EP3349733A1

EP3349733A1 - Formulation having controlled, delayed active-ingredient release

Info

Publication number: EP3349733A1
Application number: EP16760385.1A
Authority: EP
Inventors: Finn BAUER; Thorsten Wedel; Guenter Moddelmog; Gudrun BIRK; Roberto Ognibene; Dieter Lubda
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2015-09-14
Filing date: 2016-08-25
Publication date: 2018-07-25
Also published as: US20190038562A1; AU2016321659A1; CA2998422A1; WO2017045742A1; JP6841819B2; US10874615B2; US20200246270A1; JP2018530538A; KR20180052126A; CN108024966A

Abstract

The invention relates to new pharmaceutical formulations that have controlled, delayed active-ingredient release, and to a method for producing such formulations. The invention further relates to the use of these new galenic dosage forms as drugs for treating diseases that require a delayed release of the active ingredient, such as hypertension, or asthmatic diseases.

Description

Formulation with controlled, delayed

release

The present invention relates to novel pharmaceutical formulations which have a controlled, sustained-release drug delivery, and to a process for the preparation of such formulations. The invention also relates to the use of these new galenicals

Dosage forms as a medicament for the treatment of diseases which require a sustained release of the active substance, such as

Hypertension or asthmatic diseases.

State of the art

Propranolol belongs to the active ingredient group of beta-blockers with antihypertensive, anti-anginal and antiarrhythmic properties. Even if this drug was already introduced in 964 as the first ß-receptor blocker in the therapy, and now a variety of different derivatives in various dosage forms are known, especially to

Propranolol is still a commonly used beta-blocker to circumvent unwanted effects and to achieve certain beneficial effects.

The substance shows good solubility and is almost completely absorbed after oral administration, but has only a limited bioavailability of about 25-30% due to a pronounced first-pass metabolism and the elimination half-life of 2-6 hours is quite short.

Because of its lipophilicity, propranolol is almost completely absorbed from the intestine. [Asmar R, Hugues Ch, Pannier B, Daou J, Safar ME; Eur. Heart J. (1987) 8 (Suppl. M): 115-120. ]. According to the physical properties described, conventional administration forms for oral administration of

Propranolol to a rapid release of the total drug dose in the gastrointestinal tract, so that the blood pressure lowering effect starts quickly. Simultaneously with the short elimination half-life of

Propranolol can not readily produce the desired effect for 12

Hours or more can be guaranteed. With usual formulation is therefore, administer a suitable dose at least twice daily to maintain sufficient drug concentration in the patient's blood plasma over such a period of time. However, the need for repeated dosing throughout the day will easily lead to errors in ingestion as well as undesirable fluctuations in plasma concentration, which is detrimental to compliance and therapeutic benefit.

The same applies to the Purinalkaloid known since 1888 Theophylline, which is used for the treatment of asthmatic diseases. For

Theophylline, the plasma half-life in healthy adults is usually between 7 and 9 hours. In smokers, this is significantly reduced to 4 to 5 hours and in children to 3 to 4 hours. Therefore, in order to maintain the plasma level at an effective level of concentration throughout the day, it is necessary in this case to administer a dose several times a day.

In pharmacology it is known per se to provide dosage forms with prolonged or delayed release of the active substances contained therein, in order to ensure a continuous release of the active substance over a longer period of time.

Slow-release formulations for a large number of active substances are known in the prior art, including β-blockers such as propranolol or also theophylline. Usually, the retardation by suitable coatings and / or by the embedding of the drug in a the

Release controlling matrix realized.

In the case of coating retardations, an active ingredient-containing core is provided with a release-agent-delaying coating of hydrophilic and / or hydrophobic polymers. In matrix retardation, the drug is embedded in a polymer matrix that controls the release of the drug. Usually, the production of such sustained-release formulations comprises special process steps, but possibly also special ones Measures, such as the production of a special coating, and

where appropriate, the use of specially selected

Compounds or polymers which induce a delayed release of active ingredient.

Thus, in the case of the propranolol prolonged-release preparation Innopran XL ™ by the formulation and by a timed intake

"Delayed" absorption from the gastrointestinal tract can be achieved

Plasma concentrations occur only in the morning, so at a time that is considered particularly critical for hypertensive patients [Sica D., Frishman W.H., Manowitz N.: "Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or

Propranolol CR (Innopran XL ™), a new chronotherapeutic formulation "; Heart Dis (2003) 5: 176-181.]. This preparation is to be both a prolonged release of active ingredient as well as by the evening intake, the plasma concentration can be controlled, so It is highest in the morning, when the blood pressure is usually highest in patients over the course of the day, but side effects have been reported with this formulation and the route of administration, possibly with the specific course of the daytime changes

Plasma concentration [Warnke, A .; Blume, H. "Improved therapy by optimized drug forms?"; Pharm, our time Vol. 33 (6), 456 - 463].

task

The present invention is therefore based on the object, a pharmaceutical sustained release formulation of drugs such as propranolol, or one of its pharmaceutically acceptable salts, or provide theophylline, which has advantages over the formulations of

Prior art has. Due to the unfavorable kinetic properties of propranolol, a multiple dosing per day is usually necessary, which is common leads to inadequate patient compliance and, consequently, to an unsatisfactory therapeutic outcome. It is therefore desirable to reduce the frequency of taking the medication to a single dose per day.

So the dosage form should be pharmacologically effective

Ensure plasma concentrations of the drug propranolol over a longer period, preferably for at least 12 hours, but especially for 24 hours (controlled release), whereby the administration scheme can be simplified.

At the same time, it is an object of the present invention to provide a formulation with improved pharmacokinetic behavior in comparison to

To provide comparative formulations, by the possible side effects, such as a rapid onset of drug and an associated high blood pressure drop, can be reduced. Furthermore, it is an object of the present invention, by the changed

Drug release to achieve improved patient compliance.

Brief description of the invention

The object is achieved by a process for the preparation of a pharmaceutical dosage form of an extended release composition as characterized by claims 1-8, as well as by novel pharmaceutically active sustained-release compositions according to claims 9 to 26 using Co-mixtures for use in

pharmaceutical formulations of approved polyvinyl alcohols and microcrystalline celluloses have been prepared.

In particular, this object is achieved by a method for

Preparation of a galenic dosage form of a sustained-release composition, wherein

a) one for use in pharmaceutical formulations

approved polyvinyl alcohol at low temperatures in the range of minus 30 ° C to 0 ° C to a fine powder with medium Parttkelgröße Dv50 in the range of 50 - 100 μιτι, preferably in the range of Dv50 60 - 95 μιη, ground, and

b) with microcrystalline cellulose of average particle size Dv50 im

Range of 100 to 150 μηη is mixed intensively, and

c) this mixture with a sufficient amount of the active ingredient

is mixed,

e) if appropriate, additives which are advantageous for further processing, such as flow agents or lubricants, are added and

f) after sufficient mixing of the resulting mixture and

optionally after sifting through a 800 μm sieve for

Removal of remaining agglomerates by pressing at a suitable pressure is tableted.

