WO2013030119A1 - Forme galénique comprenant des particules de principe actif stabilisées - Google Patents

Forme galénique comprenant des particules de principe actif stabilisées Download PDF

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Publication number
WO2013030119A1
WO2013030119A1 PCT/EP2012/066529 EP2012066529W WO2013030119A1 WO 2013030119 A1 WO2013030119 A1 WO 2013030119A1 EP 2012066529 W EP2012066529 W EP 2012066529W WO 2013030119 A1 WO2013030119 A1 WO 2013030119A1
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WIPO (PCT)
Prior art keywords
cinnarizine
stabilizer
grinding
dosage form
particle size
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PCT/EP2012/066529
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German (de)
English (en)
Inventor
Gernot Francas
Karl-Heinz PRZYKLENK
Original Assignee
Hennig Arzneimittel Gmbh & Co. Kg
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Application filed by Hennig Arzneimittel Gmbh & Co. Kg filed Critical Hennig Arzneimittel Gmbh & Co. Kg
Publication of WO2013030119A1 publication Critical patent/WO2013030119A1/fr

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    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to pharmaceutical dosage forms which are suitable for improving the release of cinnarizine and thus its bioavailability, even with a low supply of liquid in the gastrointestinal tract. According to the invention, there are also a production process for such dosage forms and their uses. An aspect of this invention also relates to a particle matrix which contributes substantially to the effect of the invention.
  • Cinnarizine is currently used in the form of a conventional formulation as a combined preparation with dimenhydrinate (tablet) in the treatment of dizziness of various origins.
  • pH values of 2.0 to 4.9 can certainly occur individually in the human body. However, the release and thus the absorption of the active ingredient are not optimally guaranteed if the pH is too high in individual cases. There is therefore a need to increase the dissolution rate and thus the absorption of cinnarizine at pH values of> 1.6, in order to achieve optimal patient compliance and to reduce the known gastrointestinal intolerances (especially at the beginning of the therapy) ,
  • This BCS system basically differentiates between four categories, depending on the poor solubility and permeability of the respective active ingredient. Due to its poor solubility in water ( ⁇ 2 pg / ml) and its good permeability, cinnarizine is clearly classified in the BCS II category, which also contains about 40 to 50% of the known poorly soluble active ingredients.
  • nanoparticles show improved dissolution rates and supersaturated solutions, they are also absorbed by endocytosis.
  • Nanoparticles tend to form agglomerates in suspension, which reduces the surface of the drug again and avoids the positive effects. Therefore, it is the object of this invention to provide dosage forms which are suitable for releasing the active substance cinnarizine in such a way that the rate of dissolution is improved. At the same time the dosage forms should have a good shelf life. This means that the active ingredient particles in the dosage forms do not agglomerate even after a long storage time, but are present in the form of very small particles.
  • This invention is based on the object to provide dosage forms with which an improved release of the active ingredient cinnarizine can be achieved. At the same time the dosage forms should have a very good Lagerstabütician especially with regard to agglomeration of the drug particles.
  • the present invention relates to a preparation method for providing a dosage form comprising the active ingredient cinnarizine.
  • the dosage form may additionally comprise the active ingredient dimenhydrinate.
  • the manufacturing process involves the provision of nanoparticles of the active ingredient cinnarizine. If “cinnarizine” is mentioned in this description, this term also covers pharmaceutical compatible salts and prodrugs of this substance.
  • the term “cinnarizine” includes only the cinnarizine base itself.
  • the production method of the present invention is a method for producing a dosage form comprising cinnarizine, a matrix material and a stabilizer, comprising the steps of a. Comminution of cinnarizine to nanoparticles, b. if necessary, isolation of the nanoparticles, c. Embedding the nanoparticles in a matrix to obtain a particle matrix comprising a matrix material, cinnarizine and a stabilizer, wherein during the process, such amount of substance will add to stabilizer that an amount of the stabilizer of at least 0.5 nmol / m 2 is present in relation to the surface of Cinnarizins.
  • the stabilizer should not be used in smaller quantities because this minimum amount is required to stabilize the nanoparticles obtained during comminution. For smaller amounts, the particles agglomerate again into larger aggregates, so that the effect according to the invention is not achieved.
  • at least 0.8 nmol / m 2 , more preferably at least 1.2 nmol / m 2 and particularly preferably at least 2 nmol / m 2 of stabilizer based on the surface of the cinnarizine are used.
  • di amount of the stabilizer may be more than 3 nmol / m 2.
  • the amount of substance of the stabilizer during the manufacturing process preferably not more than 500 ⁇ / ⁇ ⁇ 2 , more preferably not more than 50 ⁇ / ⁇ - ⁇ 2 , even more preferably not more than 20 ⁇ / m 2 and especially ders preferably not more than 10 ⁇ / m 2 based on the surface of the
  • Cinnarizins amount is not more than 10 nmol / m 2 , more preferably not more than 7 nmol / m 2 and particularly preferably not more than 5 nmol / m 2 , based on the surface of cinnarizine.
  • this invention relates to the particulate matrix thus prepared and to the dosage forms comprising this particulate matrix. Furthermore, the use of the administration forms for the treatment of dizziness according to the invention is also.
  • the dosage form according to the invention is preferably intended for oral administration.
  • the following administration forms are preferred: tablets, coated tablets, capsules, powders, granules, pellets and MUPS.
  • the dosage form is selected from tablets and coated tablets.
  • the dosage form can be in the form of granules or extrudate-filled capsules, wherein the granules or extrudate contains the particle matrix.
  • the dosage forms may be modified release preparations.
