EP1397197A2 - Procede de production de nanodispersions - Google Patents

Procede de production de nanodispersions

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Publication number
EP1397197A2
EP1397197A2 EP02745284A EP02745284A EP1397197A2 EP 1397197 A2 EP1397197 A2 EP 1397197A2 EP 02745284 A EP02745284 A EP 02745284A EP 02745284 A EP02745284 A EP 02745284A EP 1397197 A2 EP1397197 A2 EP 1397197A2
Authority
EP
European Patent Office
Prior art keywords
range
disperse phase
mixture
outlet channel
nozzle
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.)
Withdrawn
Application number
EP02745284A
Other languages
German (de)
English (en)
Inventor
Kai Christian JÜRGENS
Bernd Kühn
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.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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 Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1397197A2 publication Critical patent/EP1397197A2/fr
Withdrawn legal-status Critical Current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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • 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
    • B01F25/20—Jet mixers, i.e. mixers using high-speed fluid streams
    • B01F25/23—Mixing by intersecting jets
    • 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
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0418—Geometrical information
    • B01F2215/0431—Numerical size values, e.g. diameter of a hole or conduit, area, volume, length, width, or ratios thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0436—Operational information
    • B01F2215/045—Numerical flow-rate values
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0436—Operational information
    • B01F2215/0468—Numerical pressure values
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0486—Material property information
    • B01F2215/049—Numerical values of density of substances
    • 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
    • B01F23/20—Mixing gases with liquids
    • 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
    • B01F23/50—Mixing liquids with solids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00889—Mixing

Definitions

  • the invention relates to the production of nanodispersions, in particular for the application of pharmaceutical substances in humans and animals, and to a method for in-situ
  • the invention relates in particular to a process for the preparation of phospholipid adducts which can be used as pharmaceutical formulations.
  • inventive use of the method described is not limited to the production of pharmaceutical end products, but is preferably used for this.
  • nanodispersion means a disperse system with a disperse phase which can be liquid, liquid-crystalline, gaseous, vesicular, micelle-like and which can be of organic or inorganic origin in a dispersant which is composed of one or more components can, described.
  • Degree of dispersity determined by measuring the dispersion by means of dynamic light scattering (photon correlation spectroscopy).
  • the disperse phase is understood as being built up from solid, spherical particles, so that the degree of dispersity can be specified as the average hydrodynamic diameter of these virtual particles.
  • the characteristic of the nanodispersion according to the invention is that the degree of dispersity is in the range of 1-5000 nm, the size distribution being such that the amount of the disperse phase, which is greater than 1000 nm, is small compared to the total amount. If the disperse phase consists of a solid, a special nanodispersion is a nanosuspension in which the dynamic light scattering measures solid particles.
  • In-situ formulation means that the final formulation of the drug takes place immediately before application.
  • turbulent mixing should be understood to mean that at least two partial flows move in such a way that their flow lines follow chaotic paths, so that it can be assumed that the phases that are formed by the partial flows are statistically uniform in the available ones Distribute space.
  • the term is used separately from the fluid mechanical definition of turbulence.
  • a medicinal substance is to be understood to mean a substance which leads to a medicament in accordance with the German Medicinal Products Act ⁇ 2 Paragraph 1 and Paragraph 2 when used accordingly, or which is defined as a substance in the sense of the German Medicinal Products Act ⁇ 2.
  • Parenteral administration is to be understood in particular as an intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intrathecal or intracardiac injection or infusion.
  • Formulation finding in parenteral applications is particularly difficult since the choice of auxiliary substances and methods is very limited.
  • the number and size of particulate components in a medium for parenteral use are regulated by the pharmacopoeia.
  • write the US pharmacopoeia states that large-volume infusion solutions should not contain more than 25 particles larger than 10 ⁇ m per mL.
  • the orientation is based on the size of the erythrocytes, which can pass through all capillaries of the body with a diameter of approx. 5-7 ⁇ m. If individual components are larger, there is a risk that they will be held in the capillaries of the body, block them and thus lead to damage to the body.
