DE19928312A1 - Drug preparation with delayed drug delivery - Google Patents

Abstract

The invention relates to pharmaceutical preparations providing delayed release of an active substance, whereby said active substance is contained in or on pellets. The invention is characterized in that the pellets are coated with a diffusion membrane which is permeable with respect to said active substance but delays the diffusion thereof. The coating is made up of talc and poleythacrylate-polymethylacrylate. Mesopram is used as an active substance. The inventive preparation provides a constant plasma level in vivo without any peaks. The medicaments produced from the pharmaceutical preparation exhibit active substance release independent of pH and have high stability in storage.

Description

The invention relates to a pharmaceutical preparation Delayed drug delivery, the drug in or is contained on pellets.

State of the art

The application of drugs to inert carriers such as e.g. B. raw pellets from a solution or suspension is called Called layering. The layering technique is used for the Production of pellets as an alternative to extrusi on / spheronization used. D. M. Jones describes in Pharmaceutical Pelletization Technology (edited by Isaac Ghebre-Sellassie; M. Dekker, New York, 1989) the devices, the general and special process parameters as well as the Product variables of layering. In Drug Dev. Ind. Pharm. 15 (1989) pp. 1137-1159 the problems become minor Yield and insufficient content addressed. Moreover the influence of the particle size of the active ingredient on Ge stop and yield explained.

Dressmann et al. describe in J. Contr. Release 36 (1995) 251-260 the pH-dependent release behavior of diffusion pellets and Bodmeier are in Pharm. Res. 13 (1996) 52-56 other possible causes for this un desired behavior of diffusion pellets. It is therefore far in the field of pharmaceutical technology going unsolved problem, the release of an active ingredient, which was incorporated into a pellet, regardless of pH shape. Should a pH-independent free succeed The next task is to achieve settlement behavior be in the state achieved over the storage period of the Drug taking into account that of the Guideli to maintain the specified storage temperature.

Task and solution

Mesopram is an enantiomeric active ingredient, which according to oral Ap application of quick release formulations such as Pills or solutions lead to nausea and vomiting.

Structural formula of (R) - (-) - 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-oxazolidinone

This will affect the effects created in the human body plasma plasma peaks. A side effect free Drug therapy therefore requires an innovative dar dosage form, which is a controlled, pH-independent Drug release rate ensures a fast To prevent flooding of the active ingredient knows. There with the passage of the gastrointestinal tract different pH values are run through is pH-independent retard formulation of particular importance.

The object of the present invention is therefore a Re Tardarzneiform manufacture the active ingredient mesopram continuously releases from the dosage form, so that Plasma levels result in people who have a are constant for a longer period and no peaks exhibit. In addition to the listed biopharmaceutical egg properties, the required prolonged-release pharmaceutical form must have a have sufficient pharmaceutical quality. That be indicates that the release behavior is robust d. H. against  Influencing factors such as B. different pH values and Rotational speeds must be independent. On "Dose dumping" must never occur. In addition, must the prolonged-release form of the required chemical and have physical stability. Mesopram is a pure enantiomer that is easily converted into the other enantiomer ZK 117 138 is converted (Equation 1).

Equation 1

Racemization of mesopram to the "wrong" enantiomer ZK 117 138

Equation 2

Degradation of mesopram to meproaminol

Equation 3

Degradation of mesopram to meproketone

In addition, mesopram easily turns into mepro when the ring is opened ketone and meproaminol degraded (Equations 2 and 3). For a storage-stable dosage form that is used in all climates it can be marketed, it is particularly necessary Lich that the release behavior of the prolonged-release drug form does not change during the storage period. Self ver Chemical stability must also be ensured len.

The object is achieved in that a drug preparation with delayed release of the active ingredient is contained in or on pellets is placed, the pellets with one for the active permeable diffusion membrane are wrapped and this wrapping talc and buttocks lyethacrylate polymethyl methacrylate.

It is preferred according to the invention that the talc in mi in a chronological form.

According to the invention it is particularly preferred that the pel lets an average diameter of 0.025 mm to 1.7 mm exhibit.

It is further preferred according to the invention that the pellets have a drug-free core and that on their Surface of the active ingredient in molecular disperse or mi Crocrystalline form with an average grain size of 100 µm is applied on average.

It is very particularly preferred according to the invention that the Active ingredient (R) - (-) - 5- (4-methoxy-3-propoxyphenyl) -5-methyl- 2-oxazolidinone (mesopram).  