  • the dosage form has the advantage of good stabilization of the nanoparticles embedded in the particle matrix.
  • the formulation of the drug in the form of nanoparticles has the advantage that it gives the cinnarizine a high specific surface area. A large specific surface facilitates the dissolution and thus the absorption of the active substance.
  • nanoparticles in pharmaceutical dosage forms tend to agglomerate. The agglomeration causes the specific surface area of the active ingredient to be reduced again and its dissolution rate to be reduced again. Cinnarizine is particularly prone to agglomeration.
  • the nanoparticles are stabilized in such a way that even after months of use. no or only little agglomeration of the nanoparticles occurs. This advantage of the dosage form is achieved by the interaction of the measures described herein.
  • the dosage form of the invention improves the absorption of the drug in the gastrointestinal tract. This is particularly important because cinnarizine has poor water solubility at pH greater than 1.6.
  • the solubility of the active ingredient is improved by the pharmaceutical dosage form such that an excellent bioavailability of the sparingly soluble active ingredient is achieved.
  • the manufacturing process comprises the step of comminuting the active substance into nanoparticles.
  • the optionally contained dimenhydrinate can be comminuted together with cinnarizine.
  • Nanopartikei The comminution of the active ingredient and thus the production of Nanopartikei is preferably carried out by high-pressure homogenization or wet grinding. Wet grinding is preferred.
  • a grinding mixture is prepared containing at least the active substance, a stabilizer and the grinding fluid.
  • Stabilized grinding media preferably zirconium- or zirconium-yttrium-stabilized, preferably zirconium oxide-stabilized grinding balls, are preferably added to the grinding mixture.
  • the grinding balls used for grinding preferably have diameters of ⁇ 5 mm, more preferably ⁇ 2 mm, more preferably -SO, 7 mm and particularly preferably ⁇ 0.5 mm. Although these mills are added to the milling mixture, they are not taken into account in the description of the percentage composition of the mixture.
  • the number of revolutions is preferably at least 400 U / min, preferably at most 800 U / min. Preferably, every 30 minutes, a change of direction.
  • Suitable machines for wet grinding are in particular nanomillers, mention may be made of the corresponding models of the companies Retsch, F ritsch,
  • the ahl toughkeit is preferably selected from water-miscible liquids, in particular lower alkanols having 1 to 5 carbon atoms and water and mixtures thereof. Water is particularly preferred.
  • the method used for comminution of the active substance is preferably carried out such that nanoparticles of the active substance having an average particle size of ⁇ 2000 nm, preferably ⁇ 1700 nm, more preferably ⁇ 600 nm and particularly preferably ⁇ 400 nm and most preferably - £ 200 nm and more preferably ⁇ 200 nm are obtained.
  • the specific surface area of the active ingredient is at least 10 m / g, more preferably at least 15 m 2 / g, and most preferably at least 20 m 2 / g. In particularly preferred embodiments, the specific surface area is even at least 30 m 2 / g. In order to further limit the agglomeration tendency, it has proved advantageous to choose the specific surface area smaller than 85 m 2 / g and more preferably smaller than 75 m 2 / g.
  • the specific surface area is determined by the BET method known to those skilled in the art (DIN ISO 9277: 2003-05). Nitrogen is used as gas.
  • the comminution is preferably for a duration of at most 48 hours, more preferably at most 24 hours, and more preferably less than
  • the grinding process can preferably within
  • the temperature during the grinding process preferably remains at ⁇ 45 ° C, more preferably ⁇ 40 ° C, further preferably at ⁇ 35 ° C and preferably at ⁇ 30 ° C. If these temperatures are exceeded, the risk of unwanted agglomeration of the active ingredient particles increases.
  • a stabilizer is added to the grinding mixture.
  • the stabilizer already reduces the agglomeration of the nanoparticles produced during the grinding.
  • Preferred stabilizers are surfactants.
  • the surfactants may be ionic or nonionic.
  • the stabilizer may be a mixture of several surfactants.
  • the stabilizer comprises at least one nonionic surfactant.
  • the stabilizer may alternatively or in addition to one or more nonionic surfactants comprise one or more ionic surfactants. It is preferred that the ionic surfactants be used in amounts of less than 10 wt .-%, more preferably less than 2 wt .-% based on the active ingredient.
  • the preferred concentrations of the nonionic and ionic surfactants just mentioned are in the range acceptable for these substances.
  • the compatibility takes into account that in the further course of the preparation process by the addition of further auxiliaries, the amount of the respective nonionic surfactant to preferably 10 wt .-% or tonic surfactants preferably ⁇ 5 wt .-% and preferably ⁇ 1 wt .-% in the prepared pharmaceutical dosage form decreases.
  • the pharmaceutical dosage form produced preferably comprises ⁇ 10% by weight of stabilizer.
  • the stabilized nanosuspensions produced with the wet grinding according to the invention are characterized by sufficient stability for the further production process, ie storage over several days does not lead to any significant changes in the particle size distribution.
  • Preferred ionic surfactants are preferably surface-active surfactants, in particular sodium dodecyl sulfate, dilauryldimethylammonium bromide and
  • Preferred nonionic surfactants are in particular TPGS (D-a-tocopherol-polyethylene glycol ⁇ 1000) succinate) and polysorbate 80 (Tween 80).
  • TPGS sodium dodecyl sulfate
  • stabilizers used are nonionic surfactants such as, in particular, TPGs with proportions of ionic surfactants, in particular SDS or ionic surfactants aHein.