In particular, polyvinyl alcohol and microcrystalline cellulose in the ratio of 2: 1 to 1: 2, preferably in the ratio of 1.5: 1 to 1: 1, 5, in particular of 1: 1 based on the total amount of co-mixture intensively mixed ,

As active ingredients, all active ingredients can be mixed as such or in the form of their pharmaceutically acceptable salts, hydrates or solvates with the co-mixture in the process according to the invention and processed into tablets which require a minimum concentration in the blood plasma for their effectiveness over the entire day. In a special

Embodiment of the method according to the invention is in c) as

Propranolol and / or its pharmaceutically acceptable salts, hydrates or solvates are added in an effective amount to the co-mixture and mixed with. In another exemplified embodiment, theophylline, anhydrous or its monohydrate in c) is used as the active ingredient.

Before compressing the active ingredient-containing mixture, additional additives can be added in small amounts as processing aids to the mixture and mixed with. These may be, for example, small amounts of silica as a flow agent and magnesium stearate as a lubricant. In the subsequent process step, the active ingredient-containing mixture obtained with sufficient pressing force to tablets pressed. Preferably, when pressed with a pressing force in the range of 5 to 32 kN, tablets having hardnesses in the range of 50 to 290 N are obtained. Regardless of their respective hardness, the tablets according to the invention produced in this way have an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours.

Consequently, the object of the present invention by the

To provide a pharmaceutically active composition having prolonged drug release and prepared by the previously characterized method. In a special

Embodiment, the present invention relates to a

corresponding pharmaceutically active composition containing the active ingredient propranolol and / or its pharmaceutically acceptable salts, hydrates or solvates as hypotensive β-blocker and a co-mixture of microcrystalline celluloses and polyvinyl alcohols. In particular, this relates to corresponding pharmaceutically active compositions containing propranolol as hydrochloride or

Succinate or theophylline.

Good release properties have pharmaceutically effective

Compositions containing a co-mixture of microcrystalline

Celluloses and polyvinyl alcohols in the ratio of 2: 1 to 1: 2, preferably in the ratio of 1, 5: 1 to 1: 1, 5, in particular 1: 1 based on the total amount of the co-mixture, and wherein the polyvinyl alcohols selected are from the types 18-88, 26-88, 40-88, 48-88 and all intermediate qualities according to the

Pharmacopoeia requirements Ph. Eur., USP or JPE, including type 28-99 according to the requirements of JPE or Ph. Eur. And those in the co-mixture of average particle size fractions in the range of Dv50 50-100 μηη, preferably in the range of Dv50 60 - 95 pm. Particular preference is given to those compositions which comprise a co-mixture of microcrystalline celluloses and polyvinyl alcohol of the type 26-88 and / or 40-88, the polyvinyl alcohols in the co-mixture before pressing having average particle size fractions in the range from Dv50 60-95 μm and a bulk density in the range of 0.40 to 0.65 g / ml, preferably 0.45 to 0.60 g / ml, and a tamped density in the range of 0.50 to 0.80 g / ml, in particular in the range of 0.55 to 0.75 g / ml. Corresponding compositions can

Silicon dioxide as a flow agent and magnesium stearate as a lubricant. There may also be added other additives.

The present invention relates in particular to those pharmaceutically active compositions which have been compressed into tablets having hardnesses in the range from 50 to 290 N and which have an average release rate of 80% of the active substance in a time of at least 9 to 12 hours. It is particularly advantageous in this context that the release profile is almost independent of the hardness of the tablets. Corresponding tablets show a moderate initial release of active ingredient and then a uniform release of active ingredient, whereby an undesirable flooding of active ingredient is avoided. The inventively provided galenic dosage form with prolonged release of active ingredient is for oral use. It contains the active substance in a matrix which releases the active substance in the presence of liquid in the gastrointestinal system (GIT) by diffusion and / or gradual erosion. The inventive

Compositions in the form of tablets contain the active ingredient in low to high amounts per dosage, such as in an amount of 10 to 140 mg of the active ingredient calculated as propranolol per dosage. Thus, a corresponding pharmaceutical dosage form in the form of a prolonged release composition with

Propranolol hydrochloride as active ingredient in an amount of 80 or 160 mg per dosage. The same applies to theophylline-containing formulations according to the invention.

Detailed description of the invention

Pharmacologically important for the development of galenic

Above all, formulations for β-blockers are the positive inotropic and chronotropic effect of catecholamines suppressed by blockade of β1 receptors at the heart. Basically, nonselective beta-blockers (including propranolol, nadolol, penbutolol, carvedilol) can be selected from β1 -selective

Receptor blockers (including metoprolol, atenolol, bisoprolol) differ. However, this selectivity of inhibition of β1 receptors is not absolute, but concentration dependent, at higher levels

Concentrations can also be an attack on the ß2 receptors

[Kendall, M.J .: Clinical Relevance of Pharmacokinetic Differences Between Beta Blockers In: Am J Cardiol (1997) 80, 15-19.]. Since the final concentrations also depend on the properties of the dosage form, the galenic aspects are likely to be of importance in this respect as well. For example, in the development of galenic

Preparations for once-daily use, care should be taken to avoid peak levels above this "selectivity limit" in order to limit the risk of pulmonary side effects.

Although active ingredients with higher lipophilicity, such as propranolol, are largely completely absorbed from the intestine, they are usually subject to a pronounced F / rsf-pass effect, which is often associated with pronounced variability. They are predominantly hepatically eliminated and have shorter plasma half-lives.

Given an elimination half-life of 2 to 6 hours,

For example, from propranolol, is the evolution of

Retardzubereitungen for such drugs from a pharmacokinetic perspective so desirable, especially to allow a once-daily application.

Due to the excellent solubility and good permeability of the active ingredients such. B. of propranolol is, as already indicated, assume that the inclusion of the active ingredients from the gastrointestinal tract in the organism depends on their release from the drug form and that the drug absorption by the biopharmaceutical

Characteristics of the respective ingested preparation is determined. Especially with regard to improving patient compliance, "once-a-day forms" offer benefits, and at the same time, this application sufficient efficacy throughout the day therapeutically desirable. For sustained-release formulations of β-blockers too, adequate blockade of the β-receptors throughout the entire day should be sought therapeutically, in particular in order to achieve a constant reduction in hypertension. In this respect, it should be ensured by the sustained-release preparation that the active substance concentration, or propranolol concentration, is above the minimum effective level during the entire dose interval. Problems to be solved in the development of such a sustained-release formulation are:

1. the simplest possible preparation of the active substance-containing formulation, wherein complex sustained-release formulations, such as e.g. Extrusion pellets should be avoided.

2. that the in vitro release behavior from such a modified formulation should be as identical or better as possible to that of already marketed retarded oral

Active ingredient preparations, such as a known

Propranololmedikation.