  • the patient's blood is often enriched with oxygen externally through oxygenators as part of the extracorporeal circulation.
  • a small size of the gas bubbles is decisive for the rapid physical absorption of the gas in the blood.
  • the gases used behave like very hydrophobic substances; they do not dissolve in the blood and can also form larger bubbles.
  • G. G. Liversidge et al. in US Pat. No. 5,145,684 use wet grinding to comminute the active ingredient to the required particle size ⁇ 5 ⁇ m.
  • surface-active substances such as polyvinylpyrrolidone or poloxamer are added to the grinding medium.
  • Lucks et al. generate active substance-containing solid lipid nanospheres (SLN) according to EP 0 605 497 by melting one or more lipids, incorporating the active substance, then mixing with water and comminuting with the aid of high shear forces (Ultra-Turrax and high-pressure homogenizer). Stabilizers can be added to stabilize the formulation thus obtained.
  • SSN solid lipid nanospheres
  • Gassmann et al. extend this method in WO 92/18105 by first dissolving a water-insoluble active ingredient with the addition of a charged phospholipid in an organic solvent and then with an aqueous solution which may contain further stabilizers, mix. The polarity of the solvent mixture is changed so that the solubility of the active ingredient is exceeded and it fails. The charged phospholipid covers and stabilizes the surface of the particles that form.
  • the authors describe various mixing methods for mixing, including a continuous one
  • MLV multilamellar phospholipid vesicles
  • SUN small unilamellar vesicle
  • Hüglin et al. in EP 0 956 851 disclose the possibility of forming lipid-containing dispersions with vesicles in the sub-micron range even without further energy input. They use special formulations that are characterized by the addition of a co-emulsifier (eg Tween ® or Pluronic ® ). Yiv et al use a concentrate in WO 97/30695 to produce a microemulsion in which they dissolve an active ingredient in a mixture of a phospholipid with propylene glycol or polyethylene glycol. You rely on the use of a surfactant with an HLB value of> 12. This concentrate is then mixed with water shortly before use.
  • a co-emulsifier eg Tween ® or Pluronic ®
  • Phospholipid in ethanol and glycerin If this formulation is applied to the mucosa, the liquid present there spontaneously forms liposomes or similar structures that contain the active substance in a molecularly disperse manner. He describes a fungicidal dosage form as an example. In EP 0 759 736 he describes a similar formulation for the production of bath oils.
  • WO 99/44642 Leigh extends the pre-liposomal concept to non-topical dosage forms. It dissolves phospholipids in a water-miscible solvent and gives an active ingredient. If this premix is now hydrated, phospholipid aggregates are formed which are also said to contain bi-layer structures. In order for such structures to occur spontaneously without further energy input, very special mono- and diacylated phospholipids must be used, which are produced by enzymatic cleavage. The formulations are preferably used orally. The phospholipid aggregates form on contact with the gastric fluid. They contain the active ingredient in a molecular dispersion.
  • the form of administration can be parenteral, oral or topical.
  • the solution to the problem according to the invention consists in a process for the production of nanodispersions, in which at least two metered partial streams are brought together so that they are subject to mixing due to turbulence, the partial streams having a flow rate in the range from 0.1 to 500 ml / h and the mixed flow has a total flow rate in the range from 1 ml h to 500 ml / h, preferably in the range from 10 to 200 ml / h, and with turbulent mixing a disperse phase with a degree of dispersity in the range from 0.1 to 5000 nm, preferably in the range from 10 to 1000 nm, particularly preferably in
  • Range of 10 to 200 nm is generated.
  • a turbulent mixing of the two or more partial streams is achieved with suitable geometric relationships of the mixing device and parameters of the partial streams in that the partial streams flow through a nozzle into an outlet channel, the nozzle having a smaller diameter than the outlet channel.
