SK72494A3 - Ipsapirone healing preparation - Google Patents

Abstract

The invention relates to ipsapirone pharmaceutical compositions with a delayed action, high bioavailability and good storage stability consisting of diffusion-controlled pellets or erosion tablets with defined release of active ingredient.

Description

The present invention relates to an ipsapirone medicament having retarded action and high storage stability, a process for its manufacture and its use.

BACKGROUND OF THE INVENTION

Ipsapirone is a new active substance that is used therapeutically against states of fear and depression.

As a result of pharmacological tests, ipsapirone was found to have a bioavailability of only 40% after oral administration. A substantial part of the active substance is already metabolised presystemically and cannot be bioavailable. This is disadvantageous since this loss of substance has to be compensated by an increased dose of the active ingredient. This results in large dosage forms that are difficult to ingest for patients and a considerable burden on patients with pharmacologically inactive metabolites of ipsapirone. Furthermore, interindividual fluctuations during plasma concentration increase with decreasing bioavailability, and therapy becomes non-calculable.

Another pharmacokinetic disadvantage of ipsapirone is the short elimination half-life. As a result, ipsapirone tablets must be taken at least three times a day. This results in a number of inconveniences, especially in the working patients, there is a great risk of forgetting to take the tablet, and the patient's willingness to undergo such therapy for a long time is negligible.

Thus, there is a great need for an ipsapirone dosage form that compensates for the poor properties of the substance, that is, to increase bioavailability while allowing the frequency of administration to be reduced.

Effective and therapeutically useful methods of reducing the presystemic metabolism of ipsapirone, and hence increasing its bioavailability, are not yet known. Absorption enhancers, such as those described for other active substances in EP 0 206 947, while increasing absorption insufficiency, cannot

composition

WO 92/06680, reduce extensive presystemic metabolism. in the C ₁₂ -C ₁₄ fatty acids described for reducing first-pass metabolism require sufficient solubility of the active ingredient in fatty acids, which is not the case for ipsapirone. In addition, the patient is then subjected to considerable and unnecessary fatty acid loading.

Methods for retarding the release of pharmacologically active active substances and thereby reducing the frequency of administration are well known to those skilled in the art. However, with all conventional methods of retardation, there are more or less great losses in bioavailability, which are already critical for ipsapirone. Retardation and enhancement of bioavailability are, according to the state of the art, two contradictory requirements for which no methods have been known to date.

SUMMARY OF THE INVENTION

It has now been found that the bioavailability of ipsapirone can be enhanced by concomitant retardation by converting the active ingredient * into a dosage form that provides an active ingredient with a median release of 80% dose / 5 hours to 80% dose / 13 hours and their initial value the release in the first two hours of release is less than 35%. Surprisingly, the ipsapirone dosage forms of the present invention exhibit an increase in bioavailability of, for example, 24%, while at the same time the course of plasma concentration is so prolonged that the frequency of administration can be reduced to once per day.

This is all the more surprising when, to date, it is assumed that the bioavailability of the active substances by controlled, slow release is rather diminishing. So SKELLY (Skelly J., Regulators of Investigation and Evaluation of Oral Controlled Release Products in:

Gundert-Remy, Moler. Oral Controlled Release Products, Wiss. Verlaggeselschaft Stuttgart 1990, p. 180) summarizes: many controlled release products are somewhat less bioaviable than their immediate release counterparts. Especially for active substances with high presystemic metabolism

WAGNER (Wagner J.G.,

Oral Sustained Release

Prolonged-Action

Pharmacokinetics,

Medication in: Fundamentals of Clinical

Hamilton Drug Intelligence Publ. 1975, p.

149) the state of the art as follows: if the drug is metabolized in the gastrointestinal barrier during absorption then it is feasible that a greater percentage of the dose in slow release will be metabolized than when the dose is administered in a fast release form. Furthermore, the preparations according to the present invention overcome the previous prejudice, namely that after about 7 hours the cessation of drug release must be achieved and otherwise the rate of bioavailability has to be expected (Lippold B.C., Biopharmazie, Wiss. Verlagsgesellschaft Stuttgart 1984, p. 69).

