent hardening of the suppository base.
  • the fluid circuit includes a dispenser which delivers the mixture to a mold. When a portion of the mixture is poured into the mold and allowed to cool, it forms a solid suppository having the shape of the mold. Once the filled mold is replaced at the dispenser by an empty mold, the dispenser can deliver another portion of the mixture to the empty mold.
  • Some pharmaceutical ingredients can be unstable - in other words, a desired property of the ingredient (such as its pharmaceutical activity) decreases over time.
  • Environmental conditions can affect the stability of an ingredient. For example some conditions (for example, exposure to elevated temperatures, light, water, oxygen, agitation, or variations in pH) can decrease the stability of the ingredient, whereas other conditions (for example, the presence of a stabilizer) can increase the stability of the ingredient.
  • Each ingredient can respond differently to different conditions, such that conditions chosen to optimize the stability of one ingredient may be less than optimal for other ingredients.
  • Biologic pharmaceuticals in particular can be unstable when held at elevated temperatures, mechanically agitated, exposed to light, oxygen, extremes of pH, or even exposed to water.
  • a suppository manufacturing system can include a first fluid circuit for the suppository base, and a second fluid circuit for the mixture of the suppository base and the active ingredient.
  • the dispenser is located in the second fluid circuit. The unstable ingredient is added to the suppository base before the base enters the second circuit.
  • a fluid dispensing system in one aspect, includes a first fluid circuit, a second fluid circuit, and a fluid source.
  • the first fluid circuit is configured to circulate a first fluid and is fluidly connected to the second fluid circuit.
  • the fluid source is fluidly connected to the second fluid circuit and configured to supply a second fluid to the second fluid circuit.
  • the second fluid circuit is configured to mix the first fluid and the second fluid and to circulate the mixture.
  • the first fluid circuit can be fluidly connected to the second fluid circuit by a bridge.
  • the fluid source can be fluidly connected to the bridge.
  • the second fluid circuit can include a reservoir, and the bridge can be fluidly connected to the reservoir.
  • the reservoir can include a mixer.
  • the fluid connection between the bridge and the reservoir can be configured to tangentially supply fluid from the bridge to the reservoir.
  • the system can be configured to maintain the first fluid at a first temperature.
  • the system can be configured to maintain the second fluid at a second temperature.
  • the system can be configured to maintain the mixture at a third temperature.
  • the second fluid circuit can include a static mixer.
  • the second fluid circuit can include a fluid dispenser.
  • the system can further include a mold configured to accept fluid from the fluid dispenser.
  • a method of dispensing a fluid includes circulating a first fluid in a first fluid circuit, mixing the first fluid with a second fluid, and circulating the mixture in a second fluid circuit.
  • the method can include maintaining the first fluid at a first temperature while circulating in the first fluid circuit.
  • the method can include maintaining the second fluid at a second temperature prior to mixing.
  • the method can also include maintaining the mixture at a third temperature.
  • Mixing the first fluid with the second fluid can include introducing at least one fluid tangentially to a reservoir.
  • the method can include dispensing the fluid from the second fluid circuit.
  • the first fluid can be a hydrophobic fluid.
  • the second fluid can be an aqueous fluid. Mixing can include forming an emulsion of the first fluid and the second fluid.
  • the first fluid can include a suppository base.
  • the second fluid can include an active pharmaceutical ingredient.
  • the active pharmaceutical ingredient can be a biologic.
  • the active pharmaceutical ingredient can include an interferon.
  • a pharmaceutical composition includes a suppository base, a biologic having an unstable pharmaceutical activity, and a stabilizer selected to preserve the unstable pharmaceutical activity.
  • the suppository base can include an emulsion.
  • the suppository base can include a hard fat and an emulsifier.
  • the suppository base can be substantially hydrophilic.
  • the suppository base can be substantially free of a fat.
  • the suppository base can include a polyethyleneoxide.
  • the biologic can be an interferon.
  • the stabilizer can include an organic acid or a salt of an organic acid.
  • the organic acid can be succinic acid, citric acid, or acetic acid.
  • the composition can be in the form of a suppository.
  • a pharmaceutical composition includes a suppository base including a polyethylene oxide, an interferon, and succinic acid.