  • the stabilizer preferably contains ionic surfactants in a proportion of 60 to 90% by weight and nonionic surfactants in an amount of 10 to 40% by weight.
  • the grinding mixture may contain further stabilizing grinding aids to further stabilize the nanoparticles. These auxiliaries can be added to the grinding mixture before grinding.
  • These grinding aids are preferably water-soluble and in particular selected from water-soluble polymers and sugars and sugar derivatives.
  • the water-soluble polymers are preferably selected from
  • Polyoxyethylene / polyoxypropylene (POE / POP) block polymers polyethylene glycols, polyvinylpyrrolidone, cellulose derivatives, condensation products of polyalkyloxides with oils or fats and mixtures thereof.
  • the condensation products are preferably ethers and / or esters.
  • the sugars and sugar derivatives are preferably selected from sugars and sugar alcohols, in particular mannose, glucose, galactose, fructose, sucrose and mannitol and mixtures thereof. Mannitol is especially preferred.
  • the condensation products of polyalkyloxides with oils or fats include in particular esters of fatty acids with polyethylene glycols and ethers of
  • esters of fatty acids with polyethylene glycols are mono-
  • Difatty acid esters of polyethylene glycols are preferably saturated and have preferred chain lengths of at least 6 and at most 22 carbon atoms.
  • a preferred example of such an ester is Gelucire® 44/14 ⁇ CAS no. 121548-04-7).
  • a preferred ether of polyalkyloxides with vegetable oils is Cremophor® (CAS No. 61791-12-6).
  • the average molecular weight (number average M N ) of the polymeric grinding aids should preferably be at least 5,000 and preferably not exceed 100,000. More preferably, this value is less than 75,000. In particular embodiments, the average molecular weight is less than 50,000, more preferably less than 20,000.
  • the millbase mixtures preferably comprise POE / POP block polymers and at least one other of the abovementioned other grinding auxiliaries.
  • the grinding mixture comprises a mixture of sugars or sugar alcohols with polyethylene glycols.
  • the grinding mixture comprises a mixture of polyethylene glycols with condensation products of polyalkyloxides with oils or fats.
  • the grinding mixture comprises a mixture of sugars or sugar alcohols with condensation products of polyalkyloxides with oils or fats.
  • the grinding mixture comprises a mixture of sugars or sugar alcohols with condensation products of polyalkyloxides with oils or fats and polyethylene glycols.
  • the grinding aids are used in the grinding mixture in an excess relative to the masses in relation to the stabilizer.
  • the mass ratio of grinding aid to stabilizer is therefore preferably at least 1.01: 1, more preferably at least 1.1: 1 and particularly preferably at least 1.5: 1,
  • the grinding mixture preferably comprises the following components in weight percent: a. Active ingredient 0.1 to 40% b. Grinding aids 0 to 10% c. Stabilizer 0.1 to 10% d. Milling liquid 50 to 99.7%
  • the proportion of grinding fluid in the grinding mixture is at least 60% by weight, more preferably at least 65% by weight. It has proved to be advantageous to limit the content of milling liquid preferably to at most 90 wt .-%, more preferably at most 87 wt .-%. An excessively high proportion of mashing liquid leads to a poor comminution, which makes the process uneconomical. Too low a proportion quickly leads to agglomeration.
  • the active ingredient content in the grinding mixture is preferably at least 5 wt .-%, more preferably at least 10 wt .-% and particularly preferably at least 14 wt .-%.
  • the active ingredient content is limited to at most 30 wt .-%, more preferably at most 20 wt .-%.
  • the stabilizer should be added to the grinding mixture in amounts of preferably at least 0.8% by weight, more preferably at least 1% by weight, and most preferably at least 3% by weight. In this case, a content of preferably at most 8% by weight and more preferably at most 5% by weight should not be exceeded. A sufficient content of stabilizer must be added in order to prevent the agglomeration of the active ingredient particles in the grinding mixture. This effect is reversed at too high concentrations to the opposite.
  • the content of auxiliaries is relatively low so as not to increase the viscosity of the grinding mixture too much. It has proven to be particularly advantageous to use a content of at most 5% by weight and more preferably at most 4% by weight. At least 0.1% by weight and more preferably at least 1% by weight of grinding aids are added in preferred embodiments. The grinding aids reduce the agglomeration tendency of the active ingredient particles.
  • the product of grinding is a suspension of active substance particles in the grinding fluid.
  • the dosage form that can be produced with the production process shown here comprises the components of the grinding mixture used in their preparation, with the exception of the grinding fluid.
  • the step of comminution of the active ingredient is optionally followed by the isolation of the nanoparticles of the active substance produced in this way.
  • the product of the comminution is usually a suspension which contains the nanoparticles of the active ingredient or of the active ingredients and at least the stabilizer in the grinding fluid. Either the suspension can be further processed directly by using it for embedding in a matrix, or the nanoparticles are first isolated and then further processed.
  • the isolation of the nanoparticles of the active ingredient is preferably achieved by spray-drying or lyophilization of the suspension of the nanoparticles obtained by the comminution. However, other methods can also be used. In this step, the suspension is removed from the grinding liquid.
  • the stabilizer mentioned above in particular together with the stabilizing grinding aids, leads to a stabilization of the particle matrix thus produced during the isolation.
  • the pharmaceutical composition of this invention prepared using these grinding aids is particularly shelf-stable without agglomerating the nanoparticles of the active ingredient and thus compromising bioavailability.
  • an insulation mixture is first prepared during the isolation.
  • the suspension of the drug particles before isolation added at least one insulation aid.
  • the isolation aids are preferably selected from water-soluble polymers, sugars and sugar alcohols and mixtures thereof.