Various methods of retarding the active ingredient are useful in the manufacture of the ipsapirone medicament, but a release rate within the range of the present invention must be achieved.

To determine the desired baseline and mean release times of the present invention, the dosage forms are tested in Apparatur 2 USP XXII (The United States Pharmacopeia USP XXII, p. 1578). 900 ml of 0.1 molar hydrochloric acid is used as the test medium. Rotation speed of the stirrer 75 min ^-1. The samples are passed through a 8 μπι filter and the active substance content is determined by HPLC. The amount of active compound, determined in this manner as dissolved, is converted to a percentage of the amount of active compound used.

Preferred medicaments according to the present invention are diffusion-controlled pellets, erosion tablets or osmotic delivery systems of ipsapirone, as well as porosity-controlled membrane tablets or pellets or triple layer erosion tablets in which only the middle layer contains the active ingredient.

according to the present invention

Controlled diffusion pellets from neutral pellets, to which they are applied with conventional diffusion binders, generally comprise a mixture of the active ingredient and are then coated with plasticizers.

and thickeners and which contain a conventional lacquer

As a binder and a thickener, hydroxypropylmethylcellulose. Likewise, natural, synthetic or, for example, methylcellulose, carboxymethylcellulose, polyacrylic acids or gelatin.

other semi-synthetic polymers such as hydroxypropylcellulose, sodium may also be used

Suitable diffusion varnish is preferably Aquacoat ^R , but also other materials such as acrylates, cellulose acetate, cellulose acetate butyrate, Surelease ^R or ethyl cellulose in the form of other aqueous dispersions or solutions.

In particular, triacetin is suitable as an emollient, but dibutyl sebacate, medium chain triglycerides, acetylated monoglycerides, triethyl citrate, acetyl tributyl citrate, diethyl phthalate or dibutyl phthalate may also be used. Since the type and amount of plasticizer affects the release value, the amount of diffusion varnish coating must optionally be varied so that the release values of the finished pellets fall within the scope of the present invention.

In the pellets of the present invention, it is particularly important that a certain ratio of the active ingredient coated pellets to the diffusion membrane be used, as well as a certain ratio of paint dryness to the amount of plasticizer.

Preferably, when using neutral pellets with a size of 0.85 to 1 mm, at a ratio of neutral pellets to active ingredient (calculated as anhydrous ipsapirone hydrochloride) of 40:10, a binder ratio, especially HPMC, to active ingredient (calculated as anhydrous ipsapirone hydrochloride) of 5: 10 and a ratio of physiologically acceptable acid, in particular potassium hydrogen tartrate, to the active ingredient (calculated as anhydrous ipsapirone hydrochloride) 10: 10 ratio of the weight of the active ingredient coated pellets to the weight of the diffusion varnish (without plasticizer) 100: 6 to 100: 21 weight of plasticizer 100: 5 to 100: 60, preferably 100: 20 to 100: 45.

It should be taken into account that parts of the plasticizer used can evaporate during the coating and subsequent tempering. Thus, for example, only about 86% of the theoretical amount of triacetin was found after applying 8.5% of the dry weight of Aquacoat ^R , after only one hour of tempering at 70 DEG C. in the fluidized bed, only about 15% of the theoretical amount of triacetin.

When changing said boundary conditions, it is necessary to change the coated amount of the diffusion lacquer according to the present invention. Thus, for example, a higher amount of coating is required when the relative amount of neutral pellets is increased or when the proportion of triacetin is reduced. The lower amount of coating is required when the relative amount of neutral pellets is reduced, the amount of hydroxypropylmethylcellulose is reduced, or when the proportion of triacetin is increased.