  • the suppository base can be substantially immiscible with water. Alternatively, the suppository base can be at least partially miscible with water.
  • This technology allows the manufacture of large amounts of pharmaceutical formulations that contain unstable ingredients. Because degradation of the unstable ingredient during manufacture is reduced, the resulting product can have improved uniformity of the unstable ingredient. When the unstable ingredient is also an active ingredient, the products have improved uniformity in biological activity, which can be important for satisfying regulatory requirements.
  • the system and method also minimizes the consumption of unstable ingredients, which often account for a major share of a drug's production costs.
  • FIG. 1 is a schematic depiction of a fluid dispensing system.
  • a fluid dispensing system 10 includes a first fluid circuit 20 which includes vessel 30 and pump 40 (in FIG. 1, arrows indicate the direction of fluid flow through the system).
  • Fluid circuit 20 includes piping or tubing for circulating a fluid.
  • Vessel 30 preferably includes mixer 35, such as a magnetically driven stir bar, or a motor-driven propeller. Mixer 35 can agitate first fluid 45 in vessel 30.
  • Pump 40 drives the flow of first fluid 45 through first circuit 20. Pump 40 can be, for example, a peristaltic pump or centrifugal pump.
  • First circuit 20 is fluidly connected to bridge 50. Fluid flow through the bridge is driven by pump 60, which can be, for example, a peristaltic pump or centrifugal pump.
  • System 10 can be configured to control the temperature of fluid 45.
  • vessel 30 can include a thermostatted temperature control system to maintain fluid 45 at a desired temperature, such as between 0 °C and 100 °C, between 15 °C and 70 °C, between, 20 °C and 50 0 C, or between 25 0 C and 45 °C.
  • Fluid circuit 20 can also be configured for temperature control, for example by being enclosed in a thermostatted enclosure.
  • Addition branch 70 is fluidly connected to bridge 50.
  • Addition branch 70 is configured to deliver second fluid 80 from second vessel 90 to bridge 50.
  • the system can be configured such that addition branch 70 delivers fluid directly vessel 110 without connection to bridge 50.
  • Pump 100 drives the flow of second fluid 80 from vessel 90 through the addition branch 70.
  • Vessel 90 can have independent temperature control for fluid 80.
  • vessel 90 can be configured to cool fluid 80, for example, vessel 90 can include a thermostat jacket for cooling; or vessel 90 can be enclosed in a thermostatted enclosure (e.g., a refrigerator).
  • a mixer need not be included in vessel 90; in some embodiments, fluid 80 preferably remains unmixed and unagitated while in vessel 90.
  • Bridge 50 is fluidly connected to third vessel 110.
  • Bridge 50 is configured to deliver first fluid 45 and second fluid 80 to third vessel 110.
  • Vessel 110 can include mixer 120.
  • Mixer 120 can be a rotary mixer, such as a magnetic stirrer or motor-driven propeller.
  • Mixer 120 can be configured to impart a generally circular motion to fluid 130 in vessel 110, particularly when vessel 110 has a rounded interior shape, such as a cylindrical shape.
  • Fluid 130 can include a mixture of fluid 45 and fluid 80.
  • the fluid connection between bridge 50 and third vessel 110 can be configured to deliver fluid tangentially to vessel 110.
  • fluid 130 when fluid 130 is given a generally circular motion by mixer 120, fluid entering vessel 110 from bridge 50 enters tangentially with respect to the generally circular motion of fluid 130.
  • the tangential configuration can be preferred for efficient mixing of first fluid 45 with second fluid 80, particularly when fluid 45 and fluid 80 are immiscible.
  • fluid 45 can be a hydrophobic fluid
  • fluid 80 can be a hydrophilic or aqueous fluid.
  • mixed fluid 130 can be an emulsion.
  • System 10 can be configured to control the temperature of fluid 130, for example, a temperature between 0 °C and 100 0 C, between 15 0 C and 70 °C, between, 20 0 C and 50 °C, or between 25 0 C and 45 °C.
  • vessel 110 can include a thermostatted temperature control system to maintain fluid 130 at a desired temperature.