Experiments have now surprisingly found that a

Dosage form of the active substance propranolol or one of its

pharmaceutically acceptable salts, or other readily soluble active substance such as theophylline, in which the active ingredient is released in a controlled manner over at least 9 to 12 hours, at best over 24 hours, and this dosage form above has even more advantages over the known dosage forms of the prior art. The present invention thus relates to a dosage form for

controlled release of an active ingredient, in particular of propranolol, or one of its pharmaceutically acceptable salts, from which in vivo after a short time an effective amount of active ingredient is released, so that a sufficient plasma level is reached, and from which, after reaching the effective plasma level, evenly distributed throughout the day drug is released in such a way that even after 9 hours, especially after 12 hours or 24 hours an effective

Plasma concentration is ensured after at least 80% of the original amount of active ingredient contained in the dosage form have been released.

In standardized experiments, such values for propranolol hydrochloride and theophylline were measured anhydrously in vitro, the

Release values according to the European Pharmacopoeia with a

Blauftrührepparatur in buffer at a pH of 6.8 (preferably 900 ml), and a temperature of 37 ° C and at 50 rev / min have been determined. The results can be found below in the paragraph "Examples".

The galenic is known to have various procedures for preparing sustained-release drug formulations. Which type of formulation is preferable in the specific case depends on the

desired effect of the drug and the field of application, but also from the chemical and physical properties of the drug. From the literature is known, sustained release formulations using

produce suitable hydrophilic macromolecules and to use the latter as soluble matrices, or hydrocolloid matrices.

Corresponding macromolecules are highly swellable in the presence of water. By using moderately soluble in water

Carrier substances form highly viscous systems, from which the incorporated active substance can be delivered with a delay. The

Release is then dependent on both the entry of the fluid into the system and the rate of diffusion of the drug through the gel layer. Often this has the consequence that initially a relatively high

Drug concentration is released, but later the

Release of active ingredient drops as a result of the longer diffusion distance.

However, other less swelling hydrocolloids are gradually dissolved. In this case, the extent and speed of the sustained-release release depend on the erosion of the system. It does not come under these conditions during the duration of the release to an extension of the diffusion path, so that under favorable conditions results in a nearly constant release rate.

In both cases, drug delivery is more dependent on the swelling or erosion of the hydrocolloid matrix than on the solubility behavior of the drug itself. Therefore, such systems can be used especially for slightly soluble drugs.

In the present case, readily water-soluble active substances, which moreover also have rather short elimination half-lives in the range of 2 to 6 hours, should be dosed uniformly over the course of at least 9 hours, preferably of at least 12 hours or of 24 hours from the formulation, In addition, for a short time high releases, so a drift of drug must be avoided because, for example, the drug propranolol acts as unselective ß-blocker by occupying the ß-receptors directly on the blood pressure of the patient. Moreover, it is desirable through the

Retarded Release also at the end of the release period of 12, or optionally 24 hours to maintain an effective plasma concentration, for example, to avoid an undesirable increase in blood pressure.

Surprisingly, it has now been found that the problems mentioned in the development of a corresponding oral formulation with a sustained release of active ingredient can be achieved in a simple manner by adding the active ingredient, or, as shown by the following examples, the propranolol (preferably as hydrochloride) or the

Theophylline (anhydrous) with a co-mixture consisting of

Polyvinyl alcohol (PVA) and microcrystalline cellulose (MCC), physically mixed and processed into a directly compressed tablet. In for the

Polycarboxylic acid (PVA) and microcrystalline cellulose (MCC) in a ratio of 2: 1 to 1: 2, preferably in the ratio of 1: 1, 5 to 1, 5: 1 based on the total weight of the sustained-release formulations according to the invention available. Particularly preferred for this purpose is a co-mixture in which the components are contained in the ratio of 1: 1 based on the total weight. To prepare the slow-release formulation according to the invention, a corresponding co-mixture with the active substance can be added and intensively mixed with very small amounts of a flow agent and a lubricant, so that the active ingredient is homogeneously distributed in the mixture. The resulting mixture is then in a

Direct compression process processed on a tabletting machine to Compressaten.

The use of the hydrophilic polymer polyvinyl alcohol (PVA) causes swelling and gelation in the presence of liquid in the gastrointestinal tract and in the course of the residence time in the GI tract (GIT) and gradual erosion of the polymer mixture, with a delayed Drug release from the PVA matrix is induced. Examinations of the tablet formulations according to the invention have surprisingly shown that the release of active ingredient is controlled over time, as required, so that there is no increased release, especially in the beginning, which leads in the case of propranolol to an undesired increased drop in blood pressure would. This drug release scheme can be described with the

Although it was in the investigated

Propranolol is a readily soluble in the presence of water active ingredient.

The formulation according to the invention is therefore characterized by the following advantages:

1. It is very simple and inexpensive, as well as complication free

producible by the individual components, including the

Substance, be formulated by simply mixing and then pressing a prolonged-release tablet. They are not complex

Granulation, extrusion or coating process necessary for the production.

2. The compressibility data show that even at low compression forces tablets with sufficient hardness and surprisingly low abrasion so that the tablets are easily processed and handled by the patients.

3. During the compression of the active substance-containing mixture very low ejection forces are needed, so that associated with even small amounts of lubricant are required. As a result, the mechanical device load (esp. Of

Tablettierwerkzeuge) reduced. 4. Experiments have shown that the in vitro drug release

These prolonged-release tablets over a very wide Presskraft- and

Talettenhärtebereich remains virtually unchanged. As a result, a good production and thus also increased patient safety is given.

5. Comparisons have shown that the invention

Tablet formulations in their in vitro release behavior are identical to the commercially available medications used therapeutically (such Dociton ^® 160 mg retard: retarding pellets filled into a hard gelatin capsule).

The present invention thus comprises a matrix tablet which is obtained by simple direct compression of an active compound with a co-mixture consisting of PVA and MCC, and which surprisingly has an in vitro release behavior analogous to one in the

Producing significantly more complex reference product.

The simple tablet formulations thus obtained show good

galenic properties in terms of compressibility and handling, but also a surprisingly good in vitro release behavior.

The good compressibility of the co-mixtures used is reflected in high hardness of the tablets produced already during compression with relatively low pressing forces. By definition, the tablet hardness refers to the force required to contain a compressed one containing the co-mixture Tablet to crush between two parallel plates or jaws. The tablet hardness can be measured by the first step

Making tablet by compressing a certain amount of the mixture in a tablet press with a predetermined compression force. In this case acts in the mold of the tablet press a stamp on the weighed, filled amount of the mixture with a pressing force of, for example, about 20 kN. The hardness of the tablet obtained in this way can then determine by measuring the force required to crush the tablet strength, for example, a tablet hardness tester Erweka Multicheck ^® 5.1 (Fa. Erweka, Germany). The determination of the tablet hardness is described below.

As already stated above, the inventively produced

Tablets as a further advantageous property in mechanical

Stress on a low abrasion (low friability) on.