  • a key figure K can be calculated according to Eq. Mean where r ⁇ i ana the radius of the outlet channel, p is the density of the mixture, v is the total flow rate, ⁇ the viscosity of the mixture ro üse the radius of the nozzle and ⁇ the circular constant. All values in the corresponding SI units must be used for the calculation.
  • the critical value is in the range from 250 to 450. In addition to the above-mentioned parameters, it depends to a lesser extent on the exact nozzle geometry, the surface quality of the walls, the temperature and the interfacial tension between the partial flows used.
  • a sharp jet (jet stream) is formed that goes through the center of the outlet channel and then widens to the entire channel width.
  • liquid molecules from the immediate vicinity adhere to its surface and are carried away.
  • An area with a relative deficiency is created directly behind the nozzle around the jet, which compensates for itself from the environment, so that a zone of negative pressure is formed, which in turn can compensate for itself by leaving the jet and the material at some distance from the nozzle Filled vacuum area.
  • the distance from the nozzle reduces the speed of the material that leaves the jet, so that the force of the suction is greater than the kinetic energy of the particles.
  • a vortex forms, which is arranged concentrically around the nozzle and surrounds the jet stream like a ruff. In it, liquid from more distant areas is returned to the nozzle.
  • the speed of rotation of the vortex depends on the speed of the jet stream.
  • the turbulent state is just behind the nozzle. From the point where the jet stream hits the channel wall, the current flows again in a laminar manner.
  • the turbulent vortex zone ensures intensive mixing of the partial flows.
  • the zone must not expand too far, since otherwise the material exchange within the vortex does not take place sufficiently quickly, so that the vortex reduces the degree of dispersity.
  • Turbulent mixing is achieved at an overall flow rate that is above a critical overall flow rate at which turbulence sets in. This critical total flow rate depends on the ratio of the diameter of the nozzle to the outlet channel, and the geometry of the nozzle and the outlet channel and the material properties of viscosity and density of the partial flows or the mixed flow.
  • the outlet channel preferably has a diameter between 0.2 and 2 mm and the nozzle has a diameter in the range from 10 to 500 ⁇ m.
  • the outlet channel is preferably at least 10 times longer than its diameter.
  • the mixed stream preferably has a viscosity in the range from 0.7 mPas to 150 mPas and the density is between 700 kg / m to 1500 kg / m.
  • the parameters total flow rate, diameter of the nozzle and the outlet channel, viscosity and density are in such a relationship that according to Eq. 1 results in a key figure K that is at least 250.
  • the degree of dispersity of the disperse phase depends on the total flow rate set. With a low total flow rate, a low degree of dispersity is initially obtained. When the total flow rate is increased, the mixture becomes more homogeneous, the degree of dispersity increases until it reaches a maximum value which cannot be increased significantly by further increasing the total flow rate.
  • the turbulent mixing of the partial streams is therefore an essential prerequisite for the production of nanodispersions with a high degree of dispersity. It was also found that the storage stability of a nanodispersion with a correspondingly high degree of dispersibility is increased compared to a dispersion with a lower degree of dispersity.
  • several mixers can also be connected in parallel. Furthermore, several mixers can also be connected in series to produce premixes of different components.
  • At least two substreams are mixed using the preceding mixing process in such a way that a nanodispersion is produced.
  • nanodispersions consist of a dispersing agent and a disperse phase with a very high degree of dispersity.
  • the disperse phase can be a solid, a liquid, a liquid-crystalline phase, a gas or a mixture thereof.
  • the reasons for the formation of the disperse phase are precipitation because the saturation solubility of the solution is exceeded, neutralization reaction, interaction between differently charged molecules, association of molecules, recomplexing or chemical reaction. Which of the causes applies depends on the choice of substances or substance mixtures in the partial flows.
  • the dispersing agent can be water or distilled water or an aqueous medium or an aqueous medium with additions of electrolytes, mono- or disaccharides, alcohols, polyols or mixtures thereof.