  • Suitable isolation aids were POE / POP block polymers
  • Polyethylene glycols in particular PEG 1000, PEG 1500, PEG 4000, PEG 6000 and / or PEG 20000
  • cellulose derivatives especially microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose and / or hydroxypropylcellulose
  • isolation aids are mixtures of poloxamer 188 and mannitol. Further preferred are mixtures of sugars or sugar alcohols with polyethylene glycols, in particular mannitol and PEG 1500. Also preferred are mixtures of
  • Polyethylene glycols with condensation products of polyalkyloxides with oils or fats in particular PEG 6000 and Gelucire 50/13 (CAS 121548-05-8).
  • mixtures of sugars or sugar alcohols with condensation products of polyalkyloxides with oils or fats in particular mannitol and condensation products of polyalkyloxides with oils or fats are used as insulation auxiliaries. Further preferred are mixtures of mannitol, PEG-6000 and Gelucire 50/13 (CAS 121548-05-8).
  • the insulation aids used and described stabilize the nanoparticles produced during the isolation process. The added during comminution Mahlosstoffe alone are often not sufficient.
  • the isolation adjuvants may also be a stabilizer. This is preferably selected from the stabilizers described above and in particular identical to the previously added stabilizer.
  • the stabilizer added during isolation is TPGS.
  • the isolation mixture comprises the active substance in the form of particles, the stabilizer, optionally one or more grinding aids and optionally one or more isolation aids and liquid.
  • the liquid may be the liquid added as the grinding liquid in the crushing step, or the liquid added later. Usually, the liquid in the isolation mixture will be a mixture of the milling liquid and later added liquid.
  • the isolation mixture contains liquid in amounts of at least 50% by weight, preferably at least 60% by weight and more preferably at least 70% by weight. However, the amount of liquid should preferably not exceed 95% by weight and more preferably at most 90% by weight. If too little liquid is contained in the insulation mixture, agglomeration of the active ingredient particles occurs. However, if the content is too high, the energy consumption during isolation is increased unnecessarily.
  • the insulation adjuvants are preferably added to the isolation mixture prior to isolation in amounts such that the isolation mixture comprises these adjuvants in proportions of preferably at least 1% by weight.
  • these adjuvants should be added in amounts of up to 20% by weight of the isolation mixture.
  • these auxiliaries are used in amounts of at least 2% by weight and at most 10% by weight, more preferably at most 7% by weight.
  • the isolation aids have the purpose of further stabilizing the particles in the insulation mixture. Therefore, in addition to the substances referred to above as such, the isolation aids may also contain one or more stabilizers.
  • the isolation aids used and the stabilizers added in the isolation step are found in the dosage form obtainable by this process.
  • the nanoparticles After comminution and optionally after isolation of the nanoparticles, they are embedded in a matrix.
  • the matrix then comprises at least one matrix material, the stabilizer and the active ingredient in the form of nanoparticles. If grinding aids and / or insulation aids were added, these are also included.
  • the embedding is preferably carried out by extrusion or fluidized bed granulation.
  • the suspension obtained after the comminution step is sprayed onto the matrix material in a fluidized bed system.
  • the nanoparticles are comminuted and extruded after comminution and isolation with a matrix material.
  • melt extrusion in particular the hot melt extrusion has proven.
  • a suitable device for carrying out the extrusion is the Leistritz ZM 18 hot melt extruder.
  • a particle matrix is obtained which contains the nanoparticles dispersed, not amorphous, embedded.
  • the matrix material has only a correspondingly minimal dissolving power for the active ingredient or the isolated nanoparticles.
  • the dissolving power should preferably be less than 10% by weight, preferably less than 5% by weight, based on the amount of active ingredient used. This means that only less than 10% by weight or less than 5% by weight of the substance to be embedded is dissolved by the matrix material.
  • Glycerol monostearate, cellulose and cellulose derivatives, polyvinylpyrrolidone, sugars and sugar derivatives, polyethylene glycols, condensation products of polyalkyloxides with oils or fats and POE / POP block polymers were identified as being particularly suitable as matrix material taking into account the dissolving power.
  • Particularly preferred matrix materials are polyethylene glycols, POE / POP block polymers and mixtures of polyethylene glycols and condensation products of polyalkyloxides with oils or fats.
  • POE / POP block polymers in particular poloxamers, or polyethylene glycols (preferably PEG 6000) are used alone as matrix material.
  • the most preferred matrix material taking into account the solubility, has been found to be polyethylene glycols (especially PEG 1500 and PEG 6000), excipients from hydrogenated fats / oils (especially Gelucire 50/13) and POE / POP block polymers (especially Poloxamer 188). preferably POE / POP block polymers (especially poloxamer 188) or polyethylene glycols (especially PEG 6000) alone.
  • the matrix material is preferably used for embedding the cinnarizine in amounts corresponding at least to the mass of cinnarizine. Preferably, however, the matrix material is used in excess, based on the mass of cinnarizine.
  • the mass of matrix material is at least in the ratio 1, 2: 1, more preferably at least 1, 5: 1, greater than that of Cinnarizins. In particularly preferred embodiments, the mass of the matrix material is at least in a ratio of 2: 1 greater than the mass of
  • the mass of matrix material according to the invention preferably does not exceed the value of 30: 1 in relation to the mass of cinnarizine.