The friability is understood to mean the abrasion that occurs in the case of solid bodies, in this case in the case of tablets, due to the action of mechanical forces

Energy, z. B. during transport, storage, but also during further processing or packaging. Friability is determined by standardized methods. In the conducted determinations of the examples described here became a

The device is operated according to Ph. Eur 7th edition "Friability of Uncoated Tablets" The device operates at a fixed speed of 25 min ^-1 of tablets loaded with tablets The measurements are carried out one day after the test

Tablet manufacturing. As already described above for the production of

Co-mixtures of polyvinyl alcohol and microcrystalline cellulose according to the invention particularly well suited. Polyvinyl alcohol (PVA) is a synthetic polymer produced by

Polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer is produced. Chemical and physical

Properties of PVA (such as viscosity, solubility, thermal

Properties, etc.) are highly dependent on its degree of polymerization (chain length of the PVA polymer) and the degree of hydrolysis. PVA is suitable for a variety of administration forms in the treatment of a variety of diseases. It can therefore be in the most diverse

pharmaceutical dosage forms, including in formulations for ophthalmic, transdermal, topical and

especially for oral applications.

The experiments carried out here have shown, in particular, that the tableted formulations have particularly advantageous properties

when the polyvinyl alcohols are selected from the group of types 18-88, 26-88, 40-88, 48-88 and all grades therebetween according to the requirements of Pharmacopoeia Ph. Eur., USP or JPE, including Type 28 -99 according to the requirements of the JPE or Ph. Eur. For the type designation, the first figure refers to the viscosity, which in aqueous solution at 20 ° C as a relative measure of the

Molar mass of the polyvinyl alcohol (measured in a 4% solution at 20 ° C according to DIN 53 015 in distilled water at a pH in the range of 4.5 to 7 for both partially and completely hydrolyzed polymer, according to DIN 19 260 / 61). The second number of the type designation refers to the degree of hydrolysis (saponification degree) of the

underlying polyvinyl acetate. For the preparation of the co-mixtures used in the invention, all commercially available

Polyvinyl alcohols that meet these criteria can be used. to

Preparation of the co-mixtures of polyvinyl alcohols (PVAs) and microcrystalline celluloses are used in particular PVAs having an average particle size greater than 100 pm.

The experiments described below were carried out with various polyvinyl alcohol types characterized above, available from Merck KGaA, Darmstadt, Germany, for use as

Excipient (EMPROVE ^® exp Ph. Eur., USP, JPE) are available with different article numbers. Particularly preferred are those compositions containing a co-mixture of microcrystalline celluloses and polyvinyl alcohol of the type 26-88 and / or 40-88. The second component of the co-mixtures used in the invention is microcrystalline cellulose (MCC) for pharmaceutical applications and is also characterized in the pharmacopoeias. It is obtained by the action of mineral acids from a pulp of plant fibers (pulp) [Ph. Eur. 2001] [USP 2002] [JP 2001], in which case subsequently from the purified solution α-cellulose having degrees of polymerization of more than 2,000 is precipitated with the aid of sodium hydroxide solution. The product obtained is subjected to partial, acidic hydrolysis. By the hydrolysis, a depolymerization occurs, whereby the degree of polymerization of the

Cellulose fibers sink and the crystalline fraction increases, since above all amorphous areas are removed. Subsequent drying, z. As spray drying or drying in air flow, provides the powdery, well-flowing products of MCC different particle size.

MCC is used in many areas of the pharmaceutical industry. It is used as a filler for capsules and tablets,

Dry binders, disintegrants or disintegrants, gelling agents and used as an additive to dragee suspensions.

For practicing the present invention, it is used in the co-mixtures of MCC, commercially available under the trade name Vivapur ^® Type 102 Premium from JRS Pharma (Rosenberg, Germany) is available. This microcrystalline cellulose has an average particle size of 100 pm per se. In addition, commercially available MCC grades are available under other product names that can be used in the same way. In general, microcrystalline celluloses of pharmaceutical grade and having an average particle size of less than 150 μm are suitable for the preparation of the novel co-mixtures. Preference is given to using such microcrystalline celluloses which have average particle sizes in the range from 100 to 140 μm. A detailed listing of the particle size distribution of the MCC used here is given later in the paragraph "Characterization of the raw materials used." This MCC points a very good flowability and is tablettierbar. In here

the addition of MCC both the tabletting of the formulation is supported as described in the application and the delayed release of active ingredient from the tablet.

Surprisingly, by using these co-mixtures of PVA and MCC, it has been possible to develop dosage forms that control the corresponding active ingredient over a longer period of time throughout

Release gastrointestinal tract (GIT). It could therefore

Drug formulations with certain release profiles can be found, by which the problems of the prior art described above can be overcome. It is crucial that an average release rate of 80% is maintained within a time of at least 9 hours to 12 hours.

By the formulations according to the invention and their special

Release profiles enable the active substance to be released in a controlled manner from the tablet after administration throughout the day and also to be absorbed from deep sections of the gastrointestinal tract (GIT).

Furthermore, these dosage forms are controlled with

Drug release also suitable for the treatment of new indications and show significant advantages over the fast-releasing

Pharmaceutical Forms of the Prior Art. By applying the new

Controlled-release dosage forms make it possible to achieve much more constant blood levels and prevent the occurrence of blood level spikes, resulting in e.g. the therapeutic efficacy can be improved and unwanted side effects can be reduced. Furthermore, the use of such dosage forms allows a reduction of

Application frequency and thereby leads to improved acceptance and compliance in the patient. execution

To determine the initial release and the mean release rate according to the definition of the invention, the release of active ingredient from the dosage forms according to the invention in the blade stirrer apparatus is tested. The release medium used is 900 ml of a phosphate buffer of pH 6.8. If necessary, the pH is adjusted to 6.8 ± 0.05 with sodium hydroxide or ortho-phosphoric acid. The release is carried out at a temperature of 37 ± 0.5 ° C and a rotational speed of the blade stirrer of 50 revolutions per minute (rpm). Samples are withdrawn from the release medium through a filtration unit which must ensure that any accompanying substances are removed, and the amount of active substance dissolved therein is determined by UV-VIS detection. The amount of active substance determined in this way is determined in percent by mass

Converted amount of active ingredient. The average release rate in the context of the present invention is over the time to reach a

Drug release of 80% defined, while the initial release describes the percent drug release after 30 minutes. The administration forms according to the invention with controlled

Drug release preferably has an average release rate of 80% in the time interval between 9 and 24 hours (80% in 9 hours and 80% in 24 hours), especially in the time interval between 9 and 12 hours. In a particularly preferred embodiment of the

The controlled release drug formulations of the present invention, the formulation has a mean

Release rate of at least 80% in the period of 9 and 15 hours and an initial release of a maximum of 10 to 15% of the active substance in the first 30 minutes of release, as measured from the

Derive release profiles is.

In a preferred embodiment of the controlled release dosage forms of the present invention having an average release rate of 80% in the period of 9 to 12 hours this initial release of 10 to 25% in the first 60 minutes of release.

Controlled sustained-release dosage forms of this invention are any formulations in which drug release is modified to have a lower release

Dose rate is given as fast-release dosage forms, e.g. a conventional tablet or capsule. For the preparation of the dosage forms according to the invention

controlled release, the active ingredient can be used in various particle sizes, e.g. in unmilled, ground or micronized form. The present invention thus enables the galenic to obtain the above-described by simply intensively mixing a pharmaceutically active substance which is readily soluble in aqueous solution

Polyvinyl alcohol / microcrystalline cellulose premix one

To produce a tablet formulation with a sustained-release release in a very simple process, resulting in a product with market or treatment-relevant product properties.

