WO2013030119A1

WO2013030119A1 - Dosage form having stabilized active-ingredient particles

Info

Publication number: WO2013030119A1
Application number: PCT/EP2012/066529
Authority: WO
Inventors: Gernot Francas; Karl-Heinz PRZYKLENK
Original assignee: Hennig Arzneimittel Gmbh & Co. Kg
Priority date: 2011-08-29
Filing date: 2012-08-24
Publication date: 2013-03-07
Also published as: DE102011053068A1

Abstract

The invention relates to pharmaceutical dosage forms that are suitable for improving the release of cinnarizine and thus the bioavailability thereof, even if there is a low amount of liquid in the gastrointestinal tract. The invention further relates to a production method for such dosage forms and to uses of such dosage forms. One aspect of the invention also relates to a particle matrix that substantially contributes to the effect according to the invention. The result according to the invention is the substantially improved solubility of the active ingredient cinnarizine. The particle matrix in the dosage form also leads to very good storage stability, particularly in regard to the particle size. Agglomeration of the particles is effectively prevented.

Description

Dosage form with stabilized active substance particles

[1] 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. The recommended daily dose is three tablets a day, given after each meal with enough liquid. Due to the known pH-dependent solubility differences of cinnarizine at pH = 1 (about 1.5 mg / ml), pH = 2 (about 0.29 mg / ml), pH = 3 (about 0.05 mg / ml) , pH = 4.9 (about 0.009 mg / ml) and pH 6.5 (about 0.0003 mg / ml), it can be assumed that absorption of cinnarizine is rapid and complete only at a pH of 1 due to salt formation. 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) ,

[3] Forms of administration with cinnarizine are already known from the prior art, in which the active ingredient is sometimes used even in small particle sizes. With the dosage forms described there, however, the desired storage stability can not be achieved. In addition, the formation of supersaturated solutions of the active ingredient is not achieved in the prior art.

[4] In recent years, the development of nanoparticulate systems has made great progress. Drug nanoparticles have a distinct advantage in dissolution rate and absorption compared to drug particles due to the larger surface area and the ability to form highly supersaturated solutions Micrometer or millimeter range. Especially for poorly soluble active ingredients, the production of nanosuspensions is a suitable way to bring these agents in solution and for absorption at all. To better characterize these sparingly soluble drugs, a classification according to the BCS system (Biopharmaceutics Classification System) was introduced (Guidance for Industry:

Immediate release of solid and oral dosage forms, FDA, 1995). 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.

[5] Not only do nanoparticles show improved dissolution rates and supersaturated solutions, they are also absorbed by endocytosis.

[6] 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.

[7] 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 Lagerstabüität especially with regard to agglomeration of the drug particles.

[8] These objects are achieved by the subject-matter of the patent claims.

[9] 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. Preferably, the term "cinnarizine" includes only the cinnarizine base itself.

[10] 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.

[11] 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. In preferred embodiments, 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. In certain embodiments, particularly when the cinnarizine is not used in very small particle sizes, di amount of the stabilizer may be more than 3 nmol / m ^2. Are very particularly preferably at least 50 nmol / m ^2, used more preferably at least 0.5 based μηιοΙ / ιτι ^2, and ¹ most preferably at least 2 μηιοΙ / ² ιτι stabilizer on the surface of the Cinnarizins.

However, if too much amount of substance of the stabilizer used, set negative effects. On the one hand, the grinding mixture starts to foam heavily and, on the other hand, limits with regard to the compatibility of the dosage form are exceeded. Therefore, the amount of substance of the stabilizer during the manufacturing process preferably not more than 500 μΓηοΙ / ι ^η2 , more preferably not more than 50 μιηοΙ / η-ι ² , even more preferably not more than 20 μπποΙ / m ² and especially ders preferably not more than 10 μιηοΙ / m ² based on the surface of the

Cinnarizins amount. In a specific embodiment, the amount of substance of the stabilizer 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.

Due to the fact that the specific surface of Cinnarizins during production and storage barely, in particular substantially not change, the restrictions made herein in terms of the amount of stabilizer and the specific surfaces and the particle sizes apply both for the manufacturing process as also for the dosage form produced therefrom.

In addition, 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.

[15] The dosage form according to the invention is preferably intended for oral administration. Thus, the following administration forms are preferred: tablets, coated tablets, capsules, powders, granules, pellets and MUPS. Preferably, the dosage form is selected from tablets and coated tablets. Preferably, the dosage form can be in the form of granules or extrudate-filled capsules, wherein the granules or extrudate contains the particle matrix. In particular, the dosage forms may be modified release preparations.

[16] 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. However, 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. However, if cinnarizine is used in the dosage form according to the invention, 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.

In addition to the stabilization of Nanopartikei is achieved with the dosage form of the invention also 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.

[18] The manufacturing process comprises the step of comminuting the active substance into nanoparticles. The optionally contained dimenhydrinate can be comminuted together with cinnarizine.