For example, the diffusion pellets of the present invention may be prepared by suspending or dissolving the microfine ipsapirone hydrochloride hydrate and optionally the physiologically acceptable acid in water and concentrating with a concentrated solution of methylhydroxypropylcellulose. The suspension thus obtained is applied to the neutral pellets in a fluidized bed apparatus by a spray process. This is followed by coating the pellets with a diffusion membrane by spraying, for example, an aqueous dispersion of ethylcellulose containing a suitable, physiologically acceptable plasticizer. The pellets are then tempered at a temperature in the range of 50 to 125 ° C, preferably 60 to 110 ° C. In doing so, higher tempering temperatures result in lower coating amounts being sufficient to achieve the release value of the present invention and the resulting pellets are physically more stable in storage.

The diffusion membrane thickness, plasticizer type and pellet size are selected such that the release rate of 80% ipsapirone results in 5 to 13 hours and less than 35% of the dose is delivered in the first two hours. An amount of pellets corresponding to a daily dose of, for example, 10 mg, 20 mg, 30 mg or 40 mg is filled into hard gelatin capsules.

In addition to the described coating of neutral pellets, other pellet production methods such as the extrusion-spheronization process, rotor granulation or tableting are also applicable.

In addition, erosion tablets are preferred. These tablets are characterized in that they contain, in addition to conventional excipients and carriers as well as tabletting aids, a certain amount of water-soluble, hydrogel-forming polymers, which polymers must have a viscosity of at least 150 mPa. s (measured as a 2% aqueous solution at 20 ° C).

Common excipients and carriers are, for example, lactose, microcrystalline cellulose, mannitol or calcium phosphates.

Conventional tabletting aids are, for example, magnesium stearate, talc or highly dispersed silica (Aerosil ^R ).

As water-soluble, hydrogel-forming polymers, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, alginate, galactomannan, polyacrylic acid, polymethacrylic acid or copolymers of methacrylic acid and methyl methacrylate are preferably used.

The use of hydroxypropylcellulose is particularly preferred.

The erosion tablets of the present invention should contain at least 50 mg of hydroxypropylcellulose type based on the weight of the tablet having a viscosity of at least 150 mPa s (measured as a 2% aqueous solution at 20 ° C).

These data are valid for hydroxypropylcelluloses with a proportion of hydroxypropoxy groups of 53-78% and a particle size of 99% <150 µm, 20-35% 150-63 µm, 50-60% 63-38 µm and 15-25% <38 µm. Deviating from these values requires adjustment of the values of the present invention.

For example, tablets of the present invention may be prepared by suspending ipsapirone hydrochloride hydrate in a solution of hydroxypropylcellulose. The suspension is used to granulate the powder mixture in a fluidized bed granulator with a hydrophilic gel-forming agent, for example, hydroxypropylcelluloses of one or more viscosity grades. The amount and viscosity degrees of the hydroxypropylcelluloses (s) are selected so as to result in tablets having an intermediate release rate and an initial release value according to the present invention. The dry granulate is then sieved, optionally mixed with a physiologically acceptable acid and a lubricant such as magnesium stearate, tableted and optionally further lacquered.

Another significant problem with the formulation of ipsapirone is its instability. According to external influences such as temperature and humidity, the active substance reacts as follows:

The reaction rate is very considerable. Thus, a solution of 6.7 mg of ipsapirone hydrochloride in 100 ml of phosphate buffer pH 6.8 was found to be 29% decomposed after 24 hours at 37 ° C. This reaction can also occur in slow-release dosage forms, so that in the gastric and intestinal passages of the active ingredient, its proportions are degraded before they are resorbed. This results in reduced bioavailability.

The same degradation reaction of storage. Thus, the table also leads to instability in Comparative Example 1 after storage for 6 months (based on the active substance content) at 40 ° C at 2.23% of the product A degraded.

It has now been found that this degradation reaction can be suppressed without other disadvantages when a physiologically acceptable acid or acid-reacting salt such as potassium hydrogen tartrate, adipic acid, ascorbic acid, aspartic acid, benzoic acid, citric acid is added to the ipsapirone dosage form. , fumaric acid, glutanic acid, maleic acid, sodium dihydrogen citrate, sodium dihydrogen phosphate, polyacrylic acid, sorbic acid, stearic acid, succinic acid, tartaric acid or combinations thereof. Particularly preferred are acids with a water solubility of less than 20% (at 20 [deg.] C.), such as adipic acid, aspartic acid, benzoic acid, fumaric acid, glutamic acid, potassium hydrogen tartrate, succinic acid and stearic acid.