  • the dispersant can contain one or more viscosity-increasing substances.
  • the dispersant can contain stabilizers and / or surface-active substances.
  • the dispersant is preferably water for injection purposes without the addition of stabilizers or surface-active substances, to which auxiliaries for adjusting isotonicity and euhydria can be added.
  • 5% glucose is added to the water for isotonization.
  • the dispersant contains additives which form micelles under the conditions of use. After mixing, the disperse phase is present within these micelles. Additives that meet these conditions are, for example, substances from the poloxamer series. Poloxamer 408 is particularly preferred.
  • the disperse phase only forms when the partial streams are mixed, directly before application. At least one of the partial streams therefore contains the later disperse phase or parts of the later disperse phase in dissolved form
  • the partial stream in its entirety represents the later disperse phase, for example in the direct dispersion of gases.
  • the disperse phase is generated by a partial stream, which is called concentrate below.
  • the concentrate consists of an aqueous or water-miscible organic solvent, which is preferably approved for parenteral use.
  • Particularly preferred solvents are water, polyethylene glycol 400, propylene glycol, ethanol, tetraglycol and glycofurol.
  • auxiliaries can be added to the concentrate, the type and amount of which are known to the person skilled in the art and for example, but not exclusively, for pH adjustment, preservation, complex formation, viscosity increase or decrease or to achieve chemical stability.
  • the concentrate can be sparingly soluble or practically insoluble in water in a substance for pharmaceutical purposes e.g. sufficient one or more drugs are added. These substances can be dissolved in the concentrate.
  • the concentration of the active ingredients can be between 0 and 50 percent by mass, preferably between 0.1 and 10%. In a very particularly preferred application form, the concentration is between 1% and 3%.
  • the active ingredient is preferably a drug from the group of cardiovascular drugs, oncologics, virustatics, analgesics, chemotherapeutics, hepatitis, antibiotics or immunomodulators.
  • the active ingredient can also be a gas, for example NO for vasodilation, O 2 for oxygenation or air as an X-ray contrast medium.
  • the anhydrous embodiment of the concentrate can lead to improved chemical stability compared to an aqueous solution or suspension for some added drugs.
  • the concentrate contains water.
  • the process according to the invention is particularly suitable for the production of phospholipid adducts as a disperse phase, which can be used as pharmaceutical formulations. It has been found that when phospholipids (first partial stream) dissolved in water-miscible organic media are mixed with water (second partial stream), without further additives, phospholipid adducts are formed by the process according to the invention, which have a degree of dispersity in the nanometer range and as pharmaceutical formulations can be used.
  • the concentrate therefore contains a phospholipid or a mixture of several phospholipids dissolved in a water-miscible organic solvent. This can consist of an anhydrous mixture of 10 to 50, preferably 25 to 35 parts by weight of ethanol with 50 to 90, preferably 65 to 75 parts by weight of polyethylene glycol 400 (PEG 400).
  • the concentrate preferably contains a phospholipid, a hydrogenated or partially hydrogenated phospholipid, a lysophospholipid, a ceramide or mixtures of these compounds.
  • Phospholipids with the trivial names lecithin or kephalin are particularly preferred; purified lecithins from are particularly preferred
  • the mass fraction of the phospholipid in the concentrate can be between 0.01% and 40%, preferably between 5% and 20%. In a particularly preferred embodiment, it is 9 to 11%.
  • the already known mixer according to FIG. 3 from patent WO 99/32175 is used for mixing the partial streams, which is manufactured in such a way that the nozzles have a cross section of approximately 100 ⁇ m.
  • the concentrate and the diluting solution via a respective syringe pump (eg Perfusor Compact ® of the company. B. Braun, Melsungen) supplied to the mixer.
  • a respective syringe pump eg Perfusor Compact ® of the company. B. Braun, Melsungen
  • the flow rate of the partial flows is selected so that the speed of the dispersion medium 8 to
  • a mixture which contains phospholipid adducts with who are associated with an active ingredient in such a way that there is no precipitation of the active ingredient which would take place without the addition of the phospholipid.