  • the system can also be configured to control the temperature of fluid 130 as it circulates in fluid circuit 140.
  • Vessel 110 is fluidly connected to second fluid circuit 140.
  • Pump 150 which can be, for example, a peristaltic or centrifugal pump, drives fluid 130 through second fluid circuit 140.
  • Fluid circuit 140 includes piping or tubing for circulating a fluid, and can optionally incorporate one or more static mixers 155.
  • a static mixer includes a series of geometric mixing elements fixed inside a pipe which use the energy of the flow stream to create mixing between two or more fluids.
  • Fluid circuit 140 can also be configured for temperature control, for example by being enclosed in a thermostatted enclosure.
  • Fluid dispenser 160 is disposed in fluid circuit 140. Dispenser 160 has one or more nozzles configured to intermittently dispense a predefined amount of fluid 130 to mold 170.
  • Intermittent dispensing can be controlled by, for example, one or more valves.
  • dispenser 160 has a plurality of nozzles each configured to dispense fluid 130 to a mold. Operation of dispenser 160 can be controlled such that it dispenses a desired amount of fluid at a desired speed and with a desired intermittent frequency. Once the fluid has been dispensed to the mold the mold can be transferred to additional manufacturing units, e.g., cooling, heat sealing and cutting units.
  • the system can be used for making suppositories.
  • components of the suppository base can be added to vessel 30.
  • the sequence of addition and temperature settings of vessel 30 can vary depending on the nature of the suppository to be made.
  • the temperature of the base is then adjusted in vessel 30 to a desired temperature.
  • the temperature used can depend on the ingredients of the suppository and the desired fluid characteristics (e.g., viscosity) of fluid 35. Meanwhile, mixer 35 and pump 40 can be activated to mix and circulate the suppository base.
  • Pump 60 supplies the suppository base from circuit 20 to bridge 50. Simultaneously, pump 100 drives a second fluid, which can include an unstable ingredient, into bridge 50.
  • the proportions of suppository base and second fluid supplied to bridge 50 can be adjusted to achieve the desired concentration of unstable ingredients in the pharmaceutical formulation.
  • pumps 60 and 100 can be equipped with flow meters that allow fine tuning and consistent delivery of the desired proportions of ingredients.
  • the combined fluids next enter vessel 110.
  • Bridge 50 can be connected to vessel 110 so as to supply the fluid tangentially with respect to the wall of the vessel. Tangential supply promotes formation of a turbulent flow of fluid 130 in vessel 110. Turbulent flow can be important for blending immiscible fluids, e.g., for emulsifying lipophilic or amphiphilic suppository bases with a hydrophilic fluid, such as an aqueous solution.
  • vessel 110 can be equipped with a magnetic propeller stirrer with a controlled speed of rotation.
  • Pump 150 circulates the final suppository mixture through circuit 140.
  • Dispenser 160 can operate cyclically. During each cycle, the dispenser takes from the circuit 140 the required amount of the suppository mixture and transfers it to the suppository mold 160. Then the suppository tape can transferred to the cooling, heat sealing and cutting units.
  • the suppository base can be a hydrophilic, lipophilic or amphiphilic material that softens or melts at body temperature.
  • the active ingredient can be a biologic, that is, an ingredient produced biologically, such as a protein, peptide, nucleic acid, saccharide, or metabolite.
  • Many active ingredients, including most biologies, can be more soluble in water than in lipophilic or amphiphilic fluids. Some active ingredients can degrade (i.e., lose biological effectiveness) when heated, exposed to light, or agitated for prolonged periods.
  • the suppository includes more than one active ingredient, for example, an anti-inflammatory ingredient and a local anesthetic.
  • Some active ingredients are readily dissolved in aqueous solutions but not in lipophilic or amphiphilic fluids.
  • the suppository mixture can be formulated as an emulsion.
  • Suppository bases should be stable, nonirritating, chemically inert, and physiologically inert.