Another object of the invention is a medicament tel for oral application containing a erfindungsge moderate pharmaceutical preparation, if necessary together with further pharmaceutically acceptable auxiliary and additive substances, in the form of tablets or capsules.

It has now been found that a sustained release drug form with the required properties can be produced if pellets layered with active ingredient with a diffusion film from a mixture of Polyethylacrylat-polymehtylmeth be provided with acrylate and micronized talc. Ent sustained release pellets have a pH independent in vitro release and lead to constant plasma levels without plasma peaks.

Surprisingly, the herge show according to the invention Retard pellets were one of external factors especially pH-independent release. Au In addition, the production of stable sustained release pellets was successful. The drug molecule could degrade after 6 months even with the ICH condition 40 ° C / 75% relative humidity not be observed. No racemization occurred breakdown products could still be identified.

In contrast, prolonged-release drug forms show just that if mesoprase pellets contain, an unfavorable pharma teutical behavior. The wording, just that if based on the layering and coating technology have been provided (Examples 4 and 5, comparative example le) have a pH-dependent in vitro release behavior At pH 4.5, the active ingredient mesopram is in both Formulations released too quickly ("dose dumping"). At high proton concentrations (pH 2), mesopram is in In contrast, formulation B is released too slowly. The free settlement behavior of formulation C according to the invention however, D is completely independent of pH.  

Based on the attached figures, the advantageous Properties of the pharmaceutical preparation according to the invention tions and / or the medicinal products manufactured therefrom purifies.

Show it

FIG. 1 shows the influence of the release rate on pH of the formulation A according to Example 4 (comparative example);

FIG. 2 shows the influence of the release rate on pH of the formulation B according to Example 5 (comparative example);

FIG. 3 shows the influence of the release rate on pH of the formulation C according to Example 1;

FIG. 4 shows the influence of the release rate on pH of the formulation D in Example 3;

Fig. 5 shows the release rate after 3 months storage time at 40 ° C / 75% rel. Moisture of formulation A according to example 4 (comparative example);

Fig. 6 shows the release rate after 3 months storage time at 40 ° C / 75% rel. Moisture of formulation B according to example 5 (comparative example);

Fig. 7 shows the release rate after 3 months storage time at 40 ° C / 75% rel. Moisture of formulation C according to Example 1 and

Fig. 8 shows the release rate after 3 months storage time at 40 ° C / 75% rel. Moisture of formulation D according to example 3.

In addition, the chemical stability of the formulations A and B insufficient. Is already after 3 months of storage an active ingredient loss of 10% and more can be observed. This loss of active ingredient goes hand in hand with an increase in wrong enantiomers ZK 117 138 (specification limit ≦ 2.0%) and a dramatic increase in breakdown products (Specification limit ≦ 3.0%) (Table 1).

Table 1

Stability data after 3 or 6 months storage at 40 ° C / 75% rel. Humidity

In contrast, formulations C and D have no out of specification values. They are chemically stable formulations. The release behavior, as shown in FIGS. 7 and 8, is also not influenced by the storage. The task - the development of a robust and pharm. stable formulation - was solved according to the Invention.

Examples example 1 Formulation C

73.3 g of hydroxypropylmethyl cellulose (HPMC) are in 594.0 g of purified water, which he at 60 to 70 ° C. has been warmed, solved. 14.78 g ZK 117 137 (mesopram) are added to the cold HPMC solution with stirring. The active ingredient suspension is made using a colloid mill homogenized. 2000 g neutral pellets, NF 18 are 3 min. at a supply air temperature of 50 ° C in a Wurster Ap heated parature. 680 g of the previously produced active ingredient suspension are at a supply air temperature of 50 ° C in Bottom spray process applied to the neutral pellets gene.

303 g of talc are dispersed in 1311 g of purified water yaws. The suspension is ho using a colloid mill mogenized so that the talc is micronized. To 1076 g of the talcum bissenison are stirred gently 541 g of a methyl acrylate methyl methacrylate suspension given. The spray suspension is stirred continuously. 1500 g of the previously layered pellets are in a Wur stere equipment by an appropriate air volume rain brought to fluidization. 1132 g of talc Coating suspensions are sprayed at a rate of 9 g / min applied to the active ingredient-containing pellets. It is maintain a product temperature of maximum 25 ° C.