  • the mass ratio of matrix material to cinnarizine is at most 10: 1, more preferably at most 5: 1, and most preferably at most 4: 1. This mass ratio is then also in the dosage form, which is available with this method. If the amounts of matrix material are too small, sufficient embedding of cinnarizine can not be achieved. The result may be insufficient stabilization by the particle matrix. Too high amounts of matrix material for embedding can in turn lead to a too large dosage form and thus a poor swallowability, so that compliance problems can occur. Also, the release from the particle matrix can be adversely affected.
  • matrix materials which are selected from cellulose, cellulose derivatives, sugars and sugar derivatives, and mixtures thereof.
  • the amount of matrix material is preferably chosen so that the mass of matrix material per granule is at least 200 mg and at most 1000 mg.
  • a preferred matrix material is microcrystalline cellulose, another preferred matrix material is lactose.
  • temperatures in a range of at least 40 ° C., more preferably at least 50 ° C., are preferably used. It should preferably not exceed maximum temperatures of 200 ° C. In preferred embodiments, extruded at temperatures of at most 150 ° C, more preferably at most 20 ° C. At too high temperatures, the dissolving power of the matrix material for the cinnarizine is often too high and the agglomeration tendency is increased.
  • the product of embedding the isolated nanoparticles in the matrix is referred to below as the "particle matrix.”
  • the particle matrix comprises the nanoparticles of the active substance and the matrix material.
  • the dosage forms of this invention comprise the particle matrix.
  • the particle matrix prepared according to the invention is preferably further processed into a dosage form in the form of capsules or tablets.
  • the particle matrix is preferably filled into suitable hard gelatin capsules or, alternatively, further processed into suitable tablets.
  • the initially produced nanoparticles are retained by the embedding and stabilization and thus lead to a much faster dissolution rate of the active substance coupled with a significant increase in absorption in the gastrointestinal tract.
  • the further processing of the extrudates or fluidized bed granules obtained can be carried out by admixing further suitable pharmaceutical excipients (in particular fillers, disintegrants, flow regulators and / or lubricants) and then filling into capsules or compression into tablets in a suitable format, or can in the case of extrusion be bottled directly.
  • further suitable pharmaceutical excipients in particular fillers, disintegrants, flow regulators and / or lubricants
  • the pharmaceutical dosage forms of this invention have cinnarizine, the stabilizer and at least one matrix material, wherein the stabilizer is contained in such an amount of fabric that a ratio of stabilizer of at least 0.5 nmol / m 2, preferably of at least 0.8 nmol / m 2 , more preferably at least 1.2 nmol / m 2, and particularly preferably at least 2 nmol / m 2, to the surface of the cinnarizine.
  • the stabilizer is contained in such a substance amount in the dosage form according to the invention that a ratio of at least 50 nmol / m 2 , more preferably at least 0.5 ⁇ / ⁇ 2 and most preferably at least 2 pmol / m 2 of the stabilizer Surface of the
  • the stabilizer is preferably at most in such a substance amount in the dosage form that a ratio of not more than 500 pmol / rn 2 , more preferably not more than 50 pmol / m 2 , still more preferably not more than 20 pmol / m 2 and more preferably not more than 10 pmol / m 2 of the stabilizer is present in relation to the surface of cinnarizine.
  • the stabilizer is present in a molar amount such that a ratio of not more than 10 nmol / m 2 , more preferably not more than 7 nmol / m 2, and especially Preferably not more than 5 nmol / m 2 of the stabilizer is achieved to the surface of Cinnarizins.
  • the pharmaceutical dosage forms prepared according to the invention can be used, for example, in the treatment of dizziness of various causes (for example vestibular disorders), cerebral and peripheral circulatory disorders.
  • the pharmaceutical dosage forms which can be prepared by the process according to the invention have a significant increase in dissolution rate and thus faster release compared to commercially available tablets at a pH> 1.6 in vitro and in vivo and are proven to result in a faster absorption of cinnarizine at a pH> 1, 6 in the gastrointestinal tract.
  • the particle matrix according to the invention leads to a long-term stabilization of the nanoparticles produced in pharmaceutical dosage forms according to the invention for oral administration. These dosage forms meet the required criteria to ensure adequate stability at 25 ° C and over a period of 6 months at 40 ° C.
  • the further processing of the resulting particle matrix into the dosage form may preferably comprise admixing further suitable pharmaceutical auxiliaries, namely in particular: a. Fillers, preferably microcrystalline cellulose, lactose, starch; b. Disintegrants, preferably croscarmellose; c. Flow regulator, preferably colloidal silica; d. Lubricant, preferably magnesium stearate.
  • the further processing preferably comprises the filling of the particle matrix, optionally with the standard excipients, in capsules or pressing the particle matrix, optionally with the standard excipients, into a tablet.
  • the particle matrix may be in the form of pellets or granules, for example, and subsequently be filled into a capsule or pressed into a tablet, so that the dosage form is obtained.
  • the dosage form according to the invention is a capsule.
  • extrusion may be followed by spheronization, such as may be achieved with a coupled extruder hot-extruder (e.g., Leistritz ZM 18 coupled spheronizer extruder).
  • a coupled extruder hot-extruder e.g., Leistritz ZM 18 coupled spheronizer extruder.
  • Extrudate particles can then be filled directly into capsules.
  • the nanoparticles in the dosage form are preferably still in sizes of less than 2000 nm, more preferably ⁇ 1000 nm, more preferably ⁇ 600 nm and more preferably ⁇ 400 nm and most preferably ⁇ 200 nm and more preferably ⁇ 200 nm ago.
  • the pharmaceutical dosage form of this invention is preferably obtainable by the method described herein.
  • the dosage form of this invention preferably comprises matrix material in amounts such that the mass ratio of matrix material to cinnarizine is at least 5:10, more preferably at least 7:10, and most preferably at least 9:10.