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.

[20] For wet grinding, 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.

[22] Suitable machines for wet grinding are in particular nanomillers, mention may be made of the corresponding models of the companies Retsch, F ritsch,

Gertzmann and WAB. [23] The ahlflüssigkeit 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.

[24] 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.

It has proved to be advantageous to comminute the active ingredient so that it has a specific surface area of at least 0.5 and at most 100 m ² / g. If the specific surface is below this value, the particles are too large and the dissolution properties of the active ingredient are not significantly improved. If the surface is higher than the specified value, the agglomeration tendency increases too much and the solution properties are impaired. In preferred embodiments, 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.

[26] 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.

[27] In case of doubt and if this description does not state otherwise or if the person skilled in the art is not aware otherwise, the methods and measurements mentioned herein will take place under standard conditions (DIN 1343).

[28] The average particle sizes given in this description have been determined by the laser diffraction method, unless stated otherwise. This size is measured with modern laser diffraction systems, in particular the Malvern Mastersizer 2000. The stirring speed, the grinding pressure and the duration of the grinding in the comminution step of this method are different from mill to mill and must be adjusted individually depending on the type of device.

The comminution is preferably for a duration of at most 48 hours, more preferably at most 24 hours, and more preferably less than

2 hours. The grinding process can preferably within

10 hours, more preferably completed within 8 hours and in particular within 6 hours.

[31] 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.

[32] In order to achieve the effect according to the invention of a particularly storage-stable particle matrix, 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. Preferably, the stabilizer comprises at least one nonionic surfactant.

[33] 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.

[34] 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. [35] 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.

[36] Preferred ionic surfactants are preferably surface-active surfactants, in particular sodium dodecyl sulfate, dilauryldimethylammonium bromide and

Sodium glycocholate.

[37] Preferred nonionic surfactants are in particular TPGS (D-a-tocopherol-polyethylene glycol {1000) succinate) and polysorbate 80 (Tween 80).

[38] It is particularly preferred to use sodium dodecyl sulfate as the ionic surfactant. As a nonionic surfactant, TPGS is particularly preferred.

[39] In particular embodiments, 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.

[40] 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.

[41] These grinding aids are preferably water-soluble and in particular selected from water-soluble polymers and sugars and sugar derivatives.

[42] 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.

[43] 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. [44] The condensation products of polyalkyloxides with oils or fats include in particular esters of fatty acids with polyethylene glycols and ethers of

Polyalkyloxides with vegetable oils,

[45] Preferred esters of fatty acids with polyethylene glycols are mono-,

Difatty acid esters of polyethylene glycols. The fatty acids 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).

[46] A preferred ether of polyalkyloxides with vegetable oils is Cremophor® (CAS No. 61791-12-6).

[47] 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.

[48] The millbase mixtures preferably comprise POE / POP block polymers and at least one other of the abovementioned other grinding auxiliaries.

[49] In a preferred embodiment, the grinding mixture comprises a mixture of sugars or sugar alcohols with polyethylene glycols. In a preferred embodiment, the grinding mixture comprises a mixture of polyethylene glycols with condensation products of polyalkyloxides with oils or fats. In a further preferred embodiment, the grinding mixture comprises a mixture of sugars or sugar alcohols with condensation products of polyalkyloxides with oils or fats. In a further preferred embodiment, the grinding mixture comprises a mixture of sugars or sugar alcohols with condensation products of polyalkyloxides with oils or fats and polyethylene glycols.

Preferably, POE / POP block polymers, in particular poloxamers, are used as grinding aids, preferably without the addition of further grinding auxiliaries. Particularly preferred is Poloxamer 188 (CAS No. 9003- 1-6). [51] Preferably, 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,

[52] Thus, 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%

[53] In preferred embodiments, 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 .-%. Preferably, the active ingredient content is limited to at most 30 wt .-%, more preferably at most 20 wt .-%. An excessively high content of active ingredient leads to agglomeration, while a content which is too low impairs the efficiency of the grinding process.

[55] 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. [56] 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.

[57] The product of grinding is a suspension of active substance particles in the grinding fluid.

[58] 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.

[61] It has surprisingly been found that 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. By this is meant that 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.

[62] Preferably, an insulation mixture is first prepared during the isolation. For this purpose, 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.

[63] Suitable isolation aids were POE / POP block polymers

(Poloxamers), sugars, sugar alcohols, 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) and condensation products of polyalkyloxides with oils or Fats and mixtures thereof identified.

[64] Preference is given to using mixtures of POE / POP block polymers and the abovementioned other isolation auxiliaries. Particularly preferred 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). In preferred embodiments, 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).

[65] In particularly preferred embodiments, POE / POP block polymers (in particular poloxamer 188 = CAS 9003-11-6) are used alone as an isolation aid. The insulation aids used and described stabilize the nanoparticles produced during the isolation process. The added during comminution Mahlhilfsstoffe alone are often not sufficient.