In a free-fall mixer, the active ingredient-containing pellets with a diffusion film containing 0.25% highly disperse silicon dioxide mixed. After the pel  lets have been spread evenly across hordes aftertreated for 24 h at 40 ° C. The pellets are in Bottled hard gelatin capsules.

Example 2

The diffusions prepared in accordance with Example 1 Pellets become after mixing the highly disperse Silicon dioxide for 6 h at 40 ° C in the fluidized bed hold. The pellets thus obtained are hard gelatin capsules filled.

Example 3 Formulation D

1500 g of neutral pellets containing the active ingredient Example 1 were prepared with 772 g Coating suspension applied with the following composition: 208 g micronized talc are cleaned in 896 g Water dispersed. The suspension is by means of a Colloid mill homogenized so that the talcum microni is settled. To 736 g of the talc suspension is under gentle stirring 368 g of a methyl acrylate methyl methacrylate Suspenison given. The spray suspension will continuously stirred.

In a free-fall mixer, the active ingredient-containing pellets with a diffusion film containing 0.25% highly disperse silicon dioxide mixed. After the pel lets have been spread evenly across hordes treated 24 hours at 40 ° C. The pellets are in Bottled hard gelatin capsules.  

Example 4 (comparative example) Formulation A

1.6 g of antifoam emulsion and 1.6 g of Poloxamer 124 are in 1560 g of purified water using Ultra-Turrax is working. 71.8 g bentonite, 7.98 g hydroxypropylmethylcel Lulose and 7.98 g magnesium stearate are mixed together mixed a grater. The powder mixture becomes the given surfactant-containing, aqueous solution and using Ul tra-Turrax stirred in. Then 7.98 g of meso pram placed on the surface of the suspension. It will stirred in with an Ultra-Turrax. It's going to be away tested by agglomerates.

1500 g of neutral pellets are placed in a granulating container Use in the top spray process with the previously made active ingredient suspension at a spray rate of 18 to 24 g / min and a supply air temperature of 35 ° C sprayed. After the end of spraying, the supply air temperature is 50 ° C until a product temperature of 40 ° C is reached dried. Finally, at a supply air temperature from 23 ° C until a product temperature of Cooled to 30 ° C. The active ingredient-loaded pellets are passed over a 1.25 mm sieve to possibly form to remove te multiples.

0.75 g of antifoam emulsion, 3715 g of talc and 3.75 g of die thyl phthalate in 750 g of water using Ultra-Turrax incorporated. 112.5 g ammonium methacrylate copolymer Type B suspension are passed through a 355 µm Sieve added to the aqueous suspension with stirring (Spray suspension A). The spray suspension is ongoing touched.

0.75 g antifoam emulsion, 30 g talc, 6 g polyvinyl pyrrolidone and 9 g of silicon dioxide are Turrax incorporated into 1350 g of purified water. 140 g  an aqueous ethyl cellulose suspension after Pass through a 355 µm sieve while stirring to the water water suspension (spray suspension B). The Spray suspension is stirred continuously.

1500 g of pellets loaded with active ingredient are in a granule Use the top spray process with the previous one prepared spray suspension A at a spray rate of 18 up to 24 g / min and a supply air temperature of 35 ° C sprays (intermediate coating). Then the spray pension B with a spray rate of 18 to 24 g / min on the sprayed precoated active ingredient pellets. After spraying de is at a supply air temperature of 50 ° C until Er range a product temperature of 40 ° C dried. From closing takes place at a supply air temperature of 23 ° C to to reach a product temperature of 30 ° C cools. 1642 g of the coated pellets are in the tray drying cabinet after-treated at 50 ° C for 6 hours (annealed). The pellets are in hard gelatin capsules bottled.

Example 5 (comparative example) Formulation B

1.6 g of Poloxamer 124 and 1.6 g of antifoam emulsion with Ultra-Turrax in 1596 g of purified water is working. 71.8 g bentonite, 7.98 g hydroxypropylmethylcel Lulose and 7.98 g magnesium stearate are mixed together mixed a grater. The powder mixture becomes the given surfactant-containing, aqueous solution and using Ul tra-Turrax stirred in. Then 7.98 g of meso pram placed on the surface of the suspension. It will stirred in with an Ultra-Turrax. It's going to be away tested by agglomerates.  