  • the dosage form comprises matrix material in a mass fraction which exceeds the mass fraction of cinnarizine.
  • the amount of matrix material in the administration form should preferably not exceed a proportion of preferably 7: 1 in relation to the cinnarizine or the active ingredient combination.
  • the dosage form comprises matrix material and active substance or combination of active substances in one Mass ratio of at most 5: 1, more preferably at most 4: 1 and more preferably at most 2: 1. To choose the mass ratio within these limits contributes to the stabilization of the active ingredient particles in the dosage form.
  • the dosage form comprises cinnarizine at a level of preferably at least 30 mg per single dose.
  • the dosage form is in particular a
  • Sustained release pharmaceutical form so that the active ingredient content is higher than in a fast-release form, which must be taken several times a day.
  • a delayed-release dosage form with cinnarizine can be realized, because the matrix promotes the solubility of the active substance even at high pH values in such a way that sufficient absorption is possible.
  • the content of cinnarizine in the dosage form is at least 46 mg, more preferably at least 55 mg. Nevertheless, the content should not exceed 99 mg per single dose.
  • the dosage form preferably contains dimenhydrinate.
  • the content of this active ingredient is then preferably at least 101 mg, more preferably at least 110 mg. This content should preferably not exceed 150 mg.
  • Example 1 Nanomahlunq (Pulverisette 6. Fritsch) with 4% TPGS: grinding media 1 mm.
  • Example 2 Nanomale (Pulverisette 6, Fritsch) with 4% TPGS and 0.8% Polsorbate 80: grinding media 1 mm. 600 rpm
  • Particle size ⁇ 1700 nm were added to this solution until the drug was homogeneously suspended.
  • Pulverisette 6 given. Subsequently, about 18 g of grinding balls (zirconium oxide) with 1 mm diameter into the grinding bowl. It was then milled at a speed of 600 rpm with a change of direction at 30 min over a period of 6,5 h. The temperature was controlled during milling and remained below 35 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • a nanosuspension with an average particle diameter of ⁇ 200 nm could be prepared after 6.5 hours of milling with the given method, which under normal conditions had no changes over two days and was stable.
  • Dilauryldimethylammonium bromide grinding media 0.5 mm, 750 rpm and life over 14 days
  • Pulverisette 7 given. Subsequently, about 36 g of grinding balls (zirconium oxide) with a diameter of about 0.5 mm were placed in the grinding bowl. Subsequently, at a revolution speed of 750 rpm with a change of direction at each Milled for 30 minutes over a period of 5.5 hours. The temperature was controlled during milling and remained below 45 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • Example 4 Nanomahluna (Pulverisette 7. Fritscm with 1% SPS and 2%
  • Poloxamer 188 Grinding media 0.5 mm, 750 rpm and service life over 14 days
  • Pulverisette 7 given. Subsequently, about 36 g of grinding balls (zirconium oxide) with a diameter of about 0.5 mm were placed in the grinding bowl. It was then milled at a speed of 750 rpm with a change of direction at 30 min over a period of 5.5 h. The temperature was controlled during milling and remained below 45 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • Pulverisette 7 given. Subsequently, about 36 g of grinding balls (zirconium oxide) with a diameter of about 0.5 mm were placed in the grinding bowl. It was then milled at a speed of 750 rpm with a change of direction at 30 min over a period of 5.5 h. The temperature was controlled during milling and remained below 45 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • Example 6 Nanomahlung (Pulverisette 7, Fritsch) with 1% sodium glucocholate and 2% Poloxamer: MahlSystem 0.5 mm. 750 rpm and service life over 14 days
  • Pulverisette 7 given. Subsequently, about 36 g of grinding balls (zirconium oxide) with a diameter of about 0.5 mm were placed in the grinding bowl. Subsequently, de milled at a speed of 750 rev / min with a change of direction at 30 min over a period of 5.5 h. The temperature was controlled during milling and remained below 45 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • Example 7 Nanomahlung (Pulverisette 7, Fritsch) with 1% SDS and 2%
  • Poivvinvipyrrolidone VA 64 grinding media 0.5 mm, 750 rpm and service life over 14 days
  • Pulverisette 7 given. Subsequently, about 36 g of grinding balls (zirconium oxide) with a diameter of about 0.5 mm were placed in the grinding bowl. It was then milled at a speed of 750 rpm with a change of direction at 30 min over a period of 5.5 h. The temperature was controlled during milling and remained below 45 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • Example 8 Nanomahlung (Pulverisette 7, Fritsch) with 1%
  • Dilauryldimethylammonium bromide and 2% povinvipyrrolidone VA 64 grinding media 0.5 mm, 700 rpm and 14-day life
  • Pulverisette 7 given. Subsequently, about 36 g of grinding balls (zirconium oxide) with a diameter of about 0.5 mm were placed in the grinding bowl. It was then milled at a speed of 750 rpm with a change of direction at 30 min over a period of 5.5 h. The temperature was controlled during milling and remained below 45 ° C.
  • grinding balls zirconium oxide
  • PSD particle size distribution
  • Example 9 Nanomahlung (Pulverisette 6. Fritsch) with 4% TPGS: grinding media 0.5 mm. 600 rpm
  • PSD particle size distribution
  • a nanosuspension with an average particle diameter of ⁇ 200 nm could be prepared after 6.5 hours of grinding with the specified method, which had no changes at normal conditions over four days and was stable.