[66] Among 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. In particularly preferred embodiments, the stabilizer added during isolation is TPGS. [67] 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.

[68] Ideally, 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.

[69] 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. In particular, these adjuvants should be added in amounts of up to 20% by weight of the isolation mixture. Preferably, 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.

[70] With the exception of the liquid, the isolation aids used and the stabilizers added in the isolation step are found in the dosage form obtainable by this process.

[71] 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.

[72] The embedding is preferably carried out by extrusion or fluidized bed granulation. [73] For fluidized bed granulation, the suspension obtained after the comminution step is sprayed onto the matrix material in a fluidized bed system.

[74] For extrusion, the nanoparticles are comminuted and extruded after comminution and isolation with a matrix material.

[75] As a particularly preferred extrusion process, the 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.

[76] In contrast to prior art processes, in the processes of this invention preferably a particle matrix is obtained which contains the nanoparticles dispersed, not amorphous, embedded. For embedding, especially in melt extrusion, it is recommended for this purpose that 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.

[78] 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. Preferably, POE / POP block polymers, in particular poloxamers, or polyethylene glycols (preferably PEG 6000) are used alone as matrix material.

[0009] 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. [80] 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. In particularly preferred embodiments, 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

Cinnarizins. 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. Preferably, 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. When embedding via fluidized-bed granulation, preference is given to using 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.

[81] If an extrusion process is used for embedding, 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.

[82] The product of embedding the isolated nanoparticles in the matrix is referred to below as the "particle matrix." In any case, it comprises the nanoparticles of the active substance and the matrix material. The dosage forms of this invention comprise the particle matrix.

[83] The embedding of the nanoparticles in the particle matrix follows the further processing of the particle matrix into the dosage form.

[84] The particle matrix prepared according to the invention is preferably further processed into a dosage form in the form of capsules or tablets. For this purpose, 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.

[86] 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. Most preferably, 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 μηηοΙ / ιτι ² and most preferably at least 2 pmol / m ^{2 of} the stabilizer Surface of the

Cinnarizins present. 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. In a specific embodiment, 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. As a result, the agglomeration tendency of the active ingredient particles is greatly reduced. With too little amount of stabilizer, this effect does not occur. On the other hand, if too much stabilizer is used, the dosage form can not be produced economically. One reason is that even the grinding mixture is prone to foaming. In addition, an excess of stabilizer hampers the structural integrity of the final dosage form. In addition, applicable limits would be exceeded in terms of compatibility.

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.

[88] 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.

[89] 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. Most preferably, the dosage form according to the invention is a capsule.

[92] If the particle matrix has been prepared using extrusion, 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). These spheronized

Extrudate particles can then be filled directly into capsules.

The storage of the pharmaceutical formulations with the particle matrix at 25 ° C and 40 ° C over a period of 6 months showed no significant change in the size distribution nanoparticles and proves the good stabilization of the nanoparticles in the particle matrix.

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.

[95] The pharmaceutical dosage form of this invention is preferably obtainable by the method described herein.

[96] 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. In particularly preferred embodiments, 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. In further preferred embodiments, 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.

[97] 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. With the particle matrix according to the invention, 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. In preferred embodiments, 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.

[98] 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.

Examples

crushing

Γ991 Example 1: Nanomahlunq (Pulverisette 6. Fritsch) with 4% TPGS: grinding media 1 mm.

600 rpm

[100] 0.38 g of TPGS-1000 (stabilizer, previously gently melted at 50 ° C) were mixed with stirring 7.61 g of water until the TPGS was completely in solution. 1, 52 g of cinnarizine (mean particle size <1700 nm) were added to this solution until the drug was homogeneously suspended.

[101] This grinding mixture was then placed in a 12 ml grinding bowl of the Fritsch Pulverisette 6. Subsequently, about 18 g of grinding balls (zirconium oxide) with a diameter of 1 mm were placed in the grinding bowl. Subsequently, it was ground at a revolution rate of 600 rpm with a change of direction at 30 minutes each over a period of 24 hours. The temperature was controlled during milling and remained below 35 ° C. [102] After intervals of Oh, 7h and 24h, the particle size distribution (PSD) in the resulting suspension was determined by laser diffraction (Malvern, Master Sizer).

The following particle sizes were determined:

[103] The suspension was again examined for particle size distribution after one day of service life (room temperature):

[104] Already after 7 h of grinding, a nanosuspension with an average particle diameter of <200 nm could be prepared by the given method, which under normal conditions had no changes over one day and was stable. Initially (Oh), the particle size in the suspension is even greater than that of the active ingredient used, apparently due to the suspending process, which leads to agglomeration without corresponding separation of the particles. Only by grinding the corresponding nanoparticles are produced and stabilized.