The conditions for preparation and for analytical and galenic testing are shown in the following examples. The preparation of the propranolol prolonged-release tablets produced by way of example is carried out by

Direct compression. Preferably, the production of the

Retardation matrix using a co-mixture of milled PVA 40-88 with the MCC Vivapur® 102 (JRS) in proportion

1: 1 by weight. However, the commercial products PVA 40-88 and MCC Vivapur® 102 (JRS) can also be replaced by other commercially available polyvinyl alcohols or other microcrystalline celluloses with comparable properties. In the co-mixture used, the ratio of the two components can be varied.

According to the invention, the ratio of the two components PVA and MCC to one another, as already described above, can be in the range between 2: 1 to 1: 2. The examples given below disclose methods and

Conditions for the preparation of the propranolol sustained-release formulations according to the invention. It will be apparent to those skilled in the art

self-explanatory that also other methods of making the

Premixes and the tablet matrices are available as described herein.

The examples show the particular advantages of these PVA-MCC combinations.

The present description enables one skilled in the art to fully embrace the invention. Without further explanation, it is therefore assumed that a person skilled in the art can make the most of the above description.

Any ambiguity goes without saying, the quoted

Publications and patent literature. Accordingly, these documents are considered part of the disclosure of the present application

Description.

For a better understanding and clarification of the invention, examples are given below which are within the scope of the present invention. These examples are also used for

Illustration of possible variants. An evaluation of the results obtained is given in each case following the respective examples.

Due to the general validity of the described principle of the invention, however, the examples are not suitable to the scope of the

present application only to reduce this. Furthermore, it is self-evident to the person skilled in the art that both in the given examples and in the remainder of the description, the amounts of components contained in the compositions are in the sum of only 100% by weight or mol% relative to the components

Aggregate composition and can not exceed it, even if higher values could result from the indicated percentage ranges. Unless otherwise stated, therefore % By weight or by weight, with the exception of ratios given by volume.

The temperatures given in the examples and the description as well as in the claims are in ° C.

Examples

Equipment and methods for the characterization of material properties

1. Bulk density: according to DIN EN ISO 60: 1999 (German version)

- indication in "g / ml"

2. Tamping density: according to DIN EN ISO 787-11: 1995 (German version)

- indication in "g / ml"

3. Schüttwinkel: according to DIN ISO 4324: 1983 (German version)

- indication in "degree"

4. Surface area determined according to BET: Evaluation and performance according to literature "BET Surface Area by Nitrogen Absorption" by S. Brunauer et al. (Journal of American Chemical Society, 60, 9, 1983) Device: ASAP 2420 from Micromeritics Instrument Corporation ( USA); nitrogen;

Weighing: approx. 3.0000 g; Heating: 50 ° C (5 h); Heating rate 3 K / min;

Indication of the arithmetic mean of three determinations

5. Particle size determination via laser diffraction with

Trockendispergierunq: Mastersizer ^® 2000 with rotor-stator

Scirocco ^® 2000 (Malvern Instruments Ltd. UK.), Provisions at 1, 2 and 3 bar back pressure; Evaluation Fraunhofer; Dispersant Rl: 1,000, Obscuration Limits: 0.1-10.0%, Tray Type: General Purpose,

Background Time: 7500 msec, Measurement Time: 7500 msec,

Execution in accordance with ISO 13320-1 and the specifications of the technical manual and the specifications of the equipment manufacturer; Figures in% by volume 6. The tableting tests are as follows:

The mixtures according to the specified in the experimental part

Compositions are placed for 5 minutes in a sealed stainless steel container (capacity: about 2 l, height: about 19.5 cm, diameter: about 12 cm outside dimension) on a laboratory tumble mixer (Turbula ^® T2A, Fa.Willy A. Bachofen, Switzerland).

As magnesium stearate is Parteck ^® LUB MST (Magnesium stearate vegetable) EMPROVE ^® exp Ph. Eur., BP, JP, NF, FCC Part no.

1.00663 (Merck KGaA, Germany), which was deposited on a 250 pm sieve.

The compression to 500 mg tablets (11 mm punches, round, flat, with facet) is carried out on an instrumented Excenter tableting machine Korsch EK 0-DMS (Korsch, Germany) with the evaluation system Catman ^® 5.0 (Hottinger Baldwin Messtechnik - HBM, Germany).

For each press force tested (target settings: ~ 5, -10, -20 and -30 kN, the effective measured actual values are given in the examples), at least 100 tablets are prepared for evaluating the pressing data and determining the galenic characteristics.

- Tablet hardening. Diameter and heights: Erweka Multicheck ^® 5.1 (Fa.

Erweka, Germany); Average data (arithmetic mean values) from 20 tablet measurements per pressing force. The measurements are made one day after the tablet is made.

- Tablet abrasion: Friabilitätsprüfgerät TA420 (Fa Erweka, Germany); Device parameters and execution of the measurements according to Ph. Eur. 7th edition "Friability of uncoated tablets" The measurements are carried out one day after tablet production.

- tablet mass: average (arithmetic mean) of the weighing of 20 tablets for each force: Multicheck ^® 5.1 (Erweka, Germany.) With Balance Sartorius CPA 64 (from Sartorius, Germany.). The measurements are made one day after the tablet is made. 7. Drug Release Test:

The propranolol HCl or theophylline anhydrous containing

Comprets (pressing with 5, 10, 20 or 30 kN pressing force) are in an in-vitro release apparatus of the company ERWEKA (Heusenstamm, Germany) with the in Ph. Eur. 8.4 under 2.9.3.

"Dissolution test for solid dosage forms" described "Apparatus 2 (Paddle Apparatus)" and under the conditions described there measured (Ph. Eur. = European Pharmacopoeia). Sampling takes place automatically via a peristaltic pump system with connection.

Measurement in a ^Lambda® 35 photometer (Perkin Elmer, USA) and a flow cell.

Measuring apparatus and parameters: - ERWEKA DT70 release apparatus equipped with Apparatus 2 (Paddle Apparatus according to Ph. Eur.)

- Temperature: 37 ° C +/- 0.5 ° C

- Speed of the paddle: 50 rpm

- Release medium: 900 ml phosphate buffer pH 6.8 acc. Ph. Eur. - Total duration of the measurements: 12 hours (with sampling after 15, 30, 45, 60 minutes and then every hour up to 12 hours

Total running time (in the tables the data for the 5, 30 and 45 minutes samples are not listed)

- Tube pump for sampling: Ismatec IPC, type ISM 931; App. No.

