DK167649B1 - SOLID DISTRIBUTION WITH EXTENDED DELIVERY, SECONDARY STRUCTURE OF THE MEDICINAL PRODUCT AND PHARMACEUTICAL PREPARATION CONTAINING THE DISPERSION OR STRUCTURE - Google Patents

Description

DK 167649 B1

The present invention relates to a prolonged release solid drug dispersion, a secondary structure of the drug, and a pharmaceutical composition containing the dispersion or structure.

By incorporating an active agent into a solid dispersion or solution, only an accelerated release has so far been obtained. For example, solid dispersion forms of drugs are known, for example from West German Publication No. 2,549,740, wherein solid dispersions of griseofulvin in polyethylene glycol are described. The low dissolution rate and consequently (see p. 11, lines 4-5) the low bioavailability of griseofulvin was improved by preparing a solid dispersion of griseofulvin in polyethylene glycol. In the specifically described drug formulation, a tablet, it was necessary to add a disintegrant to the solid dispersion granules, since it was found that a greatly improved dissolution rate of griseofulvin was again decreased. The pressure applied to the preparation of tablets led to significant cohesion between the tablet particles as a result of the strong cohesion between the polyethylene glycol molecules.

The disintegrant, crosslinked polyvinylpyrrolidone, was added to be able to recover the original granular particles in the tablet in which the griseofulvin was present in a faster release form.

The water-soluble polyethylene glycol, which is in contact with an aqueous medium, is extracted from the granulate by diffusion, causing the finely griseofulvin to dissolve rapidly.

According to West German Specification No. 2,546,577, an increased dissolution rate and resorption of salts of water-soluble ergotamine compounds (in particular of dihydroergotamine methanesulfonate, dihydroergocristine methanesulfonate, dihydroergo methane sulfonate (methanesulfonate) when the salts are present in solid solutions in polyalkylene glycols and especially in polyvinylpyrrolidone having a molecular weight greater than 10,000. Said drugs have, in methane sulfonate salt form, a water solubility of 2 υκ ib / b ^ y d in excess of 0.01% and in this respect are different from the active agents used in the present invention.

According to European patent application, publication no. 78430, an increase in the dissolution rate and retention of the absorption of dihydropyridines, especially of nifedipine and nimodipine, are obtained if these agents are dissolved together with polyvinylpyrrolidone, e.g., with a molecular weight of over 25,000, in a small amount of a liquid organic solvent, so that the solid particles are just dissolved, after which this solution is mixed and granulated with solid supports with a high ability to absorb and followed by evaporation of the organic solvent.

The drug is present in the dissolved solid polyvinylpyrrolidone and, upon contact with an aqueous medium, exhibits an increased dissolution rate. Both of these features make these known products different from the compositions of the present invention.

Chemical Abstracts, Vol. 95 (1981) No. 225681j disclosing JP 80 / 19,191 (55-19191) discloses a composition containing more than 6% of the heavily soluble compound nifedipine in a water-soluble matrix. The matrix contains polyethylene glycol 6000 as well as smaller amounts of 20 honey and menthol. This preparation has a drug release which is increased by a factor of 2 over 2 hours in in vitro experiments compared to similar preparation without polyethylene glycol 6000.

According to Canadian Patent No. 987,588, an increased dissolution rate and bioavailability of water-soluble drugs are obtained when present as solid dispersions in polyethylene glycols and in other water-soluble matrix materials, e.g., pentaerythritol, pentaerythritol tetraacetate or citrate.

The known drugs digitoxin-17-methylthestosterone, prednisolone acetate and hydrocortisone acetate are present at concentrations up to 30% in the matrix material, giving dispersions different from the dispersions of the present invention. As mentioned above, the drug griseofulvin has a water solubility of more than DK 167649 B1 0.01% and is therefore different from the active agents used in the present invention.

It has been found that if such a matrix material uses solid dispersions of pharmacologically active agents, such as practically 5. are insoluble in water, no significant expected increase in dissolution rate in an aqueous medium is observed. Instead, a decrease is obtained without any significant loss of bioavailability.

It has further been found that the decrease in dissolution rate can be attributed to the coherent crystalline form of the drug, hereinafter referred to as a secondary structure, which form can be maintained even if the water-soluble matrix material is removed by contact with an aqueous medium, e.g.

To enable the formation of the secondary structure, it is preferred that the drug be present in the solid dispersion at a concentration above 5% and for more than 5% by weight in crystalline form, preferably as particles having a diameter of below 5 μπι and with a water solubility of up to 0.01%, preferably below 0.005% by weight.

The present invention therefore relates in one aspect to a solid dispersion of a pharmacologically active agent in a water-soluble crystalline matrix carrier in which the active agent. a) has a maximum solubility of 0.01% at 37 ° C in water, b) is present in the matrix at a total concentration greater than 5% by weight of the matrix, and c) is present in the matrix at a concentration above 5% by weight of the matrix in coherent crystalline form.