[105] Example 2: Nanomale (Pulverisette 6, Fritsch) with 4% TPGS and 0.8% Polsorbate 80: grinding media 1 mm. 600 rpm

[106] 0.38 g of TPGS-1000 (stabilizer, previously gently melted at 50 ° C) and 0.08 g of Tween 80 {milling adjuvant) were mixed with stirring with 7.52 g of water until the TPGS was completely in solution. 1, 52 g of cinnarizine (mean

Particle size <1700 nm) were added to this solution until the drug was homogeneously suspended.

[107] This suspension was then placed in a 12 ml grinding bowl of the Fritsch

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.

[108] After 6.5 hours, particle size distribution (PSD) was determined by laser diffraction (Malvern, Master Sizer). The following particle sizes were determined:

[109] The suspension was again examined for particle size distribution after two days of service life (room temperature):

[1 10] In this example as well, 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.

[111] Example 3: Nanomahlung (Pulverisette 7, Fritsch) with 1%

Dilauryldimethylammonium bromide: grinding media 0.5 mm, 750 rpm and life over 14 days

[1 2] Approx. 2.25 g of cinnarizine (average particle size <1700 nm) were added to a solution of about 0.15 g Dilaur ldimethylammoniumbromid (stabilizer) in about 12.6 g of water until the drug was homogeneously suspended.

[113] This suspension was then placed in a 45 ml grinding bowl of the Fritsch

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.

[114] The particle size distribution (PSD) was determined by laser diffraction and repeated again after 14 days of service life.

[115] In this example as well, a nanosuspension with a mean particle diameter of <200 nm, which was stable, could be prepared after 5.5 hours grinding with the given method.

[116] 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

[117] Approx. 2.25 g of cinnarizine (average particle size <1700 nm) were added to a solution of about 0.15 g of SDS (stabilizer) and about 0.30 g of poloxamer 188 (grinding aid) in about 12.3 g of water until the active ingredient was homogeneously suspended.

[118] This suspension was then placed in a 45 ml grinding bowl of the Fritsch

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.

[1 19] The particle size distribution (PSD) was determined by laser diffraction and repeated again after 14 days of service life.

[120] In this example, too, a nanosuspension with an average particle diameter of <200 nm could be prepared after 5.5 hours of milling by the specified method. [121] Example 5: Nanomahlung (Pulverisette 7, Fritsch) with 1%

Dilauryldimethylammonium bromide and 2% poloxamer 188; Grinding media 0.5 mm, 750 rpm and service life over 14 days

[122] Approx. 2.25 g of cinnarizine (mean particle size <1700 nm) were added to a solution of about 0.15 g of dilauryldimethylammonium bromide (stabilizer) and about 0.30 g of poloxamer 188 (grinding aid) in about 12.3 g of water until the active ingredient was homogeneously suspended.

[123] This suspension was then placed in a 45 ml grinding bowl of the Fritsch

[124] The particle size distribution (PSD) was determined by laser diffraction and repeated again after 14 days of service life.

[125] In this example, too, a nanosuspension with an average particle diameter of <200 nm, which was stable, could be prepared after 5.5 h using the specified method.

[126] Example 6: Nanomahlung (Pulverisette 7, Fritsch) with 1% sodium glucocholate and 2% Poloxamer: Mahlkörper 0.5 mm. 750 rpm and service life over 14 days

[127] Ca, 2.25 g of cinnarizine (mean particle size <1700 nm) were added to a solution of about 0.15 g of sodium glycocholate (stabilizer) and about 0.30 g of poloxamer (grinding auxiliaries) in about 12.3 g Water was added until the drug was homogeneously suspended.

[128] This suspension was then placed in a 45 ml jar of Fritsch

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.

[129] The particle size distribution (PSD) was determined by laser diffraction and repeated again after 14 days of service life.

[30] Also in this example! After 5.5 h grinding with the specified method, a nanosuspension with an average particle diameter of

<200 nm are produced.

[131] 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

[132] Approx. 2.25 g of cinnarizine (average particle size <1700 nm) were added to a solution of about 0.15 g of SDS (stabilizer) and about 0.30 g of PVP VA 64 (grinding aid) in about 12.3 g of water, until the drug was homogeneously suspended.

[33] This suspension was then placed in a 45 ml grinding bowl of the Fritsch

[134] The particle size distribution (PSD) was determined by laser diffraction and repeated again after 14 days of service life.

[135] In this example as well, a nanosuspension with a mean particle diameter of

<200 nm, which was stable.

[136] 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

[137] Approx. 2.25 g of cinnarizine (average particle size <1700 nm) were added to a solution of about 0.15 g of dilauryldimethylammonium bromide (stabilizer) and about 0.30 g of PVP VA 64 (grinding assistant) in about 12.3 g of water, until the drug was homogeneously suspended.

[138] This suspension was then placed in a 45 ml grinding bowl of the Fritsch

[139] The particle size distribution (PSD) was determined by laser diffraction and repeated again after 14 days of service life.