  • the phospholipid adducts produced according to the invention have a degree of dispersity between 10 and 1000 nm.
  • the amount of adducts which are greater than 2000 nm is very small compared to the total amount.
  • the degree of dispersity is between 10 and 500 nm.
  • one of the partial streams can be a gas that can be dispersed as fine bubbles in the diluent by the mixing process and is stabilized by the latter against coalescence.
  • the gas is only generated by a chemical reaction in which reactants are involved, which are dissolved in different partial streams.
  • one stream may contain NaHCO 3 , while the other contains an acid.
  • the mixture produces carbon dioxide as a gas, which is present in a very high degree of dispersity.
  • the nanodispersion is produced, for example, by a neutralization reaction, in that a medicinal substance is dissolved in an aqueous solvent at an unphysiological pH and mixed in the mixer with a neutralizing diluent. At the resulting pH value, the substance is sparingly soluble and is particulate in the dispersant as a disperse phase.
  • the mixing ratio of the concentrate and the dilution solution can be fixed or temporarily variable. According to the invention, it is designed such that the volume fraction of the concentrate in the total mixture is between 0 and 90% before increases between 1 and 50%. In the particularly preferred embodiment, a fixed mixing ratio of 1 part concentrate in 10 parts mixture is used.
  • Another object of the invention is a method for the in-situ formulation of a drug dispersion, the drug dispersion being produced at the same rate at which the application takes place and thus the entire amount produced can be applied immediately (in-line application).
  • the drug dispersion is produced by a method in which at least two metered partial streams are brought together in such a way that they are subject to mixing due to turbulence, at least one partial stream being one
  • the drug dispersion is preferably administered parenterally.
  • This process which includes the parenteral in-line application of the drug dispersion, can be carried out without risk to the patient, since due to the turbulent mixing, the disperse phase produced has a degree of dispersity below the critical size of particles for parenteral administration and, at the same time, the total flow rate in one area of up to 500 ml / h.
  • the main application of the process for the production of nanodispersions is the in-situ formulation of drug dispersions for parenteral administration in humans and animals.
  • Other possible applications are oral, ophthalmic, otological, topical, nasal, vaginal, urethral and rectal application in humans and animals.
  • the pharmaceutical formulations can of course also be produced by the process according to the invention in such a way that the dispersion produced is not applied immediately. In this case it is possible to add additives to the dispersion for stabilization.
  • the mixture is preferably administered parenterally, particularly preferably intravenously.
  • the mixture can also be applied orally, ophthalmically, topically, nasally, vaginally, urethrally and rectally. It may be necessary to add other auxiliaries which are not yet listed and which are known to the person skilled in the art in terms of type and quantity.
  • the mixture can be applied directly or with a time delay, with direct application being preferred.
  • nanodispersions produced by the process according to the invention have a degree of dispersity in the nanometer range and are therefore also available for parenteral use. Any active ingredient that is present can be present in a molecularly dispersed solution in the disperse phase
  • An advantage of the formulations produced according to the invention is that they only contain components which are particularly safe for parenteral use.
  • the formulation is characterized by a very high tolerance. It thus stands out from other formulations known in the literature which contain auxiliaries with limited compatibility, such as, for example, some ionic or nonionic emulsifiers. If the process according to the invention is used to formulate in situ, the addition of stabilizers can be dispensed with.
  • the embodiment of the method for producing nanodispersions allows the use of commercially available phospholipids, poloxamers or other surfactants.
  • Fig. 1 Preferred embodiment of a mixer
  • Fig.l shows a preferred embodiment of a static mixer for performing the method according to the invention.
  • the mixer is known from WO 99/32175, Fig. 3.
  • the mixer 3 comprises a housing with a first channel 13a and a second channel 13b, a nozzle area 9, 10, 11 and an outlet channel 12.