This solid dispersion in aqueous medium has a reduced dissolution rate.

A reduced dissolution rate is described in the following known 30 references: 4 UK lb / 649 ΒΊ

West German Publication No. 1,617,362 discloses suspension of pharmacologically active agents, in particular theophylline, in molten waxes to produce reduced dissolution rate galenic forms in an aqueous medium. Polyethylene glycol is used as wax.

However, the solubility of theophylline is not sufficiently low (above 0.01%) and only further incorporation of conventional retarding excipients such as beeswax or stearic acid can cause a satisfactory decrease in drug dissolution rate.

West German Publication No. 3,318,649 discloses a two-phase solid pharmaceutical composition containing crystalline nifedipine and separately a solid solution of nifedipine in a matrix material, especially in polyvinylpyrrolidone. Upon contact with an aqueous medium, nifedipine is dissolved from the solid solution at an increased dissolution rate and from the solid nifedipine crystals at a reduced dissolution rate.

According to the present invention, there is only a solid dispersion of the drug which, upon contact with an aqueous medium, causes drug delivery at a reduced rate.

With regard to the solid dispersion of the invention, the choice of the pharmacologically active agent is not critical, provided that the conditions of its solubility and crystallization are met.

It is a simple and routine matter to investigate whether a given active agent meets the required conditions.

The practically insoluble pharmacologically active agents in the dispersion of the invention are, for example, dihydropyridines, especially 1,4-dihydro-3,5-dicarboxylic acid diester-2,6-dimethylpyridines, especially those having an optionally substituted 4- phenyl group or a 4-phenyl derivative.

For example, a 4-phenyl derivative is 4- (2,1,3-benzoxadiazol-4-yl). An example of a drug with an optionally substituted 4-phenyl group is the known 4- (2-nitrophenyl) -1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid methyl ester (nifedipine).

DK 167649 B1 5

Examples of drugs with a 4-phenyl derivative are 4- (2,1,3-benzoxa-diazol-4-yl) -1,4-dihydro-5-ethoxy carbonyl-2,6-dimethyl-3-pyridinecarboxylic acid. ethyl ester (compound A), 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester (compound B) and ( -) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid isopropyl ester ( compound C).

The dihydropyridines are extensively described in the literature and have especially calcium antagonistic effect. For example, they are described as antihypertensive agents and as drugs for the treatment of angina pectoris.

The above-mentioned dihydropyridines A and B are known, for example, from European Patent Specification No. 150 and British Patent Specification No. 2,037,766. The dihydropyridine C is known from British Patent Application No. 2,122,192 A, and is specifically described in Example 2c therein.

It has been established that the dihydropyridines, e.g., compounds A and B, are practically water insoluble and thus have a water solubility of less than 0.01%.

However, working up to a solid dispersion form did not, as expected, result in an increased dissolution rate, but surprisingly 20 in a significantly reduced dissolution rate (cf. Comparative Experiments 1-5), which is advantageous in compositions to be administered once daily.

This retarding effect is attributed to the solid dispersion, for example in granular form, independent of any excipients present. An advantage 25 is that there is no usual drug burst and that there is no significant decrease in bioavailability (cf. the comparative experiments).

Thus, the present invention also relates to a once-daily pharmaceutical composition comprising a therapeutically effective amount of the compounds A or B. The matrix materials are preferably pharmaceutically acceptable solid compounds.

Wolves 10/043 are commonly used widely as pharmaceutical excipients.

Since they must be water soluble, they should have polar properties.

Thus, most of these matrix materials have polar groups, e.g., 5 oxy groups, especially hydroxy groups.

The preferred pharmaceutical compositions contain a solid dispersion of pharmacologically active agents in a polyalkylene glycol, especially in a poly (C2 2) alkylene glycol, for example in a polyethylene glycol. The polyethylene glycol preferably has a molecular weight of 1,000-20,000, preferably 10,000 - 20,000, especially 4,000-8,000, e.g., 6,000.

The solid dispersions can be obtained by dissolving the active agents at a concentration of more than 5% by weight in the liquid dispersant and solidifying the mixture obtained.

The dispersant can be liquified by melting it or by the addition of a liquid organic solvent.

For example, solidification of the dispersion may occur by cooling or by evaporating the liquid organic solvent.

After the solid dispersion is obtained, it can be reduced to a conventional particle size, giving a granulate useful for further work-up.

At least 5% by weight of the drug particles present in the solid dispersion are so small that they can be seen by conventional optical measurements, since if suspended for measurement purposes in an aqueous medium they appear to have a continuous Brown '25 movement.

Therefore, the particles are generally assumed to have a diameter of 5 μη or less.

Laser light scattering tests in the aqueous suspension determined a particle size even below 0.5 μιη.

DK 167649 B1 7

Comparison of Guinier-de-Wolff spectra of the solid dispersion and of a corresponding mechanical mixture showed no significant difference.