The results of the bioavailability tests (Table 1) show that this could in all cases (Examples 2 to 6) avoid significant breaks in bio-utilization compared to fast-release tablets (Example 1). Further, the stored pellet capsules of Example 6 were stored for 6 months at 40 ° C. The degradation product A produced only 0.22%, which corresponds to a reduction to one tenth of the value of the unstabilized preparation according to Comparative Example 1.

To demonstrate the efficacy of the dosage form of the present invention, the ipsapirone dosage forms of the present invention and other retarded dosage forms were administered to 6 to 8 volunteer healthy recipients, and plasma duration and bioavailability were measured compared to ipsapirone fast-release tablets (Fig. 1).

The formulation of Example 6 of the present invention shows a surprising increase in the bioavailability of ipsapirone by 24.4% compared to a non-retarded standard tablet. As shown in FIG. 1, for example, a plasma concentration of 2 µg / L is guaranteed for 214 hours after a single capsule administration.

The retarded formulations of Examples 2 and 3 do not meet the criteria of the present invention. Their bioavailability lies between 78% and 85% below the bioavailability values of fast-release tablets compared to the prior art values described so far.

The formulations of Examples 4 and 5, according to their release properties, lie within the boundary region of the criteria of the present invention. Their bioavailability is increased, but to a small extent.

When comparing the retarded formulation of the present invention of Example 6 with a conventional retarded formulation corresponding to the prior art (Example 2), a particularly significant increase in bioavailability of practically 60% is achieved for therapy.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Rapid Release Tablets (prior art)

Composition for tablet

granulate:

Ipsapirónhydrochlorid lactose Avicel Maize starch Hydroxypropylmethylcellulose (HPMC) 10.0 mg 107.6 mg 48.0 mg 11.0 mg 2.8 mg addition: Magnesium stearate 0.6 mg Lacquer encapsulation: HPMC 3.3 mg Polyethylene glycol (PEG) 1.1 mg Titanium dioxide 1.1 mg

Ipsapirone hydrochloride, lactose, avicel in powder form are mixed and the mixture and the corn starch are granulated with an aqueous solution of HPMC. The granulate is dried, sieved and blended with magnesium stearate. This is followed by compression into tablets and coating with an aqueous dispersion of titanium dioxide, PEG and HPMC.

Example 2

Retarded tablets (criteria of the invention not met)

Composition for tablet

granulate:

Ipsapirone hydrochloride hydrate 10.62 mg

HPC 8 mPa.s. HPC 300 mPa.s. Succinic acid 109.7 mg 45.0 mg 5.0 mg addition: Magnesium stearate 0.3 mg Lacquer encapsulation: HPMC 3.3 mg PEG 4000 1.1 mg Titanium dioxide 1.1 mg

Ipsapirone hydrochloride hydrate is suspended in an aqueous solution of an HPC fraction of 300 mPa.s. The remaining HPC of 300 mPa · s and HPC of 8 mPa · s are granulated with this suspension in a fluidized bed granulator. The granulate is dried, sieved and blended with magnesium stearate. This is followed by compression into 8 mm tablets and coating.

The initial release value from the dosage form is 40% in two hours, the median release value is 80% in six hours.

Example 3

Retarded pellets (criteria of the invention not met)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm Ipsapirone hydrochloride Potassium hydrogen tartrate

HPMC

40.0 mg

10.62 mg

10.0 mg

5.0 mg

Diffusion membrane:

Aquacoat ^R ECD30 - dry matter

Triacetin, quantity used

Hard gelatin capsules no. 4

15.09 mg

5.03 mg

39.0 mg

Ipsapirone hydrochloride hydrate and potassium hydrogen tartrate are suspended in an aqueous solution of HPMC and sprayed onto neutral pellets in a fluidized bed. The aqueous dispersion of Aquacoat ^R -triacetin is then sprayed. The weight of the sprayed diffusion membrane (calculated as the dry matter of Aquacoat ^R ) was 23% by weight of the unencapsulated pellets. The injection process is interrupted three times and the pellets are dried for one hour at 60 ° C. The coated pellets are then tempered at 60 ° C for one hour and filled into hard gelatin capsules.