[140] In this example as well, a nanosuspension with an average particle diameter of <200 nm, which was stable, could be prepared after 5.5 hours grinding with the given method.

[141] Example 9: Nanomahlung (Pulverisette 6. Fritsch) with 4% TPGS: grinding media 0.5 mm. 600 rpm

[142] 0.38 g of TPGS-1000 (stabilizer, previously gently melted at 50 ° C) were mixed with stirring 7.61 g of water until the TPGS was completely in solution. 1, 52 g of cinnarizine (mean particle size <1700 nm) were added to this solution until the drug was homogeneously suspended. [143] This suspension was then placed in a 12 ml Mahtbecher of the Fritsch Pulverisette 6. Subsequently, about 18 g of grinding balls (zirconium oxide) with a diameter of 0.5 mm were placed in the grinding bowl. The mixture was then ground at a speed of 600 rev / min with a change of direction at 30 min over a period of about 22 h. The temperature was controlled during milling and remained below 35 ° C.

[144] After 6.5 hours, particle size distribution (PSD) was determined by laser diffraction (Malvern, Master Sizer). The following particle sizes were determined:

[145] The suspension was again examined for particle size distribution after four days of service life (room temperature):

[146] In this example as well, 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.

[147] Example 10: Nanomahluna (VMA Getzmann) with 4% TPGS: grinding media 0.4- 0.7 mm. 6000 rpm

20.0 TPGS (stabilizer) were dissolved with 398.0 g of water and 2% of ethanol with stirring, and then 80.0 g of cinnarizine (average particle size <1700 nm) were homogeneously suspended in this solution. [149] The suspension was milled with grinding media (zirconium oxide) with diameters of 0.4 to 0.7 mm and a rotational speed of 6000 rpm for 4.5 h.

[150] This resulted in 469.4g nanosuspension with the following particle size distribution (Mastersizer):

[151] Example 1: Nanomouting (WAB) with 4% TPGS: grinding media 0.2-0.3 mm

[152] 60.0 g TPGS-000 (stabilizer, previously carefully melted at 50 ° C) were mixed with stirring with 600.1 g of water at about 45 ° C until the TPGS was completely in solution. 240.0 g of cinnarizine (mean particle size <1700 nm) were added to this solution until the drug was homogeneously suspended.

[153] 600.1 g of water were then added again to the TPGS solution.

1500 g of this suspension were then added to the grinding bowl of the WAB mill. Subsequently, grinding balls (zirconium oxide) with 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 0.65 to 0.75 bar. The temperature remained below 45 ° C.

[154] Milling runs of several hours were carried out. The results of the individual milling runs are listed in the following table.

[155] The desired particle size distribution with a d50 of <200 nm was reached after the second milling pass.

[156] Example 12: Nanofibre fWAB) with 2% TPGS: grinding media 0.2-0.3 mm

[157] 30.1 g TPGS-1000 (stabilizer, previously carefully melted at 50 ° C) were mixed with stirring with 6 5.0 g of water at about 45 ° C until the TPGS was completely in solution. 240.0 g of cinnarizine (mean particle size <1700 nm) were added to this solution until the drug was homogeneously suspended.

[158] Afterwards, another 615.0 g of water were added to the TPGS solution.

1290 g of this suspension was then added to the grinding bowl of the WAB mill. Subsequently, 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 0.8 bar. The temperature remained below 35 ° C.

[159] Milling runs of several hours were carried out in each case. The results of the individual milling runs are listed in the following table.

[160] Already after the second grinding pass the desired

Particle size distribution achieved with a d50 of <200 nm.

[161] Example 13: Nanomolar (WAB ^ with 1% TPGS: grinding media 0.2- 0.3 mm

[162] 16.0 g TPGS-1000 (stabilizer, previously carefully melted at 50 ° C) were mixed with stirring 664.0 g of water at about 45 ° C until the TPGS was completely in solution. 256.0 g of cinnarizine (mean particle size <1700 nm) were added to this solution until the drug was homogeneously suspended. [163] Thereafter 664.0 g of water were again added to the TPGS solution. 1588 g of this suspension were then added to the grinding bowl of the WAB mill. Subsequently, 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.

[164] Milling cycles of several hours were carried out in each case.

After the third grinding pass, it was stopped because the mean particle diameter of cinnarizine in the nanosuspension was still 1460 nm. The concentration of 1% TPGS thus leads to long meals in order to achieve the desired particle size (see Example 13).

Isolation of the nanoparticles

[165] Example 14: Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and TPGS

[166] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[167] 1 ml of this nanosuspension was added to 1 ml of a solution of 0.8 g of mannitol (isolation adjuvant) in 10 ml of water and 0.16 g of TPGS (stabilizer) with stirring until the suspension was homogeneous.