The spectra further show that both drug and matrix material in the dispersion are in crystalline form.

The concentration of the drug in the matrix can range from 5 to 80% by weight, preferably from 20 to 50% by weight and especially from 20 to 40% by weight and contributes to the retarding effect of the invention. (A greater concentration may cause a greater decrease in the dissolution rate, cf. curve 14-18 in Fig. 5 for the dissolved amount in 10 wt.% Over time T in hours; increasing concentrations of 10-50 wt.% Of compound A may cause a decreasing the dissolution rate).

Curves 14-18 of FIG. 5 relates to solid dispersion granules of the same subfraction containing 10, 20, 30, 40 and 50% by weight of Compound A.

A suitable dose of the active agent is preferably up to 250 mg and preferably up to 200, especially up to 100 mg for compound A and up to 50, preferably up to 30, especially 10-25 mg for compound B per dose. day. For a rationally manageable dispersion amount, a concentration of 10-80% by weight of active agent in the matrix is indicated, averaging up to 50% by weight, e.g. 40% by weight of Compound A and 20% by weight of Compound B.

If the chemical stability of the active agent is not high, the temperature of the molten matrix material, e.g., the polyalkylene glycol, should be kept appropriately low. If more active agent is added to the polyalkylene glycol, it can be dissolved at the maximum permissible temperature; the profits will not be dissolved, but incorporated as a suspension.

The undissolved fraction particles should preferably have a particle size of not more than 100 μια.

DK 167649 B1 8

Upon cooling of the suspension, these particles can be found in the dispersion of a similar size in addition to the active agent fraction which was dissolved and, after cooling, can again be found in the form of crystals having a diameter not exceeding 5 µm.

During the granulation process as briefly described above, the solid dispersion is preferably reduced to a particle size of 50-2000 µm, especially 90-1000 µm, more particularly 125-500 µm.

The particle size of the granulate contributes to the controlled release of the invention (larger particles cause a greater decrease in dissolution rate, cf. curve 19-22 in Fig. 6; dissolved amount by weight in relation to time T; an increased particle size causes a decrease in The rate of dissolution, curve 19-22 relates to sieve factors of 90-180, 180-355, 355-500 and 500-710 µm of the dispersion granulate of a 40% dispersion of compound A in polyethylene glycol 6000).

In summary, it can be concluded that the release of the pharmacologically active agent can be regulated by changing the concentration of the active agent in the solid dispersion and by varying the particle size of the solid dispersion granulate.

Surprisingly, it has been found that when the dispersion granule particles, for example those of Example 1, are placed in water, their matrix fraction dissolves rapidly and quantitatively. The particles in the active agent, which in the dispersion, for example, have a size of up to 5 µm, form continuous secondary structures, their density and diameter varying according to the concentration of the active agent in the matrix and the diameter of the granulate particles.

Thus, the present invention also relates to a secondary structure of an active agent formed from the solid dispersion after selective extraction of the matrix material, for example, in an aqueous medium.

This secondary structure may have a diameter comparable to the diameter of the dispersion granulate. In water, it has a delayed dissolution rate. It can be partially restored to its original particles up to 5 pm by intensive ultrasound treatment.

DK 167649 B1 9

Active agent particles, which in the dispersion granule, for example, can have a diameter of up to 100 μπι, are enclosed in the unaltered state in the secondary structure, which has been prepared from the particles up to 5 μιη.

Since the original particles of the agent up to 5 μπι and the additional particles of the contained agent up to 100 μιη contribute to the controlled release, both the solid dispersions and the secondary active agent structures belong to the present invention.

The diameter and surface of the particles of the secondary structure of the active agent have been investigated. They have irregular crack-like channels and have an outer and an inner surface.

Both the size and structure of the outer surface influence the rate of dissolution in, for example, an aqueous solvent medium. The inner surface has narrow pores of up to 1 μπι, which hardly contribute to the release of the active agent, since their mobility is greatly reduced if they contain a solvent medium.

The size of the secondary structure corresponds to the size of the solid dispersion granule particles from which they originate.

After removal of the solvent medium, e.g. by drying, the specific surface and pore volume can be measured.

The present invention relates to the secondary structure of an active agent having a diameter of preferably 50-2000 µπι, more particularly 90-1000 µm, especially 125-500 µπι, with porous structure characterized by a specific surface of 1-15 m / g, preferably 2-12 wP / g, as measured by the BET method, and at a pore volume of 20-95%, measured by mercury trace asymmetry.

The solid dispersion particles as well as the secondary structure particles are useful for the preparation of pharmaceutical compounds.

DK 167649 Pg 10

Thus, the present invention also relates to pharmaceutical compositions containing the solid dispersion granular or the secondary structure particles.

Pharmaceutical compositions containing the solid dispersion granule 5 can be considered as galenic precursor forms of similar compositions containing the particles of the secondary structure, since their behavior in the body can be compared to the behavior of pro-drugs.