  • materials suitable for use in a suppository base include oils and fats of animals or vegetable origin, e.g., olive oil, corn oil, palm oil, palm kernel oil, castor oil, cottonseed oil, wheat germ oil, cacao butter, soybean oil, sesame oil, or hydrogenated oils; hydrocarbons, e.g., squalane, petrolatum, solid paraffin, or liquid paraffin; or waxes, e.g., jojoba oil, carnauba wax, beeswax, cocoa butter, or lanolin; partially or totally synthesized fatty acid esters of glycerol, mono-, di-, or triglycerides of medium or higher fatty acid, such as saturated linear fatty acid, e.g., lauric acid, myristic acid, palmitic acid, and stearic acid, or unsaturated linear fatty acid, e.g
  • Polymers can be included in the suppository base formulation, for example to adjust the rate of release of the active ingredient.
  • Some exemplary polymers include water insoluble polymers, e.g., ethylcellulose, aminoalkyl methacrylate copolymer, polyvinyl acetate; intestinally soluble polymers, e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, styrene-acrylic acid copolymer, methacrylic acid copolymer, maleic acid anhydride copolymers; acid soluble polymers, e.g., polyvinylacetaldiethylamino acetate, aminoalkyl-methacrylate copolymer E; water-soluble polymers, e.g., hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, arginic acid, sodium arginate, acacia, a
  • the suppository base can include other components for adjusting properties of the base, such as, for example, glycerol or other alcohols to adjust the mechanical properties of the suppository; acids, bases, or buffers to adjust pH; emulsifiers; salts; whiteners; or other components as are known in the art.
  • the active ingredient can be a biologic, such as an interferon. Suppositories including interferon are described in, for example, Russian Patent Nos. 2216345 and 2201212, each of which is incorporated by reference in its entirety. Interferon products, mostly gene-engineered, have been extensively introduced in public health practice. Their application is based on multiple effects produced by interferon (immunomodulating, antiviral, antitumoral, antimicrobial, etc.).
  • Interferon products are well known and widely used both for parenteral injections and topical application (ointments, suppositories, drops, gels, etc.). Some products for topical application are more effective, because they are able to ensure higher concentrations at lesion sites with reduced side effects. Side effects can be a problem for parenteral administration of high doses of interferon.
  • Interferon effect on host immune response, and its antiviral, antitumor, antibacterial, effects have been investigated, justified theoretically and proved in multi-year practical application of interferon products in the treatment of various diseases.
  • Those diseases include a variety of oncological diseases, viral infections (e.g., viral hepatitis, herpes infection, herpes of genitalia, cytomegalovirus infection, human papilloma virus infection, influenza, etc.), multiple sclerosis, acute and chronic infectious diseases (chlamydiosis, mycoplasmosis, ureaplasmosis, dysbacteriosis, candidosis, etc.) and disorders of immune or interferon status.
  • viral infections e.g., viral hepatitis, herpes infection, herpes of genitalia, cytomegalovirus infection, human papilloma virus infection, influenza, etc.
  • multiple sclerosis e.g., acute and chronic infectious diseases (chlamydio
  • Some of these diseases can become chronic illnesses, and/or show pathogen persistence in the human body, for example herpes of types I and II, cytomegalovirus infection, hepatitis B, D, C, chlamydiosis, mycoplasmosis, ureaplasmosis, etc. This persistence is caused both by specific features of microorganisms and the human protective system (immune system disorders, compromised innate immunity, dysbacterioses, etc.). Consequences of these diseases include effects on birth rate (infertility, higher percentage of premature deliveries, etc.) and infant's health.
  • antibiotic therapy does not produce the desired results, because antibiotic-resistant microbial associations emerge rapidly and further deteriorate the patient's condition.
  • a product based on interferon, (which can be natural or human recombinant of a or ⁇ and/or 7 interferon) and taurine (taufone) in the following quantity can include:
  • Taurine is an amino acid widely used in medications (including, for example, tablets, eye drops, solutions for parenteral administration, e.g. for parenteral feeding of infants). It normalizes metabolic processes, induces regenerative, reparative, membrane- and hepatoprotective effects, and increases work capability when physical loads are applied.
  • the interferon-taurine product can be provided in liquid form and presented as solution for injections, instillations, lotions, and spray, including, as supplementing substances, benzyl alcohol and acetate buffer; solution for rinsing contains chlorobutanol hydrate 0.005 g and borate buffer; eye drops contains supplementing substances - sorbic acid 0.002 g and borate buffer.