  • Example 10 Nanomahluna (VMA Getzmann) with 4% TPGS: grinding media 0.4- 0.7 mm. 6000 rpm
  • TPGS stabilizer
  • cinnarizine average particle size ⁇ 1700 nm
  • Example 1 Nanomouting (WAB) with 4% TPGS: grinding media 0.2-0.3 mm
  • Example 12 Nanofibre fWAB) with 2% TPGS: grinding media 0.2-0.3 mm
  • Example 13 Nanomolar (WAB ⁇ with 1% TPGS: grinding media 0.2- 0.3 mm
  • grinding balls zirconium oxide having a diameter of 0.2 to 0.3 mm were placed in the grinding bowl and ground at a pumping speed of 10 m / s and a pressure of 0.1 to 0.25 bar. The temperature remained below 45 ° C.
  • Example 14 Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and TPGS
  • nanosuspension was prepared as described in Example 9 and had the same particle size distribution.
  • the isolation mixture thus prepared was dried in the freeze dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in the primary and secondary drying was in each case at 0.7 mbar.
  • the dried lyophilizate gave the following particle size distribution:
  • Betspiel 15 Lvophilisation of the nanosuspension with 4% TPGS in the presence of mannitol and PEG 1500
  • the nanosuspension was prepared as described in Example 9 and had the same particle size distribution.
  • the isolation mixture thus prepared was dried in the freeze-dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in the primary and secondary drying was in each case at 0.7 mbar.
  • the dried lyophilizate gave the following particle size distribution:
  • Example 16 Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and Gelucire 44/14
  • nanosuspension was prepared as described in Example 9 and had the same particle size distribution.
  • the isolation mixture thus prepared was dried in the freeze-dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in the primary and secondary drying was 0.7 mbar in each case.
  • the dried lyophilizate gave the following particle size distribution: D50 [nm] D90 [nm]
  • Example 17 Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and poloxamer 188
  • nanosuspension was prepared as described in Example 9 and had the same particle size distribution.
  • Example 18 Lvophilization of the nanosuspension with 2% TPGS in the presence of poloxamer 88
  • nanosuspension was prepared as described in Example 0 and had the same particle size distribution. [187] 300.0 g of this nanosuspension were added to a solution of 271.2 g of water and 28.8 g of poloxamer (isolation aid) with stirring until the suspension was homogeneous.
  • the isolation mixture thus prepared was dried in the freeze dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in the primary and secondary drying was 0.7 mbar in each case. The whole process lasted 39h.
  • Example 19 Lyophilizates of nanosuspension with 4% TPGS in the presence of poloxamer
  • nanosuspension was prepared as described in Example 9 and had the same particle size distribution.
  • the isolation mixture thus prepared was dried in the freeze-dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in the primary and secondary drying was in each case at 0.7 mbar.
  • Example 20 Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and poloxamer
  • nanosuspension was prepared as described in Example 9 and had the same particle size distribution.
  • the isolation mixture thus prepared was dried in the freeze-dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in primary and secondary drying was 0.7 mbar.
  • Example 21 Lvophilization of the nanosuspension with 4% TPGS in the presence of PEG 6000 and Gelucire 50/13
  • Example 22 Lyophilization of the nanosuspension with 4% TPGS in the presence of mannitol. PEG 6000 and Gelucire 50/13
  • the isolation mixture thus prepared was dried in the freeze-dryer (Christ LPC-16 / NT).
  • the glass transition temperature was -45 ° C.
  • In the primary drying step was increased to + 5 ° C, then in the secondary drying then dried at + 25 ° C.
  • the vacuum in primary and secondary drying was 0.7 mbar.
  • Example 23 Lvophilization of the nanosuspension with TPGS and poloxamer 188
  • Example 24 Fluidized bed drying of the nanosuspension with 1%
  • the nanosuspension was prepared analogously to Example 7, but with a 25% concentration of cinnarizine.
  • Example 25 Fluidized bed drying of nanolosuspension with 1%
  • the nanosuspension was prepared analogously to Example 7, but with a 25% concentration of cinnarizine.
  • Example 26 Hot Melt Extrusion of Cinnarizine Nanoparticles with Poloxamer 188
  • Example 27 Hot melt extrusion of cinnarizine nanoparticles with PEG 6000
  • Example 28 Hot Melt Extrusion of Cinnarizine Nanoparticles with PEG 6000 and Gelucire 50/13
  • Example 29 Hot Melt Extrusion of Cinnarizine Nanoparticles with Kollidon VA 64 and Imwitor 900 (Glvcerol Monostearate)
  • Example 30 Hot melt extrusion of cinnarizine nanoparticles with Kollidon and Imwitor 900
  • Example 31 Hot melt extrusion of cinnarizine nanoparticles (containing TPGS) with oloxamer 188
  • Poloxamer 188 (matrix material) in a Turbula mixer approx. 5 min. mixed. Thereafter, the mixture was extruded in a laboratory extruder from. Thermo Haake at a temperature of 62 ° C (screw speed 100 U / min). The white, smooth Extrudate strands were then ground in a small laboratory mill and filled into hard gelatin capsules for analytical testing.
  • the particle size of the active ingredient used has increased slightly compared with the dried nanoparticles.
  • Example 32 Hot melt extrusion of cinnarizine nanoparticles (containing TPGS) with poloxamer 188
  • Poloxamer 188 (matrix material) in a Turbula mixer approx. 5 min. mixed. Thereafter, the mixture was extruded in a laboratory extruder from. Thermo Haake at a temperature of 62 ° C. The white, smooth extrudate strands were then ground in a small laboratory mill and filled into hard gelatin capsules for analytical testing.