The initial release from the dosage form is 3% at two hours, the mean release at 80% at 14 hours.

Example 4

Retarded pellets (according to the invention)

Composition for tablet

granulate:

Ipsapirone hydrochloride hydrate 10.62 mg

HPC 300 mPa.s 154.1 mg

Succinic acid 5.0 mg

addition:

Magnesium stearate

0.3 mg

Lacquer encapsulation:

HPMC • PEG 4000

Titanium dioxide

3.3 mg

1.1 mg

1.1 mg

Weigh for one batch of tablets:

First

Second

HPC 300 mPa.s.

Water

1.5

348.8

HPC 300 mPa.s is dissolved in water.

Third

Ipsapirone hydrochloride micronized

60.0

Ipsapirone hydrochloride is suspended to give a granulating liquid.

HPC-M solution.

4th

5th

HPC 300 mPa.S Succinic acid

923,1

30.0

6th

HPC 300 mPa.s with fluidized bed.

Magnesium stearate

Magnesium stearate with granulate. Obtained to tablets with and weight and acid granulated, mix amber with spray mixture to a diameter of 8 mm

170 mg.

1.8 with dried granulator granulating screened tabletting machine compresses (12 mm camber radius)

8th

9th

Water 85-95 ° C

Polyethylene glycol

HPMC

1,270.0

30.0

90.0

PEG 4000 is dissolved in hot water and dissolved in this solution

7th

4000 dissolves HPMC.

10. Water

11. Titanium dioxide

635.0 g

30,0 g

The titanium dioxide is suspended in water. The suspension is mixed with the HPMC-PEG 4000 solution and sprayed onto the tablets until the prescribed lacquer coating is achieved.

The initial release value from the dosage form is 32% in the first two hours, the median release value is 80% in 10 hours.

Example 5

Retarded pellet (according to the invention)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm Ipsapirone hydrochloride potassium hydrogen tartrate micronized by HPMC 40,00 mg 10.62 mg 10,00 mg 5,00 mg

Diffusion membrane Aquacoat ^R - dry matter Triacetin, quantity used 5,577 mg 1,859 mg Hard gelatin capsules no. 4 39.0 mg

For one batch of 62 500 retarded capsules, weigh:

1. neutral pellets 0.85 - 1.0 mm 2. Ipsapirone HCl hydrate 3. Potassium hydrogen tartrate 2500,00 g 663.75 g 625,00 g

4. Methylhydroxypropylcellulose

5. Purified water for coating suspension production (evaporates during the process)

312,50 g

5300,00 g

Ipsapirone HCl and potassium hydrogen tartrate are suspended in a portion of the indicated amount of water. Methylhydroxypropylcellulose is dissolved in the remaining amount of water, then the two solutions are combined and mixed. This suspension is homogeneously applied to the neutral pellets in the fluidized bed apparatus by the spray process.

The following shall be weighed:

6. Ethyl cellulose, aqueous dispersion 30% (Aquacoat ^R )

7. Triacetin

8. Purified water for the production of lacquer suspension (evaporates during the process)

1161.88 g

116.19 g

1045.69 g

Aquacoat ^R ECD 30 and triacetin are suspended in the indicated amount of water. With this lacquer dispersion, the active substance pellets are coated in a fluidized bed apparatus. After varnishing, the pellets were heated in an oven at 60 ° C for one hour.

As a process control, the content and release are determined so that the release values according to the present invention can be achieved, if necessary, by additional painting.

The final amount for filling the capsules is determined from the content determination. A number of pellets corresponding to 10 mg of ipsapirone are filled into hard gelatin capsules.