  • the product can be prepared in a solid form, such as a powder for topical application. It can additionally contain chlorobutanol hydrate 0.005 g, aerosil and talc in the proportion of 1 :1 and in the amount of up to 1 g; powder for oral and cutaneous application can contain chlorobutanol hydrate 0.002 g, magnesium stearate 0.3 g and lactose of up to 1 g.
  • the product can be made in the form of gel, film, or sponge intended for cutaneous application.
  • it can contain anesthetic and dextran, collagen, or gelatin 0.01-0.5 g, chlorobutanol hydrate 0.005 g and acetate buffer of up to 1 ml.
  • the product can also be prepared in a form for oral intake.
  • the oral intake form can include in addition anesthetic and cellulose 0.01-0.3 g, chlorobutanol hydrate 0.001 g and acetate buffer of up to 1 ml.
  • Formulations as sprays or aerosols for cutaneous application can additionally contain anesthetic and such polyacrylates 0.05 g, chlorobutanol hydrate 0.005 g, propellent, and acetate buffer of up to 1 ml.
  • the products can be formulated as suppositories; vaginal tablets; vaginal solutions, emulsions, or suspensions; cream; gel; foam; ointment; or vaginal insert.
  • composition of tablets with the weight of 1.0 g
  • composition per gelatin capsule with the weight of 1.5 g
  • composition per solid capsule with the weight of 1.0 g
  • composition per solid capsule with the weight of 1.37 g
  • composition per solid capsule with the weight of 1.0 g
  • the product When formulated as a suppository, the product can include:
  • the suppository can include a solid, food-quality fat (for example, a hard fat) and an emulsifier.
  • the suppository can include an oil and water sensitive base, including a polyethylene oxide, a solid food-quality fat and an emulsifier.
  • the suppository can include a hydrophilic base, including a polyethylene oxide and an emulsifier.
  • the emulsifier can be, for example, a polysorbate, such as polysorbate 80 or Tween 80.
  • the polyethylene oxide also known as a polyethylene glycol or PEG
  • PEG polyethylene oxide
  • the polyethylene oxide also known as a polyethylene glycol or PEG
  • PEG polyethylene oxide
  • a polyethylene oxide 400 or a polyethylene oxide 1500.
  • the polyethylene oxide can be present in an amount of 0.05 g to 0.2 g.
  • the suppository can further include chlorobutanol hydrate in the amount of 0.05 - 0.01 g.
  • the suppository can further include a anesthetic, such as, for example, benzocaine.
  • the suppository can further include a stabilizer.
  • the stabilizer can help to preserve the level of interferon activity during periods of storage.
  • the stabilizer can include an organic acid, such as, for example, succinic acid, citric acid, or acetic acid.
  • the stabilizer can also include a salt of an organic acid, such as a sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt, or other pharmaceutically acceptable salt.
  • An acid and a salt can be combined in a desired proportion to act as a buffer.
  • Disodium succinate concentrations ranging from 1 mM to 50 mM were tested with buffer pH ranging from 3.8 to 6.0.
  • the maximal stability of interferon alpha (IFNa) was achieved when 20 mM buffer with pH 5.6 was used. These conditions provided maximal IFNa stability in suppositories with both amphiphilic and hydrophilic suppository bases.
  • Amphiphilic formulation 1 (amounts per 180 kg batch)
  • formulation 1 After two years, formulation 1 retained 90% of the initial specific IFNa activity. In case of formulation 2, the specific IFNa activity after 2 years was 70% of the original one. In case of formulation 3, the specific IFNa activity after 1 year decreased by more than 50%.
  • the required amounts of hard fat and emulsifier are melted together in the vessel. Then polysorbate 80 is added while the melted hard fat is being stirred. The required amount of PEG 1500 is melted, and benzocaine is added into the melted PEG while it is being stirred.