  • the particle size of the active ingredient used has increased slightly compared to the dried nanoparticles.
  • Example 38 Production of a capsule from extrudates with cinnarizine nanoparticles [256] 300 g extrudate were further processed as described in Example 26 with the excipients corn starch, microcrystalline cellulose, croscarmellose sodium, hypromellose, fumed silica, talc and magnesium stearate to form a tablet containing 20 mg cinnarizine. Subsequently, the tablets were stored under ICH standard conditions at 25 ° C and 60% relative humidity and at 40 ° C and 75% relative humidity and then examined for impurities and on the particle size of Cinnarizinpumble.
  • the dosage forms according to the invention were investigated in a release apparatus required by the European and American drug approval authorities (Ph.Eur., USP) at a constant 37 ° C. with a "US paddle" system with a number of revolutions of 50 to 200 rpm. whereby a significant increase in the dissolution rate and concomitantly a significantly faster release of cinnarizine from the dosage form compared to a commercially available tablet could be observed .
  • the in vitro release media were the biorelevant media introduced by Dressman et al.
  • Cinnarizine is an excellent model substance for studying the behavior of poorly water-soluble drugs and was therefore chosen for the investigations.
  • FIG. 1 A graphical representation of the release is shown in Figure 1, taking into account the following assignment: a. Ext 1: Ex. 28 b. Ext 2: Ex. 29 c. Ext 3: Ex. 30 d. Ext 4: Ex. 31 e. Ext 5: Ex. 32 f. Tablet: Aleverl® g. Pure substance: cinnarizine [263] Figure 2 shows the drug release of cinnarizine from the
  • Particle matrix which was in the form of extrudates or nanosuspensions (product of comminution) of this invention, in FaSSIF according to Dressman et al.
  • active ingredient cinnarizine as a pure substance and the commercially available tablet Arlevert® were examined. In two extrudates and all nanosuspensions, a considerable increase in the dissolution rate and the amount released could be observed.
  • Figure 3 shows the drug release of cinnarizine from the extrudates and nanosuspensions of this invention in FeSSIF according to Dressman et al.
  • the active ingredient cinnarizine as a pure substance and the commercially available tablet Arlevert® were examined. In two extrudates and all nanosuspensions, a considerable increase in the dissolution rate and the amount released could be observed.
  • Figure 4 shows the drug release of cinnarizine from fluidized bed granules of this invention in FaSSIF according to Dressman et al.
  • the active ingredient cinnarizine as a pure substance and the commercially available tablet Arlevert® were examined.
  • An advantage of the nanoated forms of this invention is that the formation of supersaturated solutions of cinnarizine is favored. This effect occurs even in media in which cinnarizine is almost insoluble.
  • the experiment shown here was carried out in a pH 7 medium. Normally cinnarizine hardly dissolves here.
  • Figures 1 to 4 clearly demonstrate a faster dissolution rate and release in vitro of the dosage forms prepared by the process according to the invention compared with the commercially available Cinnarizine tablet Arlevert®.
  • the presence of the active ingredient dimenhydrinate has no influence on the release profile of the active substance cinnarizine.
  • the examined pH values are the physiologically most interesting pH values that are discussed in connection with absorption in the small intestine with and without food.

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Abstract

L'invention concerne des formes galéniques pharmaceutiques qui conviennent pour améliorer la libération de cinnarizine et donc sa biodisponiblité - même en présence d'un faible apport de liquide dans le système gastro-intestinal. L'invention concerne également un procédé de production de telles formes galéniques et leurs utilisations. Un aspect de l'invention concerne en outre une matrice de particules qui contribue sensiblement à l'effet selon l'invention. Le succès de l'invention consiste en une solubilité nettement améliorée du principe actif cinnarizine. La matrice de particules dans la forme galénique conduit en outre à une très bonne stabilité à l'entreposage, en particulier pour ce qui est de la taille des particules. Une agglomération des particules est efficacement empêchée.
PCT/EP2012/066529 2011-08-29 2012-08-24 Forme galénique comprenant des particules de principe actif stabilisées WO2013030119A1 (fr)

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EP2959887A1 (fr) 2014-06-26 2015-12-30 Hennig Arzneimittel GmbH&Co. Kg Médicament pour le traitement des vertiges de diverses origines

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DE102005026755A1 (de) * 2005-06-09 2006-12-14 Basf Ag Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung
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WO2014001268A1 (fr) * 2012-06-25 2014-01-03 Hennig Arzneimittel Gmbh & Co. Kg Forme galénique pour la libération prolongée de substances actives
KR20150041612A (ko) * 2012-06-25 2015-04-16 헨니그 아르쯔나이미텔 게엠베하 운트 코. 카게 활성 물질의 연장된 방출을 위한 약제학적 형태
EA028064B1 (ru) * 2012-06-25 2017-10-31 Хенниг Арцнаймиттель Гмбх Унд Ко. Кг Лекарственная форма для продленного высвобождения действующих веществ
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EA035815B1 (ru) * 2012-06-25 2020-08-14 Хенниг Арцнаймиттель Гмбх Унд Ко. Кг Лекарственная форма в форме слоистой таблетки, способ её изготовления и её применение для лечения головокружения
KR102160837B1 (ko) 2012-06-25 2020-09-29 헨니그 아르쯔나이미텔 게엠베하 운트 코. 카게 활성 물질의 연장된 방출을 위한 약제학적 형태
EP2959887A1 (fr) 2014-06-26 2015-12-30 Hennig Arzneimittel GmbH&Co. Kg Médicament pour le traitement des vertiges de diverses origines

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