The initial release value from the dosage form is 22% in the first two hours, the median release value is 80% in 5 hours.

Example 6

Retarded pellet (according to the invention)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm

Ipsapirone hydrochloride potassium hydrogen tartrate micronized by HPMC

40.00

10.62

10.00

5.00 mg mg mg mg

Diffusion membrane

Aquacoat ^R - dry matter

Triacetin, quantity used

12.47

4.11 mg mg

Hard gelatin capsules no.

39.0 mg

Production is carried out in the same way, but the dispersion spraying is discontinued and the pellets are always kept at 60 ° C.

as described in Aquacoat / triacetin for one hour at Example 5, twice

Initial value of drug release in the first two hours, mean value of hours.

of the form is 6.6% release of 80% in 10

Example 7

Retarded pellet (according to the invention)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm

Ipsapirónhydrochloridhydrát

120,00 mg

31.86 mg

Potassium hydrogen tartrate micronized by HPMC

Diffusion membrane

Aquacoat ^R - dry matter

Triacetin, quantity used

Hard gelatin capsules

30.00

15,00

17.72

5.85 mg mg mg mg

Manufacture, however, of pellets 65 ’C.

is carried out in the same way as after painting at the temperature of Example 5 for 4 hours,

Initial in the first two hours.

the release rate of hours, the median median of the form is 3.2% release 80% at 9

Example 8

Retarded pellet (according to the invention)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm

Ipsapirónhydrochloridhydrát

Potassium hydrogen tartrate micronized by HPMC

80.00

21.24

20.00

10.00 mg mg mg mg

Diffusion membrane

Aquacoat ^R - dry matter

Triacetin, quantity used

18.37

6.06 mg mg

Hard gelatine capsules

The production is carried out as in Example 5, but the pellets are tempered for 1 hour at 60 DEG C. after painting.

The initial release value from the dosage form is 4.2% in the first two hours, the median release value is 80% in 9 hours.

Example 9

Retarded pellet (according to the invention)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm Ipsapirone hydrochloride Potassium hydrogen tartrate HPMC 80,00 mg 21.24 mg 20,00 mg 5,00 mg Diffusion membrane Aquacoat · ¹ '· - dry matter 12.62 mg Triacetin, quantity used 4.21 mg

Hard gelatine capsules

The production is carried out as described in Example 5.

The initial release value from the dosage form is 8% in the first two hours, the median release value is 80% in 11 hours.

Capsule composition

Example 10

Retarded pellet (according to the invention)

Pellet base:

Neutral pellets 0.85 to 1.00 mm

Ipsapirónhydrochloridhydrát

Potassium hydrogen tartrate micronized

160,00 mg

42.48 mg

40,00 mg

HPMC

20,00 mg

Diffusion membrane

Aquacoat ^R - dry matter

21,00 mg

Triacetin, quantity used

6.93 mg

Hard gelatine capsules

Production is carried out as described in Example 5, but the pellets were varnished tempera JUNE for 1 hour at 65 ^o C in the fluidized bed.

The initial release value from the dosage form is 19% in the first two hours, the median release value is 80% at 7 hours.

Example 11

Retarded tablets (according to the invention)

Composition for tablet

Uncoated tablet:

Ipsapirónhydrochloridhydrát 21.24 mg HPC 8 mPa.s. 49.60 mg HPC 300 mPa.s. 141.10 mg Succinic acid 7,5 mg Magnesium stearate 0.5 mg

Lacquer encapsulation:

HPMC

3.60 mg tablets are produced having a radius

PEG 4000

Titanium dioxide

1,20 mg

1,20 mg

By the method described in the example with a weight of 226 mg and a diameter 9 of 15 mm.

The initial release value from the dosage form is 29% in the first two hours, the median release value is 80% in 12 hours.