  • the benzocaine and PEG mixture is added to the melted hard fat in the reactor, then mixed and sterilized in the reactor. Dextran and taurine are dissolved in the buffer and sterilized. The sterile solution is added to the melted suppository base. Then the content of the vessel is emulsified. A small amount of suppository base is mixed with the buffered IFN solution. The suppository base and the IFN emulsion in the suppository base are used in suppository production according to the methods described above. To make a suppository with a hydrophilic base, the required amount of
  • PEG 1500 is melted in the vessel. Then benzocaine is added into the melted PEG while it is being stirred. The mixture is sterilized in the vessel. Glycerin and polysorbate 80 are added next.
  • Dextran and taurine are dissolved in the buffer and sterilized.
  • the sterile solution is added to the melted suppository base. Then the contents of the vessel are emulsified. A small amount of suppository base is mixed with the buffered IFN solution.
  • the suppository base and the IFN emulsion in the suppository base are used in suppository production according to the methods described above.
  • Other embodiments are within the scope of the following claims.

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Abstract

L'invention concerne un système de distribution de fluide comprenant un premier circuit de fluide pour la circulation d'un premier fluide, une alimentation de fluide pour fournir un deuxième fluide, et un deuxième circuit de fluide permettant de mélanger le premier et le deuxième fluides. Le premier fluide peut être hydrophobe et le second fluide peut être aqueux. Le mélange peut être une émulsion. Le premier fluide peut être un excipient pour suppositoire, et le deuxième fluide peut comprendre un ingrédient pharmaceutique actif. Le système permet de distribuer les fluides mélangés dans un moule pour former un suppositoire.
PCT/RU2006/000173 2006-04-07 2006-04-07 Système, méthodes et produits de distribution de fluide Ceased WO2007117173A1 (fr)

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PCT/RU2006/000173 WO2007117173A1 (fr) 2006-04-07 2006-04-07 Système, méthodes et produits de distribution de fluide

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101927054B1 (ko) 2010-07-28 2018-12-10 그뤼넨탈 게엠베하 시스-테트라하이드로스피로(사이클로헥산-1,1'-피리도[3,4-b]인돌)-4-아민 유도체

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU676613A1 (ru) * 1976-12-10 1979-07-30 Всесоюзный Проектно-Конструкторский И Научно-Исследовательский Институт Автоматизации Пищевой Промышленности Система автоматического управлени процессом обесцвечивани сиропов
US4675184A (en) * 1981-11-28 1987-06-23 501 Sunstar Kabushiki Kaisha Pharmaceutical composition containing interferon in stable state
US4871777A (en) * 1987-03-25 1989-10-03 Henkel Kommanditgesellschaft Auf Aktien Emulsifying compositions for suppository bases and suppositories produced therefrom
US6247838B1 (en) * 1998-11-24 2001-06-19 The Boc Group, Inc. Method for producing a liquid mixture having a predetermined concentration of a specified component
RU2240591C2 (ru) * 1998-09-09 2004-11-20 Элопак Системс Аг Способ и устройство для производства молочного продукта

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU676613A1 (ru) * 1976-12-10 1979-07-30 Всесоюзный Проектно-Конструкторский И Научно-Исследовательский Институт Автоматизации Пищевой Промышленности Система автоматического управлени процессом обесцвечивани сиропов
US4675184A (en) * 1981-11-28 1987-06-23 501 Sunstar Kabushiki Kaisha Pharmaceutical composition containing interferon in stable state
US4871777A (en) * 1987-03-25 1989-10-03 Henkel Kommanditgesellschaft Auf Aktien Emulsifying compositions for suppository bases and suppositories produced therefrom
RU2240591C2 (ru) * 1998-09-09 2004-11-20 Элопак Системс Аг Способ и устройство для производства молочного продукта
US6247838B1 (en) * 1998-11-24 2001-06-19 The Boc Group, Inc. Method for producing a liquid mixture having a predetermined concentration of a specified component

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GEORGIEVSKY V.P. ET AL.: "Tekhnologiya i standartizatsiya lekarstv. Tom 2", TOM 2, KHARIKOV, IZD. GR. "RIREG", 2000, pages 419 - 422, 424 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101927054B1 (ko) 2010-07-28 2018-12-10 그뤼넨탈 게엠베하 시스-테트라하이드로스피로(사이클로헥산-1,1'-피리도[3,4-b]인돌)-4-아민 유도체

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