1500 g of neutral pellets are placed in a granulating container Use in the top spray process with the previously made active ingredient suspension at a spray rate of 18 to 24 g / min and a supply air temperature of 35 ° C sprayed. After the end of spraying, the supply air temperature is 50 ° C until a product temperature of 40 ° C is reached dried. Finally, at a supply air temperature from 23 ° C until a product temperature of Cooled to 30 ° C. The pellets loaded with active ingredient passed through a 1.25 mm sieve to possibly ge formed to remove multiples.

0.75 g of antifoam emulsion, 37.5 g of talc and 3.75 g of die thyl phthalate in 750 g of water using Ultra-Turrax incorporated. 112.5 g ammonium methacrylate copolymer Type B suspension are passed through a 355 µm Sieve added to the aqueous suspension with stirring (Spray suspension A). The spray suspension is ongoing touched.

0.75 g antifoam emulsion, 22.5 g talc and 7.5 g die Ethyl phthalate in Ultra-Turrax in 1500 g of water incorporated. 150 g Type B ammonium methacrylate copolymer Suspension is passed through a 355 µm sieve added to the aqueous suspension with stirring (spray Suspension B). The spray suspension is continuously ge stirs.

1500 g of pellets previously loaded with mesopram are in egg with a granulation container insert using the top spray process the previously prepared spray suspension A at a Spray rate of 18 to 24 g / min and a supply air temperature sprayed at 35 ° C (intermediate coating). Then will the spray suspension B with a spray rate of 18 to 24 g / min sprayed onto the precoated active ingredient pellets. After the end of spraying, the supply air temperature is  50 ° C until a product temperature of 40 ° C is reached dried. Finally, at a supply air temperature from 23 ° C until a product temperature of Cooled to 30 ° C. 1312 g of the coated pellets are in transferred a pelletizer insert and in a we brought to fluidization. The pellets are 6 h in the fluidized bed at a supply air temperature aftertreated from 50 ° C (annealed). Before emptying Ren is at a supply air temperature of 23 ° C except for Product temperature cooled from 30 ° C. The pellets are filled in hard gelatin capsules.

Example 6

216 g of hydroxypropylmethyl cellulose (HPMC) are in 1974 g of purified water, which he to 60 to 70 ° C. has been warmed, solved. 8.6 g mesopram (ZK 117137) who added to the cold HPMC solution with stirring. The Active ingredient suspension is homo by means of a colloid mill embarrassed. 5000 g neutral pellets, NF 18 are 3 min. at a supply air temperature of 50 ° C in a Wurster Appara door warmed. 1684 g of the previously prepared active ingredient pension are at a supply air temperature of 50 ° C in Bottom spray process applied to the neutral pellets gene.

540 g micronized talc are cleaned in 2485 g Water dispersed. To the talc suspension un After gentle stirring, 1692 g of a polyethylacrylate me given methyl methacrylate dispersion. The finished spray pension is continuously stirred. 5000 g of the ge Layered pellets are passed through in a Wurster apparatus a corresponding air volume control for fluidizing brought. 4127 g of the talc-containing coating suspension are effective at a spray rate of 30 g / min applied pellets. There is a pro product temperature of maximum 25 ° C.  

In a free-fall mixer, the active ingredient-containing pellets with a diffusion film with 0.20% highly disperse silicon dioxide mixed. After the pel lets have been spread evenly across hordes aftertreated for 24 h at 40 ° C. The pellets are in Bottled hard gelatin capsules, size 4.

Claims (6)

1. Pharmaceutical preparation with a delayed delivery of active ingredient, the active ingredient being contained in or on pellets, characterized in that the pellets are coated with a diffusion membrane which is permeable to the active ingredient and retarding, this covering comprising talc and polyethacrylate-polymethyl methacrylate. 2. Pharmaceutical preparation according to claim 1, characterized ge indicates that the talc in micronized form is present. 3. Drug preparation according to one of the preceding the claims, characterized in that the Pel lets an average diameter from 0.025 mm to 1.7 mm. 4. Drug preparation according to one of the above the claims, characterized in that the Pel lets have a drug-free core and that on the surface of the active ingredient in molecular disperse or microcrystalline form with a medium grain size of 100 µm on average. 5. Drug preparation according to one of the above the claims, characterized in that the effect substance (R) - (-) - 5- (4-methoxy-3-propoxyphenyl) -5-methyl- 2-oxazolidinone (mesopram).   6. Medicinal products for oral administration containing one Pharmaceutical preparation according to one of the above the claims together with others if necessary pharmaceutically acceptable auxiliaries and additives, in the form of tablets or capsules.