For the preparation of pharmaceutical oral administration forms containing the solid dispersion, the granular of the solid dispersion can be mixed in the usual manner with suitable pharmaceutical excipients, for example fillers such as lactose, lubricants, e.g. silicon dioxide and a lubricant, e.g. magnesium stearate (see eg Example 2, 5 , 6 and 9) and optionally a designing agent such as cross-linked polyvinylpyrrolidone, e.g., cross-linked povidone (see, e.g., Examples 2, 3, 5 and 6) or sodium carboxymethyl cellulose (see Example 9), and they can be prepared in conventional solid oral. forms of administration such as tablets or capsules.

For the preparation of tablets, the solid dispersion granulate 20 may preferably be mixed with, for example, lactose, silica and magnesium stearate (see Examples 4, 5, 6 and 9).

The porous particles of the secondary structure are preferably used in capsules as they are less able to withstand the tableting pressure.

For the preparation of capsules, the solid dispersion granulate of the particles of the secondary structure can be mixed in the usual manner, preferably with a placebo granule from suitable excipients such as lactose, starch and polyvinylpyrrolidone and with a mixture of crosslinked povidone, silica and magnesium stearate ( see Examples 2 and 30 3). The disintegrant can be used to suspend the capsule contents.

DK 167649 B1 11

In general, pharmaceutical forms of administration, especially capsules and, to a lesser extent, tablets, are disintegrated during passage through the stomach, which can be greatly prevented by applying an enteric soluble coating to them. Suitable enteric soluble coatings include hydroxypropyl methyl cellulose phthalate (see Examples 3, 5, 6 and 12). If the active agent is resorbed in the upper intestine - dihydropyridines are such agents - such a coating is very favorable and does not impair the resorption process.

Tablets containing the components in compressed state may need this coating to a lesser extent, but then the disintegrant should be omitted (see the tablet of Example 4, which does not contain any cross-linked polyvinylpyrrolidone).

It has been found that capsules or tablets without an enteric soluble coating can be prepared if a hydrophobic excipient such as a fatty acid glyceryl ester is added to the solid dispersion (see Examples 8 and 9 and Comparative Experiment # 4). This hydrophobic ester reduces the drug burst in the stomach and cannot significantly interfere with the gut resorption process. Such preparations can be prepared by dissolving the pharmacologically active agent in the liquid matrix and emulsifying the obtained mixture with the hydrophobic substance, for example the fatty acid glyceryl ester, as much as possible, after which the obtained mixture can be solidified by cooling.

Preferred fatty acid glyceryl esters are physiologically acceptable esters such as 2q fatty acid, e.g., palmitic and / or stearic glyceryl esters. These esters may be, for example, mono-, di- and / or triesters of glycerol.

Preferably, the amount of fat is up to 60% of the total weight of the solid dispersion, eg 5-60%, and most preferably of 15-25%, eg 20%.

The retarding compositions of the present invention can be used to administer very different, practically water-insoluble classes of active agents. They can be used for their known indications.

12 DK Ί6 / 649 ΒΊ

The amount of active agent to be administered may depend on various factors, for example, the condition to be treated, the desired treatment duration and the rate of release of the active agents.

The amount of each active agent required and the rate of release 5 can be determined using in vivo techniques, for example, by measuring the concentration of active agent in the blood serum.

For example, the pharmaceutical compositions of compounds A and B can be used for the same indications as described in European Patent Specification No. 150 and in British Patent Specification No. 2,037,766.

For example, for antihypertensive use, up to 250 mg, especially up to 200 mg, preferably 50-100 mg of compound A and up to 50 mg, especially up to 25 mg, preferably 10-20 mg of compound B, is used. day.

FIG. 1-4 and FIG. 7-8 indicate the plasma level of a pharmaceutical composition containing compound A / ml and compound 15 B / ml, respectively, over at least 22 hours. FIG. 5-6 shows the dissolution rate of compound A in vitro.

In particular, the present invention relates to a pharmaceutical composition which provides plasma levels of 2-8 ng of compound A per day. ml for at least 22 hours when containing one dose of 50 mg of the active agent. The basis for this observation is the plasma level curves 1, 3, 4, 5 and 6-13 in FIG. 1-4.

The present invention also relates to a pharmaceutical composition which provides plasma levels of 1-2.5 ng of compound B ml for at least 22 hours when containing one dose of 10 mg of the active agent. The basis for this observation is the plasma level curves 23 and 26 of FIG. 7 and 8.

The plasma level of compound A in the curves 1-13 in FIG. 1-4 (concentrations relative to time) can be determined by gas chromatography.

A 1 ml plasma sample adjusted with NaOH to a pH of 30 13 was extracted with toluene, the toluene was evaporated and the residue was dissolved in 0.5 ml of toluene. 2 µl of the resulting solution was separated at 300 ° C in an OV 17 column (6% on Gaschrom Q 0.149-0.125 mm) using an argon / methane gas mixture (95: 5 v / v) as carrier gas ( speed 60 ml / minute). The assay can be performed using an electron capture detector. The retention time of compound A was 3.1 minutes.