[168] 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:

[169] The mean particle sizes of the nanoparticles were determined by the

Lyophilization process not significantly increased. [15] Betspiel 15: Lvophilisation of the nanosuspension with 4% TPGS in the presence of mannitol and PEG 1500

[171] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[172] 1 ml of this nanosuspension was added to 1 ml of a solution of 0.8 g of mannitol (isolation aid) in 10 ml of water and 0.16 g of PEG 1500 (isolation aid) with stirring until the suspension was homogeneous.

[173] 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:

[174] The mean particle size of the nanoparticles was determined by the

Lyophilization process not significantly increased.

[175] Example 16: Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and Gelucire 44/14

[176] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[177] 1 ml of this nanosuspension was added to 1 ml of a solution of 0.8 g of mannitol (isolation adjuvant) in 10 ml of water and 0.16 g of Gelucire 44/14 (isolation adjuvant) with stirring until the suspension was homogeneous.

[178] 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]

PSD 190 610

[179] The mean particle size of the nanoparticles was determined by the

Lyophilization process not significantly increased.

[180] Example 17: Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and poloxamer 188

[181] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[182] 1 ml of this nanosuspension was added to 1 ml of a solution of 0.8 g of mannitol (isolation adjuvant) in 10 ml of water and 0.16 g of Poloxamer 188 (isolation adjuvant) with stirring until the suspension was homogeneous. The final isolation mixture 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.

[183] The dried lyophilizate gave the following particle size distribution:

[184] The mean particle size of the nanoparticles was determined by the

Lyophilization process not significantly increased.

[185] Example 18: Lvophilization of the nanosuspension with 2% TPGS in the presence of poloxamer 88

[186] The 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.

[188] 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.

[89] The dried lyophilizate (yield 79.9 g) gave the following

Particle size distribution:

[190] The mean particle size of the nanoparticles was determined by the

Lyophilization increased only slightly.

[191] Example 19: Lyophilizates of nanosuspension with 4% TPGS in the presence of poloxamer

[192] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[193] 1 ml of this nanosuspension was added to 1 ml of water and 0.1 g of Poloxamer 188 (isolation aid) with stirring until the suspension was homogeneous.

[194] 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.

[195] The dried lyophilizate gave the following particle size distribution:

D50 [nm] D90 [nm] PSD 180 760

[196] The mean particle size of the nanoparticles was determined by the

Lyophilization process not significantly increased.

[197] Example 20: Lvophilization of the nanosuspension with 4% TPGS in the presence of mannitol and poloxamer

[198] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[199] 1 ml of this nanosuspension was added to 1 ml of water containing 0.05 g Poloxamer 188 (isolation adjuvant) and 0.05 g mannitol (isolation adjuvant) with stirring until the suspension was homogeneous.

[200] 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.

[201] The dried lyophilizate gave the following particle size distribution:

[202] The mean particle size of the nanoparticles was determined by the

Lyophilization increased only slightly.

[203] Example 21 Lvophilization of the nanosuspension with 4% TPGS in the presence of PEG 6000 and Gelucire 50/13

[204] The nanosuspension was prepared analogously as described in Example 10.

[205] 235 g of this nanosuspension were added with stirring to a solution of 226 g of water and 14.4 g of PEG 6000 (isolation aid) and 9.6 g of Gelucire 50/13 (isolation aid), followed by lyophilization. [206] The lyophilization takes place in a Christ LPC -16 / NT plant. The freezing temperature was -45.degree. C. and was gradually raised to 5.degree. C. in the course of the primary drying, finally the temperature was further increased and the secondary drying was carried out at 25.degree. The vacuum was 0.7 mbar for the primary and secondary drying. The total freeze-drying time was about 36h.

[207] The particle size distribution of the dried nanoparticles was determined by laser diffraction:

[208] Lyophilization only marginally increased the mean particle size from 159 to 220 nm.

[209] Example 22: Lyophilization of the nanosuspension with 4% TPGS in the presence of mannitol. PEG 6000 and Gelucire 50/13

[2 0] The nanosuspension was prepared as described in Example 9 and had the same particle size distribution.

[211] 1 ml of this nanosuspension was added to 1 ml of water containing 0.03 g of PEG 6000 (isolation adjuvant), 0.05 g of mannitol (isolation adjuvant) and 0.02 g of Gelucire 50/3 (isolation adjuvant) with stirring. until the suspension was homogeneous.

[212] 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.

[213] The dried lyophilizate gave the following particle size distribution:

[214] The mean particle size of the nanoparticles was only slightly increased by the lyophilization process.

[215] Example 23: Lvophilization of the nanosuspension with TPGS and poloxamer 188

[216] The nanosuspension was prepared analogously as described in Example 10.

[217] 230 g of this nanosuspension became a solution with stirring

226 g of water and 24 g Poloxamer 188 (isolation aid) and then lyophilized.