12369-00031

®

- Photometer Lambda 35 (Perkin Elmer)

Measurement at 214 nm for propranolol and 293 nm for theophylline in a flow cell

Evaluation by Dissolution Lab Software Version 1.1, Perkin Elmer Inc. (USA)

Commercial compound preparation:

Dociton 160mg retard; Hard capsules, retarded;

Active substance: propranolol hydrochloride, batch: 131203, usable until:

12/2018; Fa. Mibe GmbH Arzneimittel (Brehna, Germany); consisting of propranolol-containing pellets filled in hard capsules (with 160 mg propranolol hydrochloride per capsule); other ingredients are: ethylcellulose, microcrystalline cellulose, hypromellose, gelatin,

Titanium Dioxide (E171), Natnum Dodecyl Sulfate, Iron (III) Oxide (E172), Shellac

Drug release from the dociton 160 mg retard was performed using Spider Sinkers (Erweka, Germany) to prevent the floating of the capsules in the release vessels

carried out.

Characterization of the raw materials used

1. PVA 40-88 and PVA 26-88

1.1 Raw materials for grinding

1.1.1. PVA 26-88: polyvinyl alcohol 26-88, suitable for use as excipient EMPROVE® exp Ph. Eur., USP, JPE, article no. 1.41352, Merck KGaA, Darmstadt, Germany

1.1.2. PVA 40-88: polyvinyl alcohol 40-88, suitable for use as excipient EMPROVE® exp Ph. Eur., USP, JPE, article no. 1.41353, Merck KGaA, Darmstadt, Germany

These PVA grades are originally available as coarse-grained - several millimeters large - particles that can not be used in this form as a directly compressible tableting matrix.

The large particles do not permit reproducible filling of the stamp dies and thus also no constant tablet weight at high rotational speeds of the (rotary) tableting machines. In addition, only fine-grained PVAs a homogeneous distribution of the drug - without the occurrence of

Detoxification effects - ensure in the tablet. This is absolutely necessary for ensuring the single dose accuracy of the ingredient (content uniformity) in each tablet produced. In addition, a homogeneous gel formation in the entire tablet body can be ensured only by a fine-grained PVA which is also necessary for a reproducible retardation.

For these reasons, the o.g. coarse-grained PVA grades prior to their use as directly compressible retardation matrices, i. be ground.

1.2 Milled PVA grades .2.1 Ground PVA 26-88, made of polyvinyl alcohol 26-88 Article no.

1.41352 batch F1862862 with the mean grain fraction Dv50 (laser diffraction, dry dispersion): Dv50 80-90 μm

1.2.2 Ground PVA 40-88, made of polyvinyl alcohol 40-88 Article no.

1.41353 batch F1862963 with the mean grain fraction Dv50 (laser diffraction, dry dispersion): Dv50 68-75 μm

Marriage:

The grinding of the PVA types takes place in a cold grinding on a

®

Aeroplex spiral jet mill (type 200 AS from Hosokawa Alpine, Augsburg, Germany) under liquid nitrogen as cold grinding at temperatures in the range of 0 ° C to -30 ° C. The desired particle size is generated empirically, in particular by varying the grinding temperature, i. through ongoing in-process checks of the

Particle size, the grinding conditions are varied until the desired grain size is obtained.

The resulting product properties of the milled PVA types, in particular the powder indices, such as bulk density, tamped density, angle of repose, BET surface area, BET pore volume, and the

Particle size distributions are shown in the following tables Bulk density. Tapped density. Angle of repose, BET surface area. BET pore volume:

(For details on the measuring methods see Methods)

^* milled PVA

Particle distribution determined by laser diffraction with dry dispersion (1 bar counterpressure):

Information in μητι (for details on the measurement method, see Methods)

^* milled PVA

Particle distribution determined by laser diffraction with dry dispersion (2 bar counterpressure):

Information in pm (for details on the measuring method see Methods)

^* milled PVA

Particle distribution determined by laser diffraction with dry dispersion (3 bar counterpressure):

Data in μιη (for details on the measuring method see Methods)

ground PVA 2. Microcrystalline celluloses (MCP

®

Vivapur Type 102 Premium, microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, Rosenberg, Germany

Particle distribution determined by laser diffraction with dry dispersion (1 bar back pressure):

Details in μιτι (for details on the measuring method see Methods)

Details in prn (for details on the measuring method see Methods)

Information in pm (for details on the measuring method see Methods)

3. Other materials

3.1 Propranolol HCl BP, EP, USP Batch no. M130302 (Changzhou Yabang Pharmaceutical Co., LTD., China)

3.2 Parteck® LUB MST (vegetable magnesium stearate) EMPROVE® exp Ph. Eur., BP, JP, NF, FCC Article No. 1.00663 (Merck KGaA, Germany)

3.3 Colloidal silica, highly dispersed suitable for use as an excipient EMPROVE ^ exp Ph. Eur., NF, JP, E 551 Article No. 1.13126 (Merck KGaA, Germany)

3.4 Theophylline Anhydrous EP Expiry 10/2016 Article No. 000983

(Selectchemie, Switzerland)

test results

A) Goal:

Retarded oral drug formulations are often complex. In the following it can be surprisingly shown that by the

Using hydrophilic PVA types as retarding polymer matrices in a simple way propranolol and theophylline tablets with a

extended drug delivery (cumulative> 80% drug release after 12 hours) can be produced. The in vitro release behavior, in particular of the propranolol tablets according to the invention, comes to the

Release profile to a commercially available, therapeutic

very close to the applied product.

The following examples use co-mixtures as described in patent applications PCT / EP2015 / 001355, PCT / EP2015 / 001356 and PCT / EP2015 / 001357. These are co-mixtures of ground polyvinyl alcohols (PVAs) with microcrystalline celluloses (MCCs) of specific particle sizes.

B) Summary of the experiments with propranolol:

With the following data can be shown that with the help of

described co-mixtures Propranololtabletten with a prolonged release of active ingredient are particularly easy to produce, wherein

Surprisingly, it was found that

1. even at low press forces tablets of high hardness and low friability are obtained;

2. the drug release from these tablets is virtually independent of the applied pressing force; 3. the drug release remains unchanged over a very large tablet hardness range;

and that

4. This simple manufacturing process makes it possible to develop a retarded propranolol formulation which, in its in vitro release behavior, is virtually identical to a commercial, but much more complex formulation of the same

Dosage is.

Because of these advantages, it is possible to have the described

To prepare sustained release formulations in a simple manner. At the same time tablets of the invention have improved drug safety.

Procedure:

1. Preparation of the two co-mixtures of PVA 26-88 and MCC and PVA 40-88 and MCC, and in each case the blending with the active ingredient and other additives and subsequent compression at 5, 10, 20 and 30 kN pressing force, as well as galenic characterization of the

obtained compacts

2. Measurement of in vitro drug release in phosphate buffer pH 6.8 over 12 hours: Testing of the pellets obtained at 10, 20 and 30 kN pressing force

®

3. Measurement of in vitro release of dociton 160 mg retard capsules in phosphate buffer pH 6.8 over 12 hours: comparison of in vitro

Propranolol release from these capsules against the in vitro

Propranolol release from the PVA-based prolonged-release tablets according to the invention Results: for 1 .: Preparation and galenic characterization of propranolol

Prolonged-release tablets: a. Preparation of the co-mixtures of the two ground PVA types

26-88 and 40-88 with the microcrystalline cellulose (MCC) in the

Amount ratio 1: 1 (see patent applications PCT / EP2015 / 001355, PCT / EP2015 / 001356 and PCT / EP2015 / 001357). It will be to

Preparation of the co-mixtures, consisting of the two

Components microcrystalline celluloses (commercial product) and PVA with the appropriate grain fraction in the ratio 1: 1 im

Turbula ^® mixer mixed for 5 minutes. b. 337.5 g (Example A) or 335.0 g (Example B) of these co-mixtures are mixed with 160 g Propranolol HCL and 1, 25 g highly dispersed

Silica (Example A) or 2.5 g of fumed silica (Example B) was mixed in the Turbula mixer for a further 5 minutes.