The concentration of the compound was calculated by peak measurement in comparison with the peak of an internal standard. The detection limit is 0.5 ng of active agent per day. ml of plasma.

10 The dissolution rate of compound A in vitro shown by curves 14-22 of FIG. 5 and 6, of Compound C in Example 13 and of nifedipine in Example 14 (dissolved amounts by weight over time) were determined in 1000 ml of solvent medium at 37 ° G according to the Rotation-Paddle method (USP XX) at 50 ° C. RPM minute. For compound A and nifedipine, an aqueous 0.1 HCl solution was used as the solvent medium. After 2 hours, the pH was adjusted by adding a surfactant-containing buffer solution with a pH of 6.8. Compound C was tested in a neutral surfactant-containing aqueous solution.

20 liters of a filtered sample of the active agent solution and of a comparative solution were chromatographically separated into 2 columns of 10 cm length and 4.6 mm diameter containing the substance RP.18; 5 μια as stationary phase and with methanol / water 85:15 (v / v) as mobile phase and at a pressure of 150 bar at room temperature and was measured 25 at a wavelength of 326 nm.

The plasma levels of compound B for curve 23-26 in FIG. 7 and 8 were also chromatographically determined. A 2 ml plasma sample, adjusted to pH 13 with NaOH, was extracted with toluene.

The toluene was evaporated and the residue was dissolved in 25 μΐ toluene. 2 30 μΐ of the resulting solution was separated at a temperature of 300 ° C in an OV 17 capillary column (inner diameter 0.3 mm and length 25 m) using helium as a carrier gas (inlet pressure: 0.7 atm). overprint).

DK 167649 Pg 14

The analysis was performed at a temperature of 300 ° C using an electron detector and with an argon / methane gas landing (90:10 v / v) (speed 30 ml / min) as additional gas. The retention time of compound B was 11.5 minutes.

The calculation of the concentration of compound B was performed in an analogous manner as described for compound A. The detection limit is 50 pico grams of active agent per ml. ml of plasma.

Example 1 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-carboxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid ethyl ester (Compound A)

Preparation of the solid dispersion: 4 parts by weight of flaked polyethylene glycol 6000 are melted at 55-63 ° C and heated to approx. 85 ° C with stirring.

One part by weight of compound A is added and dissolved completely under stirring at constant temperature. The solution is then cooled rapidly by pouring it onto a sheet of metal where it solidifies with a layer thickness of approx. 2 mm. After cooling to room temperature, the solidified layer is released from the sheet, reduced to coarse pieces and then passed in steps through decreasing mesh sizes (2.5, 1.0 20 and 0.5 mm) or reduced to small pieces in a hammer mill, thus preparing a granulate suitable for preparing a tablet or capsule mixture.

Example 16 Hard gelatin capsules Ingredients Amount in mg 5 1. Compound A - polyethylene glycol 6000 granules (20%), prepared according to Example 1 250.0 2. Placebo granules of

Lactose 83 parts 10 Corn starch 10 parts

Polyvinylpyrrolidone 6 parts 41.0 3. Crosslinked polyvinylpyrrolidone 6.0 4. Silicon dioxide 1.5 5. Magnesium stearate 1.5 15 - 300.0

The granules 1 and 2 are mixed. The ingredients 3-5 are also mixed, after which the mixture of 1 and 2 is mixed with the mixture of 3-5 and filled into gelatin capsules of suitable capacity.

EXAMPLE 3

The hard gelatin capsule of Example 2 is coated with an enteric soluble coating in the usual manner in a Wurster column with a mixture of hydroxypropyl methylcellulose phthalate 33.3 mg 25 and diethylphthalate 3.3 mg 16 UK lb / 649 bl EXAMPLE 4 Tablets

Ingredients Amount in mg 5 1. Compound A - polyethylene glycol 6000 granules (20%), prepared according to Example 1 250.0 2. Lactose, anhydrous 188.5 3. Silicon dioxide 2.5 10 4. Magnesium stearate 9.0 450.0

Ingredients 1-4 are blended for a short time, the mixture is sieved (630 µm mesh size), blended again and tabulated in conventional manner.

EXAMPLE 5

Tablet

Ingredients Amount in mg 1 2 3 4

Compound A - Polyethylene Glycol 20 6000 Granules (20%), prepared according to Example 1,250.00 2

Lactose, anhydrous 177.25 3

Crosslinked polyvinylpyrrolidone 11.25 4

Silicon dioxide 2.50 5. Magnesium stearate 9.00

The ingredients 1-5 are mixed and tableted as described in Example 4.