Example 12

Retarded tablets (according to the invention)

Composition for tablet

Uncoated tablet:

Ipsapirónhydrochloridhydrát HPC 300 mPa.s. Succinic acid Magnesium stearate 21.24 mg 190.70 mg 7.50 mg 0.50 mg Lacquer encapsulation: HPMC 3,60 mg PEG 4000 1,20 mg Titanium dioxide 1,20 mg

* Using the method described in Example 4, tablets having a weight of 226 mg and a diameter of 9 mm are produced having a radius of curvature of 15 mm. The initial release value from the dosage form is 29% in the first two hours, the median release value is 80% in 12 hours.

Example 13

Retarded tablets (according to the invention)

Composition for tablet

Uncoated tablet:

Ipsapirónhydrochloridhydrát 31.86 mg HPC 8 mPa.s. 195,70 mg HPC 300 mPa.s. 58,60 mg Succinic acid 12.50 mg • Magnesium stearate 0.70 mg

Lacquer encapsulation:

HPMC

4,20 mg

PEG 4000

1.40 mg

Titanium dioxide

1.40 mg

By the method described in Example 4, tablets having a weight of 307 mg and a diameter of 10 mm were produced having a radius of curvature of 15 mm. The initial release value from the dosage form is 35% in the first two hours, the median release value is 80% at 7.5 hours.

Example 14

Retarded tablets (according to the invention)

Composition for tablet

Uncoated tablet:

Ipsapirónhydrochloridhydrát 31.86 mg HPC 300 mPa.s. 254.90 mg Succinic acid 12.50 mg Magnesium stearate 0.70 mg

Lacquer encapsulation: HPMC 4.20 mg PEG 4000 1.40 mg Titanium dioxide 1.40 mg

The method with a camber weight of 15 is 28% as described

307 mm.

in the first in 13 hours.

in Example 4, mg tablets with a diameter of 10 mm are produced having a radius of Initial release value from the dosage form of two hours, median release value 80

Example 15

Retarded pellets (according to the invention)

Capsule composition

Pellet base:

Neutral pellets 0.85 to 1.00 mm

Ipsapirone hydrochloride potassium hydrogen tartrate micronized by HPMC

80.00

21.24

20.00

10.00 mg mg mg mg

Diffusion membrane

Aquacoat ^R - dry matter

Triacetin, quantity used

18.36

6.00 mg mg

Hard gelatin capsule

Manufacture, however, pellets 65 ° C.

is carried out in the same way as after the tempering is given for 2 hours at Example 5, the temperature

Initial in the first two hours.

the release value of hours, the median value from the dosage form 80 is 5%% at 12 k

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Claims (10)

PATENT CLAIMS An Ipsapirone medicinal product with a median release value between 80% / 5 hours to 80% / 13 hours and an initial release value of less than 35% ipsapirone in the first two hours of release. The Ipsapirone medicinal product according to claim 1 in the form of controlled diffusion pellets or tablets. Controlled diffusion pellets according to claim 2, characterized in that they consist of neutral pellets coated with a mixture of the active ingredient and a binder, which are coated with a diffusion layer. Controlled diffusion pellets according to claims 2 and 3, characterized in that the diffusion layer consists of a conventional diffusion varnish and a conventional plasticizer. Controlled diffusion pellets according to claims 2 to 4, characterized in that hydroxypropylmethylcellulose is used as the binder, Aquacoat ^R as the diffusion lacquer and triacetin as the plasticizer. Process for the production of controlled diffusion pellets according to claims 2 to 5, characterized in that the active substance, optionally with additives, is suspended or dissolved in water, concentrated by a binder solution, coated with neutral pellets and coated with the pellets. mixture of diffusion varnish and plasticizers. Tablets according to claim 2 containing, in addition to the active ingredient and conventional tabletting aids, water-soluble hydrogel-forming polymers. Tablets according to claim 7, characterized in that they contain, in addition to the active ingredient, at least 50 mg of hydroxypropylcellulose with a viscosity of at least 150 mPa.s. Ipsapirone medicinal preparations according to claims 1 to 7, characterized in that they additionally contain a physiologically acceptable acid. Use of the ipsapirone dosage forms according to claims 1 to 9 for the treatment of states of fear and depression.