Thereafter, the resulting mixture is deposited over a 800 pm hand screen. c. After adding 1.25 g of Parteck LUB MST (Example A) or 2.5 g

®

Parteck LUB MST (Example B) is mixed again for 5 minutes and then tabletted into 500 mg tablets on a Korz EK 0-DMS eccentric press; this corresponds to 160 mg Propranolol HCL per tablet d. The tablet characterization is done in terms of parameters

Tablet hardness, tablet mass, tablet height, tablet abrasion

(Friability) and necessary ejection force Composition (in% by weight) Example A: with PVA 26-88 as

Retardierungsmatrix

^* : milled PVA

Composition (in% by weight) Example B: with PVA 40-88 as

Retardierungsmatrix

^* : milled PVA

tablets characterization

Table 1: Tableting Data Example A and Example B

Legend:

A: Pressing force [kN] B: Tablet hardness after 1 day [N]

C: tablet mass [mg] D: tablet height [mm]

E: abrasion [%] F: ejection force (N)

In Figure 1, the press force-tablet hardness profiles of the two examples are shown graphically for ease of illustration.

All tablets show at pressing forces equal to / greater than 10 kN unusually high tablet hardness combined with a very low abrasion after mechanical stress (low friability) and relatively low ejection forces.

There are virtually no differences in tabletting data between the tablets based on matrices PVA 26-88 or PVA 40-88. In particular, the tablet hardnesses are almost identical at the same pressing forces.

to 2 .: in vitro release of propranolol prolonged-release tablets at pH 6.8 Table 2a: In vitro release data of Example A at pH 6.8

The cumulative amounts of released propranolol HCl (in%) from the tablets are given at 10, 20 and 30 kN pressing force.

FIG. 2 a graphically shows the release data of example A at pH 6.8 for better illustration.

Example A shows a practically identical release behavior for tablets produced with pressing forces of 20 and 30 kN at resulting tablet hardnesses of 212 and 259 N, respectively; the tablets produced at 10 kN pressing force (with 102 N tablet hardness) show only a slightly faster in vitro release in comparison.

Table 2b: In vitro release data of Example B at pH 6.8

In Figure 2b, the release data of Example B are plotted at pH 6.8 for clarity of illustration.

Surprisingly, Example B for tablets prepared in the relevant press force range of 10 to 30 kN shows an identical

Release behavior. Based on the tablet hardness (Table 1) this corresponds to an identical release behavior over a very large hardness range of 110 to 247 N.

Conclusion: both examples, but in particular Example B, show an unchanged in vitro drug release over very wide press force and tablet hardness ranges. This effect gives a great security in the industrial production of such prolonged-release tablets, as occurring

Fluctuations in the tabletting force as well as in the resulting

resulting changes in tablet hardness over very wide ranges have no effect on drug release. This is for the

Drug safety of considerable importance. 3: In vitro release of a commercial propranolol sustained-release formulation at pH 6.8

Dociton® 160 mg retard from mibe GmbH Arzneimittel (Brehna, Germany) was tested.

®

Table 3: In vitro release data dociton at pH 6.8

Indicated are the cumulative amounts of released propranolol HCl (in%) from the sustained-release capsules.

These release data are practically congruent with the data from Example A (Table 2a) pressed at 20 and 30 kN and Example B (Table 2b) pressed at 10, 20 and 30 kN.

®

FIG. 3 a shows the release data of the dociton 160 mg retard at pH 6.8 in comparison with the release data from Example A and in FIG. 3b in comparison with the release data from Example B. FIG.

Conclusion: You can by a simple direct compression process of a co-mixture, consisting of PVA and MCC, a retarding

Matrix tablet obtained in their in vitro release behavior

Equivalent to a much more complex in their construction pellet or capsule formulation. C) Summary of the experimental results with theophylline:

With the following data can be shown that with the help of

PVA / MCC co-mixtures Theophyllin tablets are particularly easy to produce with a prolonged release of active ingredient, wherein

Surprisingly, it was found that

1 . even at low press forces tablets of high hardness and low friability are obtained;

2. the drug release from these tablets is practically independent of the applied pressing force

and

3. the drug release remains unchanged over a very large tablet hardness range.

Table 4: Ingredients and amounts of the theophylline-containing tablets

85 g of PVA 40-88 (ground) and 185 g of MCC are thoroughly mixed for 10 minutes in a Turbula mixer. Subsequently, 125 g of theophylline, anhydrous, and 2.5 g of silica are added and homogenized for a further 10 minutes. The resulting mixture is placed over a sieve (800 pm). 2.5 g of magnesium stearate are passed through a 250 [in the sieve on the mixture and all components for 5 minutes mixed together again in a Turbula tumble mixer. The powder mass thus obtained is compressed into 500 mg tablets (11 mm diameter, flat, faceted) with pressing forces of 5, 11, 21 and 32 kN.

Table 5: Physical data of the resulting theophylline-containing tablets (125 mg theophylline anhydrous per tablet)

By using the PVA-containing mixture, sustained-release theophylline tablets with high tablet hardness are obtained, with the required ejection forces being extremely low.

Table 6: In vitro release data Theophylline prolonged-release tablet at pH 6.8

Indicated are the cumulative amounts of released theophyll%) from the tablets obtained at 5, 11, 21, 32 kN pressing force.

Press force Press force Press force Press force

5 kN 11 kN 21 kN 32 kN

Time Average Mean Average Mean

(Hours) (%) (%) (%) (%)

1 20 18 17 17

2 30 30 28 29

3 38 39 38 39

4 45 46 47 48

5 51 52 54 56

6 57 57 61 62

7 63 62 67 68

8 68 66 72 72

9 72 71 77 77

10 77 75 82 80

11 81 78 86 84

12 85 81 89 87 FIG. 4 graphically depicts the release data of theophylline for better illustration.

Surprisingly, the theophylline prolonged-release tablets prepared in the press force range of 5 to 32 kN show an identical

Release behavior. Based on the tablet hardness (Table 5) this corresponds to an identical release behavior over a very large hardness range of 50 to 289 N.

List of pictures:

Figure 1: Press force tablet hardness profile (from Table 1) of Examples A and B.