The tablet is coated with enteric soluble coating as described in Example 3 with a mixture of DK 167649 B1 17 hydroxyp r opylme thylcellulose phthalate 9% and diethyl phthalate 9% 50.00 5 - 500.00 EXAMPLE 6 By analogy as described in Example 1 a 40% dispersion of Compound A in polyethylene glycol 6000 is prepared at a temperature 10 of 125 ° C. The dispersion granules are compressed in a manner as described in Example 5 for tablets containing 50 and 100 mg of active agent.

tablets

Ingredients Amount in mg 15 Compound A - polyethylene glycol 6000 granules (40%) 125.0 250.0 2. Lactose, anhydrous 65.0 130.0 3. Cross-linked polyvinylpyrrolidone 5.0 10.0 20 4. Silicon dioxide 1 , 2.0 2.0 5. Magnesium stearate 4.0 8.0 Enteric soluble coating * 20.0 40.0 220.0 440.0 25 * A weight percent hydroxypropyl methyl cellulose phthalate coating 93

Titanium Dioxide 3.5

Iron oxide, yellow 3.5

The coating is applied in a conventional manner in a Wurster column.

18 DK Ί67649 ΒΊ

Comparative Experiment # 1

A conventional uncoated hard gelatin capsule containing a granulate of constituents 1-5 and an outer phase of a mixture of constituents 6-9 Amount in mg 1. Compound A 50.0 2. Lactose 216.0 3. Cross-linked polyvinylpyrrolidone 6, 0 4. Polyoxyethylene-polyoxypropylene polymer 10.0 10 5. Polyvinylpyrrolidone 7.5 6. Cross-linked polyvinylpyrrolidone 5.5 7. Polyethylene glycol 6000 (solubilizing agent) 10.0 8. May's starch 52.0 15 9. Magnesium stearate 3.0 360.0 was compared with the enteric-soluble coated retard capsule of Example 3 and with the non-coated retard capsule 20 of Example 2.

In 8 healthy fasting male subjects aged 19-40 years, the enteric-coated coated retard capsules of Example 3 provided nearly constant plasma levels of Compound A (about 5 ng / ml) for 3 hours to 28 hours after administration (mean curve 1 in Figs. .

25 1).

Conventional hard gelatin capsules, in the same subjects, gave the conventional image of average curve 2 in FIG. 1, the active agent being for the most part delivered within 6 hours. The areas under both curves 1 and 2 are almost the same: 30 AUC0 °° * = 210 and 210 respectively. 196.2 ng / ml / hour [* = AUCq "= area under the curve (extrapolated to infinity)]. This shows that the capsule according to the invention has no significant loss of bioavailability.

DK 167649 B1 19

In another experiment, the uncoated retard capsule of Example 2 was administered to 8 healthy male subjects. Four of the subjects also participated in the first test with the enteric soluble coating coated retard capsule. Compared to the 5 conventional capsule (curve 2), a retarding effect is obtained (average curve 3 in Figure 1). However, the uncoated retard capsule of Example 2 tends to cause drug burst (curve 3).

From both experiments it can now be determined that the combination of the novel solid dispersion granulate with the enteric soluble coating has an excellent controlled release effect.

With the retard capsules of Examples 2 and 3, especially the enteric-soluble coated capsule of Example 3, administration once daily is possible; of the conventional form, 15 2-3 capsules a day should be taken at regular intervals.

Comparative Experiment # 2

The conventional uncoated hard gelatin capsule from Comparative Trial # 1 was again compared, but instead with the enteric-soluble coated retard tablet of Examples 5, 20 and tested in another group of 8 healthy male subjects.

The enteric coating coated with enteric soluble coating from Example 5 gave plasma levels of the average curve 4 in FIG. 2, and the conventional capsule from Comparative Experiment # 1 gave an average result, comparable to curve 2. The enteric coating coated with enteric soluble coating of Example 5 gave practically constant plasma levels of compound A (about 6-7 ng / ml ) from 5 up to and including 32 hours after administration (curve 4).

Again, there is no significant loss in (relative) bioavailability when using the enteric-soluble coating retarded tablet. This makes administration possible once a day. The conventional hard gelatin capsule should be taken 2-3 daily.

DK 167649 B1 20

Comparative Experiment # 3 In a further study of humans with 8 healthy subjects, the normal uncoated capsule described in Comparative Experiment # 1 was compared in a crossover trial with three additional formulations, including the enteric-soluble coated retard tablet from Example 6 containing 50 mg of compound A in a 40% solid dispersion in polyethylene glycol 6000.

In this study, all formulations were administered to the fasting subjects with 150 ml of water. A standard lunch was given 10 2 1/2 hours later.

The average curve 5 in FIG. 3 shows the plasma levels of the enteric soluble coating retarded tablet for up to 72 hours.

Concentrations of between 3 and 5 ng / ml are obtained from 7 to 36 hours after ingestion, an absorption duration lasting 29 hours. Compared to the normal capsule, the relative bioavailability of the retard tablet was 88% with a standard deviation of 36%. This value is not statistically different from 100% on the basis of a paired t-test, which shows that there is no loss of bioavailability.