  • the first channel 13a and the second channel 13b serve as supply lines for the
  • Sub-streams la and Ib the organic, water-miscible concentrate containing the phospholipid is brought into the mixer as a partial stream Ib via the feed channel 13b.
  • the dispersion medium reaches the mixer as a partial flow Ia via the channel 13a and is accelerated by the narrowing of the channel 9 into the nozzle 11.
  • the concentrate is added. Behind the
  • Nozzle 11 is intimately mixed in the region 10 by intensive longitudinal mixing of the two streams la and lb, which then leave the mixer as a mixed stream 5 through the downstream outlet channel 12.
  • the outlet channel 12 is arranged in the extension of the first feed channel 13a and at an angle of 90 ° to the second feed channel 13b.
  • Fig. 2 shows a graphical representation of the degree of dispersity depending on the
  • the degree of dispersity can therefore be determined by turbidity measurements.
  • the turbidity measurement is next to the
  • Measurement on the photon correlation spectroscope is another method for the degree of dispersity. If the turbidity is recorded as a reciprocal transmission value in a spectrophotometer, the degree of dispersity correlates directly with the transmission.
  • Concentrate uses the placebo concentrate described in Example 1. Water was used as the dispersion medium. The degree of dispersity was determined by measuring the directly correlating transmission value on a UV-VIS photometer (Lambda 2, Perkin Elmer) at 620 nm. In a preliminary test it was confirmed that the mixture has no appreciable absorption at 620 nm.
  • the concentrate and the dispersion medium were drawn up into a 50 ml Perfusor ® syringe and placed into a Perfusor ® -Compact syringe pump.
  • the syringes were with a mixer according to FIG. 1 with nozzle cross sections of
  • the degree of dispersion depends on the flow rate. At low flow rates, the degree of dispersion is low and then increases with increasing flow rate. From a kink point, which is around 80 ml / h, the degree of dispersion does not change much even with a further increase in the flow rate. At this flow rate, the beginning of the turbulent flow in the mixer could be observed with microscopic examinations.
  • Example 1 Active ingredient-free concentrate
  • Ethanol and PEG 400 are mixed. Epikuron 170 is added and dissolved with stirring. The solution is sterile filtered through a nylon filter. The solution is clear, particle-free and yellow in color.
  • Ethanol and PEG 400 are mixed. Nimodipine and Epikuron 170 are added and dissolved with stirring. The solution is sterile filtered through a nylon filter. The solution is clear, particle-free and dark yellow in color.
  • Example 3 Ibuprofen Concentrate 1% Ibuprofen 100 mg
  • Example 4 Clotrimazole concentrate 0.5%
  • Example 5 Paclitaxel concentrate 1%
  • Example 6 Concentrate 1% of a taxoid active ingredient Taxoid active ingredient 100 mg
  • Ethanol and PEG 400 are mixed.
  • the taxoid active ingredient, Epikuron 170 and the sorbic acid are added and dissolved with stirring.
  • the solution is sterile filtered through a nylon filter.
  • the solution is clear, particle-free and yellow in color.
  • the taxoid active ingredient used is known from the literature as 5 ⁇ , 20-epoxy-l, 2 ⁇ , 4, 7ß, 10ß, 13 ⁇ , 14ß-heptahydroxytax-l l-en-9-one l, 14-carbonate-4,10-diacetate-2 -ben- zoate, 13 - [(2R, 3S) -3- (N-tert-butoxycarbonyl) amino-2-hydroxy-5-methylhexanoate] from US Pat. 5,705,508 (listed there under the name SB-T-101131).
  • Dilution solution the glucose is dissolved in the water. Both solutions are drawn onto a 50 ml Perfusor ® syringe and placed in a Perfusor ® -Compact syringe pump.
  • the syringes are connected with a mixer according to FIG. 1 with a nozzle cross-section of 100 ⁇ m via hoses and the inlets of the mixer are provided with check valves.