Figure 2a: Release data Example A at pH 6.8 (from Table 2a)

FIG. 2b: Release data Example B at pH 6.8 (from Table 2b)

FIG. 3a: Release data of Dociton® 160 retard in comparison with Example

A at pH 6.8

FIG. 3b: Release data of Dociton® 160 retard in comparison with Example

B at pH 6.8

Figure 4: drug release of based on PVA-containing

Mixtures of prepared tablets with theophylline, anhydrous

Claims

P A T E N T A N S P R E C H E

A process for the preparation of a pharmaceutical dosage form of an extended release composition, characterized in that

a) one for use in pharmaceutical formulations

approved polyvinyl alcohol at low temperatures in the

Range from minus 30 ° C to 0 ° C to a fine powder with average particle size Dv50 in the range of 50 - 100 pm,

preferably in the range of Dv50 60-95 pm, ground and sieved through a 800 μm sieve, and

b) with microcrystalline cellulose of average particle size Dv50 im

Range of 100 to 150 pm is intensively mixed,

c) mixing this mixture with a sufficient amount of the active ingredient,

f) after sufficient mixing of the resulting mixture and

optionally after sieving to remove remaining coarse grain by pressing at a suitable pressure is tabletted.

A method according to claim 1, characterized in that

Slow release tablets are produced, which have a very wide

Preßkraft- and Talettenhärtebereich have a virtually unchanged drug release profile.

A method according to claim 1, characterized in that

Retardtabletten be prepared with a compressive force in the range of 5 to 32 kN, the hardnesses in the range of 50 to 290 N and despite a changed hardness, a nearly the same

Have drug release profile.

4. The method according to claim 1, 2 or 3, characterized in that polyvinyl alcohol and microcrystalline cellulose in the ratio of 2: 1 to 1: 2, preferably in the ratio of 1, 5. 1 to 1: 1, 5, in particular of 1: 1 based on the total amount of co-mixture are intensively mixed together.

Method according to one or more of claims 1 to 4, characterized in that in c) as the active ingredient propranolol and / or its pharmaceutically acceptable salts, hydrates or solvates or theophylline, anhydrous or its monohydrate

is added in an effective amount and mixed with.

Method according to one or more of claims 1 to 5, characterized in that small amounts of additives

Silicon dioxide as a flow agent and magnesium stearate as a lubricant are added to the mixture and mixed with.

Process according to one or more of Claims 1 to 6, characterized in that the active substance-containing mixture obtained is pressed at a pressing force in the range from 5 to 32 kN into tablets with hardnesses in the range from 50 to 290 N, which have an average release rate of 80%. of the active ingredient in a period of at least 9 to 12 hours.

Method according to one or more of claims 1 to 6, characterized in that the propranolol-containing mixture are pressed with a pressing force in the range of 10 to 30 kN into tablets with hardnesses in the range of 100 to 260 N, which has a mean

Release rate of 80% of the active ingredient in a period of at least 9 to 12 hours.

Pharmaceutical composition with prolonged

Drug release, prepared by a process according to claims 1 to 8, comprising the active ingredient propranolol and / or its pharmaceutically acceptable salts, hydrates or solvates as hypotensive β-blocker and a co-mixture of

microcrystalline celluloses and polyvinyl alcohols.

10. Pharmaceutically active composition with extended

Drug release, produced by a process according to claims 1 to 8, containing the active substance theophylline and / or its pharmaceutically acceptable salts, hydrates or solvates, preferably its anhydrate, and a co-mixture of

microcrystalline celluloses and polyvinyl alcohols.

11. Composition according to claim 9, characterized

that it contains propranolol as the hydrochloride or succinate.

12. The composition according to one or more of claims 9 to 11, characterized in that it comprises a co-mixture of

microcrystalline celluloses and polyvinyl alcohols in the ratio of 2: 1 to 1: 2, preferably in the ratio of 1, 5: 1 to 1: 1, 5,

in particular from 1: 1 based on the total amount of the co-mixture, and wherein the polyvinyl alcohols are selected from the types 18-88, 26-88, 40-88 and all intermediate qualities according to the requirements of Pharmakopoen Ph. Eur., USP or JPE, including type 28-99 according to the

Have requirements of JPE or Ph. Eur. And in the co-mixture average particle size fractions in the range of Dv50 50-100 pm, preferably in the range of Dv50 60-95 pm.

13. Composition according to one or more of claims 9 to 11, characterized in that it comprises a co-mixture of

microcrystalline celluloses and polyvinyl alcohol of the type 26-88 and / or 40-88, wherein the polyvinyl alcohols in the co-mixture before pressing have average particle size fractions in the range of Dv50 60-95 pm.

14. A composition according to one or more of claims 9 to 13, characterized in that it contains a co-mixture of microcrystalline celluloses and polyvinyl alcohols, wherein the polyvinyl alcohols used before pressing a bulk density in the range of 0.40 to 0.65 g / ml, preferably from 0.45 to 0.60 g / ml, and a tamped density in the range of 0.50 to 0.80 g / ml, in particular in the range of 0.55 to 0.75 g / ml.

15. A composition according to one or more of claims 9 to 14, which has been pressed into tablets having hardnesses in the range of 50 to 290 N, the latter, regardless of the hardness, a mean release rate of 80% of the active ingredient in a time of at least 9 to 12 hours.

16. The composition according to one or more of claims 9 to 14, which contains propranolol as an active ingredient and has been compressed into tablets having hardness in the range of 100 to 260 N, the latter having an average release rate of 80% of the active ingredient in one regardless of the hardness Have at least 9 to 2 hours.

17. Composition according to one or more of claims 9 to 14, which contains as active ingredient theophylline and has been compressed into tablets with hardnesses in the range of 50 to 290 N, the latter, regardless of the hardness, a mean release rate of 80% of the active ingredient in one Have at least 9 to 12 hours.

18. Composition according to one or more of claims 9 to 17, characterized in that it has a moderate initial

Release and then a uniform drug release, whereby an undesirable flooding of active ingredient is avoided.

19. The composition according to one or more of claims 9 to 17, characterized in that it contains silica as a flow agent.

Composition according to one or more of Claims 9 to 17, characterized in that it comprises magnesium stearate

Contains lubricant.

21. A galenic dosage form in the form of an extended release composition according to one or more of claims 9 to 20 for oral use.

22. Galenic dosage form in the form of an extended release composition according to one or more of claims 9 to 21, characterized in that it contains the active ingredient in a matrix, the drug in the presence of liquid in the gastrointestinal system by diffusion and / or gives off gradual erosion.

23. Galenic dosage form in the form of an extended release composition according to one or more of claims 9 to 22, characterized in that it contains 10 to 140 mg of the active ingredient calculated as propranolol per dosage.

24. Galenic dosage form in the form of an extended release composition according to one or more of claims 9 to 22, characterized in that it contains 100 to 600 mg of the active ingredient calculated as theophylline per dosage.

25. Galenic dosage form in the form of an extended release composition according to one or more of claims 9 to 22, characterized in that it

Propranolol hydrochloride as active ingredient in an amount of 80 or 160 mg per dose contains.

26. Galenic dosage form in the form of an extended release composition according to claim 24, characterized in that it contains theophylline anhydrous as an active ingredient.