[218] The lyophilization took place in a Christ LPC -16 / NT plant. The glass transition temperature was -45 ° C and was gradually increased in the course of primary drying to 5 ° C and finally the temperature further increased and carried out the secondary drying at 25 ° C. The vacuum was 0.7 mbar for the primary and secondary drying. The total freeze-drying time was about 36h.

[219] The particle size distribution of the dried nanoparticles was determined by laser diffraction:

[220] Due to lyophilization, the average particle size increased only insignificantly from 159 to 220 nm.

[221] Example 24: Fluidized bed drying of the nanosuspension with 1%

Dilauryldimethylammonium bromide on the carrier lactose (matrix material)

[222] The nanosuspension was prepared analogously to Example 7, but with a 25% concentration of cinnarizine.

[223] Approx. 60 g (equivalent to about 15 g of cinnarizine) of the nanosuspension prepared was by top spray method in a Glatt Mini fluidized bed granulator at a fluidized bed temperature of about 45 ° C and a spray rate of about 30 ml / min. sprayed on the carrier lactose monohydrate. It was then cooled to about 20 ° C and the granules in a drying oven at 55 ° C over several Hours dried. The dried granules were processed with standard excipients to the tablet.

[224] The cinnarizine nanoparticles were measured by laser diffraction before fluidized bed granulation and immediately after granulation in fluid bed granules:

By embedding was only a very small increase in

Particle diameter observable.

[226] Example 25: Fluidized bed drying of nanolosuspension with 1%

Dilauryldimethylammonium bromide on the carrier microcrystalline cellulose (Matrix materiah

[227] The nanosuspension was prepared analogously to Example 7, but with a 25% concentration of cinnarizine.

[228] Approx. 60 g (equivalent to about 15 g cinnarizine) of the nanosuspension prepared was by Top-spray method in a Glatt Mini fluidized bed granulator at a fluidized bed temperature of about 45 ° C and a Sprühgeschwindigkett of about 30 ml / min. sprayed on the carrier microcrystalline cellulose. It was then cooled to about 20 ° C and dried the granules in a drying oven at 55 ° C for several hours. The dried granules were processed with standard excipients to the tablet.

[229] The cinnarizine nanoparticles were measured by laser diffraction before fluidized bed granulation and immediately after granulation in fluid bed granules:

PSD of the granules 63 122 251

By embedding was only a very small increase in

Particle diameter observable

[231] Example 26: Hot Melt Extrusion of Cinnarizine Nanoparticles with Poloxamer 188

[232] 15.0 g of cinnarizine (mean particle size distribution <1700 nm) and 15.0 g of poloxamer 188 (matrix material) were mixed in a Turbula mixer and 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.

[233] The results of the particle size measurement (after dissolving the water-soluble matrix) revealed:

[234] The particle size of the active ingredient used remained virtually unchanged.

[235] Example 27: Hot melt extrusion of cinnarizine nanoparticles with PEG 6000

[236] 15.0 g of cinnarizine (mean particle size distribution <1700 nm) and 15.0 g of PEG 6000 (matrix material) were mixed in a Turbula mixer and 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.

[237] The particle size of the active ingredient used remained virtually unchanged.

[238] Example 28: Hot Melt Extrusion of Cinnarizine Nanoparticles with PEG 6000 and Gelucire 50/13

[239] 15.0 g of cinnarizine (mean particle size distribution <1700 nm), 9.0 g of PEG 6000 (matrix material) and 6.0 g of Gelucire 50/13 (matrix material) were mixed in a Turbula mixer and used in a laboratory extruder from the company. Thermo Haake at one ner temperature of 62 ° C extruded. The white, smooth extrudate strands were then ground in a small laboratory mill and filled into hard gelatin capsules for analytical testing. The yield of the extrudate was about 83%.

[240] The particle size of the active ingredient used remained virtually unchanged.

[241] Example 29. Hot Melt Extrusion of Cinnarizine Nanoparticles with Kollidon VA 64 and Imwitor 900 (Glvcerol Monostearate)

[242] 12.0 g of cinnarizine (mean particle size distribution <1700 nm), 12.6 g of Kollidon VA 64 (matrix material) and 5.4 g of Imwitor 900 (matrix material) were mixed in a Turbula mixer and placed in a laboratory extruder from Thermo Haake extruded at a temperature of 110 ° C. The white, smooth extrudate strands were then ground in a small laboratory mill and filled into hard gelatin capsules for analytical testing. The yield of the extrudate was 86%.

[243] The particle size of the active ingredient used remained virtually unchanged.

[244] Example 30: Hot melt extrusion of cinnarizine nanoparticles with Kollidon and Imwitor 900

[245] 9.0 g of cinnarizine (mean particle size distribution <1700 nm), 14.7 g of Kollidon VA 64 (matrix material) and 6.3 g of Imwitor 900 (matrix material) were mixed in a Turbula mixer and used in a laboratory extruder from Thermo Haake extruded at a temperature of 1 10 ° C. The white, smooth extrudate strands were then ground in a small laboratory mill and filled into hard gelatin capsules for analytical testing. The yield of the extrudate was 86%.