  • the concentrate is then pumped into the mixer at a flow rate of 10 ml / h and the dilution at 90 ml / h.
  • the mixture is collected.
  • the mixture is measured by means of photon correlation spectroscopy (Brookhaven BI 90) at 25 ° C and 90 ° measuring angle.
  • the average hydrodynamic diameter is 106 nm with a polydispersity index of 0.26.
  • the mixture is measured by means of photon correlation spectroscopy (Brookhaven BI 90) at 25 ° C and 90 ° measuring angle.
  • the average hydrodynamic diameter is 119 nm with a polydispersity index of 0.24.
  • the mixture is measured by means of photon correlation spectroscopy (Brookhaven BI 90) at 25 ° C and 90 ° measuring angle.
  • the average hydrodynamic diameter is 95 nm with a polydispersity index of 0.24.
  • Example 12 Preparation of a formulation of a taxoid active ingredient
  • the mixture is measured by means of photon correlation spectroscopy (Brookhaven BI 90) at 25 ° C and 90 ° measuring angle.
  • the average hydrodynamic diameter is 156 nm with a polydispersity index of 0.26.
  • the taxoid active ingredient used is known from the literature as 5 ⁇ , 20-epoxy-l, 2 ⁇ , 4, 7ß, 10ß, 13 ⁇ , 14ß-heptahydroxytax-l l-en-9-one l, 14-carbonate-4,10-diacetate-2 -ben- zoate, 13 - [(2R, 3S) -3- (N-tert-butoxycarbonyl) amino-2-hydroxy-5-methylhexanoate] from US Pat. 5,705,508 (listed there under the name SB-T-101131).
  • Poloxamer 408 lg NaCl 0.9% ad 100 ml The two concentrates and the dispersion medium were prepared by dissolving the solids in the solvents by stirring. The solutions were filtered through a 0.22 ⁇ m filter before use.
  • the degree of dispersity was determined by measuring the particle size on the photon correlation spectroscope.
  • a degree of dispersity of 20-25 nm was found for the two mixtures of concentrates with the dispersion medium. This degree of dispersity could only be achieved if the poloxamer was added to the dispersion medium.
  • the active ingredient present is derived from the
  • Poloxamer is encapsulated in a micelle-like manner and is thus prevented from precipitation.

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Abstract

Procédé de production de nanodispersions selon lequel au moins deux flux partiels dosés sont réunis de manière telle qu'ils sont soumis à un mélange produit par turbulence. Lesdits flux partiels possèdent un débit allant de 0,1 à 500 ml/h et le flux mélangé possède un débit total de l'ordre de 1 ml/h à 500 ml/h. Le mélange par turbulence produit une phase dispersée dans un milieu de dispersion, ayant une dispersité de 0,1 à 5000 nm. La présente invention concerne également un procédé de production in situ d'une dispersion de substance médicamenteuse, ladite dispersion étant appliquée immédiatement après avoir été produite.