A notable feature of the pharmacokinetic behavior of this retard tablet is the relatively low intraindividual variability, as evidenced by the individual kinetic profile curves 6-13 in FIG. 4th

In all cases, plasma levels are seen to fall within the 2-8 ng / ml range and no significant drug bursting occurs in any person. Furthermore, the presence of the 25 gastroresistant coating gave a highly reproducible time delay before absorption (2.6 ± 0.8 hours) when the tablets were administered in the fasted state.

These results show that an enteric-soluble coating coated tablet of a 40% solid dispersion constitutes a 30 excellent dosage form which allows for once-daily use of 50 mg and possibly higher doses, e.g., 100 mg of drug.

EXAMPLE 7 21 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ether (Compound B)

Preparation of a solid dispersion and of a dispersion granulate: 5 6 parts by weight of polyethylene glycol 6000 are mixed with 2 parts by weight of a commercial mixture comprising mono-, di- and triesters of palmitic and stearic acid and glycerol (Precirol®, available from Gattefosse) and with 2 parts by weight of compound B, and then melted at a temperature of 75-85 ° C and dissolved as best as possible under intensive stirring at a constant temperature of 70 ° C. The mixture is then rapidly cooled to room temperature by being poured onto a pre-cooled sheet of metal and kept at 4 ° C for 3 hours. It solidifies as a layer with a thickness of approx. 4 mm.

The solidified layer is reduced to coarse particles which are passed through a hammer mill (Fitzpatrick type, USA) to provide a granulate which can be used to prepare a tablet or capsule mixture.

The characteristic grain size of the RRS-B distribution = X '= approx. 320 μπι.

n = ca. 3 (a reciprocal measure of the distribution range) (H. Sucker, c.s.

20 Pharmaceutical Technology, Georg Thieme Verlag, Stuttgart, 1978, p.

110).

EXAMPLE 8 Tablet

Ingredients Amount in mg 5 1. Compound B - polyethylene glycol 6000 - fatty acid glyceryl ester granulate mixture (prepared according to Example 7) 50.0 2. Lactose, anhydrous 68.8 10 3. Magnesium tearate 1.2 120.0

Ingredients 1 and 2 are mixed briefly (5 minutes). The mixture is sieved (mesh size 800 μτα.), Sieved again (10 minutes), mixed with 15 component 3 (5 minutes) and tableted in a conventional manner on a rotary tableting machine.

The tablets have a diameter of 7 mm and have a compressive strength of 46 Newton.

EXAMPLE 9 Tablet

Ingredients Amount in mg 1. Compound B - polyethylene glycol 6000 - fatty acid glyceryl ester granulate mixture (prepared according to Example 7) 50.00 2. Lactose, anhydrous 61.42 3. Silicon dioxide 0.23 4. Sodium carboxymethyl cellulose 2.20 30 5. Magnesium stearate 1.15 115.00 DK 167649 B1 23

Ingredients 1, 2 and 4 are mixed briefly (5 minutes), sieved (mesh size 800 μπι) and mixed again (10 minutes).

Ingredients 3 and 5 are mixed together with part of the mixture of 1, 2 and 4, sieved (800 μα) and mixed with the rest of the mixture of 1, 2 and 5 4 (5 minutes).

Comparative Experiment # 4

A conventional uncoated hard gelatin capsule containing a mixture of ingredients 1-6

Ingredients Amount in mg 10 1. Compound B 10.0 2. Lactose (filler) 167.0 3. Sodium lauryl sulfate (solubilizing agent) 5.5 15 4. Silica (lubricant) 1.5 5. Corn starch (disintegrant) 128 Polyethylene glycol 6000 (solubilizing agent) 8.0 20 - 320.0 was compared with the retard tablet of Example 8.

In 8 fasting healthy male subjects aged 19-40 years, the retard tablet of Example 8 showed practically constant plasma 25 drug levels of between 2.3 and 1 ng / ml and on average between 1.5 and 1 ng / ml for 2 to 24 hours after administration (see average curve 23 in Fig. 7). The conventional non-retard capsule showed in the same subjects the conventional image of mean curve 24 and drug delivery within 6 hours.

DK 167649 B1 24

The areas under both curves 23 and 24 are practically the same.

By comparing the AUC0 °° of curves 23 and 24, a relative bioavailability of even 96.2% for the retard tablet of Example 8 could be established.

The retard tablet of Example 8, when compared to the conventional uncoated hard gelatin capsule, gave a barely detectable drug burst.

While administering 2-3 conventional capsules per per day, distributed over regular periods, the retard tablet administration 10 once daily is possible.

EXAMPLE 10

Preparation of a solid dispersion and of a dispersion granule: 10 parts by weight of compound B is dissolved at a temperature of 125 ° C in liquid polyethylene glycol 6000.

The mixture is rapidly cooled to room temperature by pouring it onto a pre-cooled sheet of metal and kept overnight.