[246] The particle size of the active ingredient used remained virtually unchanged.

[247] Example 31: Hot melt extrusion of cinnarizine nanoparticles (containing TPGS) with oloxamer 188

[248] 62.3 g of the dried nanoparticles (see Example 23) are mixed with 5.1 g

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.

[249] The results of the particle size measurement {after dissolving the water-soluble matrix) showed:

[250] The particle size of the active ingredient used has increased slightly compared with the dried nanoparticles.

[251] Example 32: Hot melt extrusion of cinnarizine nanoparticles (containing TPGS) with poloxamer 188

[252] 60.0 g of the dried nanoparticles {s. Example 25) are 8.8 g

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.

[253] The results of the particle size measurement (after dissolving the water-soluble matrix) revealed:

[254] The particle size of the active ingredient used has increased slightly compared to the dried nanoparticles.

Further processing to the dosage form

[255] 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 Cinnarizinpartikel.

[257] The impurities and cinnarizine content are constant over the storage period, i. the larger surface of the contained nanoparticles does not lead to a change of the purity profiles.

[258] The following table shows stability data of the particle size distribution of the cinnarizine active ingredient in the produced hot melt extrudates over the storage time at about 25 ° C.

[259] The following table shows stability data of the particle size distribution of the cinnarizine active ingredient in the produced hot melt extrudates over the storage time at 40 ° C./75%

D90 2894mm

pictures

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. [Dressman 1998] Fast State Simulated Gastric Fluid (pH 6.1), FaSSIF (Fast State Simulated Intestine Fluid, pH = 6.5) and FeSSIF (Fed State Simulated Intestine Fluid pH = 5.8) were used taken periodically during the release process and analyzed by HPLC for cinnarizine content Mean data were plotted and the resulting release profiles compared with those of the standard commercial preparation.

[261] Cinnarizine is an excellent model substance for studying the behavior of poorly water-soluble drugs and was therefore chosen for the investigations.

[262] 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. For comparison, 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.

[264] Figure 3 shows the drug release of cinnarizine from the extrudates and nanosuspensions of this invention in FeSSIF according to Dressman et al. For comparison, 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.

[265] Figure 4 shows the drug release of cinnarizine from fluidized bed granules of this invention in FaSSIF according to Dressman et al. For comparison, 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.

[266] It can be seen from the figure that the cinnarizine is initially released very rapidly from the matrices according to the invention. It forms a supersaturated solution from which the active substance crystallizes out again. Since the crystallization effect occurs very quickly, it can be assumed that the initially released amount is even greater than was measured. The dissolution curve is superimposed by the opposite crystallization curve.

[267] 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.

Claims

claims

A process for the preparation of a pharmaceutical dosage form comprising cinnarizine, a matrix material and a stabilizer, comprising the steps of: a. Comminution of cinnarizine to nanoparticles, b. Embedding the nanoparticles in a matrix such that a particle matrix is obtained which comprises a matrix material, cinnarizine and a stabilizer, during which process an amount of stabilizer is added such that an amount of substance of the stabilizer of at least 0.5 nmol / m ^{2 is present} in relation to the surface of Cinnarizins.

A process according to claim 1, wherein for the purpose of comminuting the cinnarizine or a milling mixture is prepared comprising cinnarizine, a milling fluid and the stabilizer.

3. The method of claim 1 or 2, wherein the stabilizer is an ionic surfactant, a nonionic surfactant or a mixture of surfactants.

4. The method according to at least one of claims 1 to 3, wherein the stabilizer

Sodium dodecyl sulfate, dilauryldimethylammonium bromide, sodium glycocholate, TPGS, polysorbate 80, or mixtures thereof.

5. The method of claim 2, wherein the grinding mixture also comprises grinding aids selected from water-soluble polymers, sugars, sugar derivatives and mixtures thereof.

6. The method according to any one of the preceding claims, wherein the nanoparticles have an average particle size of less than 2000 nm.

7. The method according to any one of the preceding claims, wherein a molar amount of the stabilizer of not more than 10 μιηοΙ / m ² based on the surface of Cinnarizins present.

A pharmaceutical dosage form comprising cinnarizine, a matrix material and a stabilizer, wherein the stabilizer is present in a molar amount of at least 0.5 nmol / m ² relative to the surface of the cinnarizine.

9. Dosage form according to claim 8, wherein this can be produced by a method according to one of claims 1 to 5.

10. Dosage form according to claim 8 or 9, comprising dimenhydrinate.

11. The dosage form according to any one of claims 8 to 10, wherein the active ingredient is present in an average particle size of less than 2000 nm.

12. Dosage form according to any one of claims 8 to 10, wherein the amount of substance of the stabilizer is not more than 10 μητιοΙ / ηη ² based on the surface of Cinnarizins.