EP02745284A 2001-05-21 2002-05-08 Procede de production de nanodispersions Withdrawn EP1397197A2 (fr)

Applications Claiming Priority (3)

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DE10124952A DE10124952A1 (de) 2001-05-21 2001-05-21 Verfahren zur Herstellung von Nanodispersionen
DE10124952 2001-05-21
PCT/EP2002/005048 WO2002094222A2 (fr) 2001-05-21 2002-05-08 Procede de production de nanodispersions

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Families Citing this family (20)

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BR0211028A (pt) * 2001-06-22 2004-06-15 Pfizer Prod Inc Solução aquosa, método para formação de associações de fármaco e polìmero, composições farmacêuticas, método para formação de uma composição farmacêutica e produto
CA2625862A1 (fr) * 2005-10-14 2007-04-26 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques liquides de nimodipine
DE102006011881A1 (de) * 2006-03-09 2007-09-13 Vortex-Nanofluid Gmbh Langzeitstabile Dispersion und Verfahren zur Herstellung der Dispersion
DE102006037318A1 (de) * 2006-08-08 2008-02-14 Celanese Emulsions Gmbh Verfahren zur Applikation eines Dispersionsklebstoffes mittels Düsenauftrag und Verwendung von Dispersionsklebstoffen
DE102006050748A1 (de) * 2006-10-27 2008-04-30 Evonik Degussa Gmbh Nanoskalige Partikel enthaltende Lackbindemittel mit verbesserter Kratzfestigkeit und Flexibilität, Verfahren zu deren Herstellung sowie diese enthaltende hochtransparente Lacke
US8309129B2 (en) 2007-05-03 2012-11-13 Bend Research, Inc. Nanoparticles comprising a drug, ethylcellulose, and a bile salt
WO2008135855A2 (fr) 2007-05-03 2008-11-13 Pfizer Products Inc. Nanoparticules contenant un inhibiteur de la protéine de transfert d'ester de cholestéryle et un polymère non ionisable
EP2162120B1 (fr) 2007-06-04 2016-05-04 Bend Research, Inc Nanoparticules comportant un polymère cellulosique non ionisable et un copolymère bloc amphiphile non ionisable
US9545384B2 (en) 2007-06-04 2017-01-17 Bend Research, Inc. Nanoparticles comprising drug, a non-ionizable cellulosic polymer and tocopheryl polyethylene glocol succinate
US9724362B2 (en) 2007-12-06 2017-08-08 Bend Research, Inc. Pharmaceutical compositions comprising nanoparticles and a resuspending material
EP2240162A4 (fr) 2007-12-06 2013-10-09 Bend Res Inc Nanoparticules comprenant un polymère non ionisable et un copolymère de méthacrylate fonctionnalisé par amine
WO2009087678A2 (fr) * 2007-12-24 2009-07-16 Sun Pharma Advanced Research Company Limited Nanodispersion
JP6444062B2 (ja) * 2013-06-17 2018-12-26 花王株式会社 分散液の製造方法
WO2017180718A1 (fr) * 2016-04-13 2017-10-19 Grace Therapeutics Llc Formulation parentérale stable de nimopidine
US10092553B2 (en) * 2016-04-13 2018-10-09 Nortic Holdings Inc. Stable nimodipine parenteral formulation
WO2019006134A1 (fr) * 2017-06-30 2019-01-03 Nortic Holdings Inc. Formulation parentérale stable de nimodipine
EP3755326A4 (fr) * 2018-02-22 2021-11-03 Nortic Holdings Inc. Formulation parentérale stable de nimodipine
DE102019120020A1 (de) * 2019-07-24 2021-01-28 Analytik Jena Ag Herstellung von Nanopartikeln
EP4008322A1 (fr) * 2020-05-25 2022-06-08 Leon-Nanodrugs GmbH Particules de lécithine de l'ordre de nanomètre comme support de principe actif destinées l'administration parentérale
EP4059491A1 (fr) * 2021-03-17 2022-09-21 Evonik Operations GmbH Dispositif et procédé de production de nanoporteuses et/ou de nanoformulations

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4533254A (en) * 1981-04-17 1985-08-06 Biotechnology Development Corporation Apparatus for forming emulsions
DE19757224A1 (de) * 1997-12-22 1999-07-01 Bayer Ag Verfahren und Vorrichtung zur in-situ-Formulierung einer Arzneistofflösung zur parenteralen Applikation
GB9919693D0 (en) * 1999-08-19 1999-10-20 Rhone Poulenc Rorer Ltd Process
DE10007816A1 (de) * 2000-02-21 2001-09-06 Bayer Ag Verfahren zur Herstellung von Nanosuspensionen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02094222A2 *

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WO2002094222A2 (fr) 2002-11-28
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AU2002316896A1 (en) 2002-12-03
US20040180005A1 (en) 2004-09-16

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