The solidified layer is reduced to coarse particles and passed through a hammer mill (Fitzpatrick type, USA) to provide a granulate which can be used to prepare a tablet or capsule mixture.

EXAMPLE 11 Tablet

Ingredients Amount in mg 5 1. Compound B - polyethylene glycol 6000 - granulate (20%, prepared according to Example 10) 50.00 2. Lactose, anhydrous 63.85 3. Magnesium stearate 1.15 10 - 115.00

The tablet is prepared in an analogous manner as described in Example 8 (the screen had a mesh size of 1250 µm).

Tablets: diameter 7 mm 15 compressive strength: 40 Newton.

EXAMPLE 12

The tablet of Example 11 is coated with an enteric soluble coating in a conventional manner in a Wurster column with a mixture of Amount in mg 20 Hydroxypropylmethylcellulose phthalate 13.8

Iron oxide pigment, red 0.6

Titanium oxide 0.6 15.0 DK 167649 B1 26

Comparative Experiment # 5

Two conventional non-retard capsules each containing a mixture of the ingredients 1-6 Amount in mg 5 1. Compound B 5.0 2. Lactose 172.0 3. Sodium lauryl sulfate 5.5 4. Silicon dioxide 1.5 5. Corn starch 128.0 10 6. Polyethylene glycol 6000 (solubilizing agent) 8.0 320.0 was compared to the enteric soluble coating retarded tablet of Example 12.

The experiment was performed as described in comparative experiment # 4 with the difference that the number of subjects was now 11.

The conventional non-retard capsules both together showed the conventional image of the average curve 25 of FIG. 8, and drug 20 was delivered within 10 hours.

The enteric-soluble coated retard tablet of Example 12 gave an average plasma level of between 2.5 and 0.8 ng / ml of compound B (mean curve 26) from 3 to 28 hours after administration and had an unaffected relative bioavailability in comparison with the conventional capsules.

The enteric-soluble coated retard tablet of Example 12 allows administration at once a day, whereas the conventional capsule should be taken regularly 2-3 times daily.

DK 167649 B1 28

Dispersionsgranulat

Time in hours 20%. 40%% solute 5 0 0 0 2 5 0 3 29 11 4 56 20 5 77 31 10 6 90 41 7 96 46 8 97 51 12 98 63 16 99 72 15 20 101 79

patent claims

1. Solid dispersion of a pharmacologically active agent in a water-soluble crystalline matrix as carrier, characterized in that the active agent a) has a maximum solubility of 0.01% at 37 ° C in water, b) is present in and the c) is present in the matrix at a concentration greater than 5% by weight in continuous crystalline form.

Dispersion according to claim 1, characterized in that the active agent is a dihydropyridine. 1

Dispersion according to claim 1 or 2, 30, characterized in that the matrix is a polyalkylene glycol.

Claims (10)

10 Dispersion granules Time in hours 20% 30% 40% 50%% solute 0 0 0 0 0 15 2 100 86 54 27 3 88 60 33 4 88 63 38 5 89 68 44 6 90 72 48 20 _ EXAMPLE 14 Nifedipine By analog As described in Examples 1 and 7, a 20% and a 40% dispersion of nifedipine in polyethylene glycol 25 6000 was prepared. The dissolution rates of the obtained dispersion granules containing 50 mg of nifedipine were determined in an aqueous medium according to Rotating Paddle method (USP XX). DK 167649 B1 Dispersion according to any one of claims 1-3, characterized in that it contains more than 5% by weight crystalline particles of the active agent with a diameter of up to 5 μπι. Dispersion according to any one of claims 1-4, characterized in that it is in granular form. Secondary structure of an active agent, characterized in that it is obtained from the solid dispersion according to any one of claims 1-5 by selectively removing the matrix material. Secondary structure of an active agent according to claim 6, characterized in that it has a surface of 1-15 m 2 / g, measured by the BET method, and a pore volume of 20-95%, measured by mercury porosimetry. Pharmaceutical composition, characterized in that it contains a dispersion or structure according to any one of claims 1-7. Pharmaceutical composition according to claim 8 for oral administration once daily, characterized in that it contains a therapeutically effective amount of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5 -ethoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid ethyl ester as active agent. Pharmaceutical composition according to claim 8 for oral administration once daily, characterized in that it contains a therapeutically effective amount of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5 -methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester as active agent. Pharmaceutical composition according to claim 9, characterized in that, by oral administration, it is capable of producing a plasma level of 2-8 ng of active agent / ml for at least 22 hours in case it contains one dose of 50 mg. 4- (2,1,3- DK 167649 B1 b enz oxadiazol-4-yl) -1,4-dihydro-5-ethoxycarbonyl 1 -2,6-dimethyl-3-pyridinecarboxylic acid ethyl ester as active agent . Pharmaceutical composition according to claim 10, characterized in that, by oral administration, it is capable of forming a plasma level of 1-2.5 ng of active agent / ml for at least 22 hours in case it contains one dose of 10 mg of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester as active agent.