NL8501578A - NEW GALENIC RETARD FORM. - Google Patents

Description

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New galenic retard shape.

The invention relates to forms of pharmacologically active agents with controlled release properties and in particular to solid dispersion forms of such agents which release the agent continuously in a water medium.

By incorporating an active substance in a solid dispersion or solution, hitherto only accelerated release has been achieved.

For example, solid dispersion forms of drugs are known, such as from German Offenlegungsschrift 2,549,740, which describes solid dispersions of griseofulvin in polyethylene glycol. The slow dissolution rate and accordingly (see page 11, lines 4-5) the poor bio-availability of griseofulvin were improved by preparing a solid dispersion of griseofulvin in polyethylene glycol. In the particularly disclosed drug formulation, a tablet, a disintegrant had to be added to the solid dispersion granulate since it appeared that the greatly improved rate of dissolution of griseofulvin was again counteracted. The pressure used in the manufacture of tablets led to significant cohesion between the tablet particles due to the strong cohesion between the polyethylene glycol molecules.

The disintegrant, cross-linked polyvinylpyrrolidone, was added to convert the original granules of the tablet, in which the griseofulvin was present in a more soluble form.

The water-soluble polyethylene glycol is extracted from the granulate upon contact with a water medium, causing the finely divided griseofulvin to dissolve rapidly.

According to German Auslegeschrift No. 2,546,577, an increase in the dissolution rate and resorption of salts of ergotamine compounds which are sparingly soluble in water (especially of dihydroergotamine methanesulfonate, dihydroergocristine-578 V * - 2 -methanesulfonate, dihydroergocryptine methanesulfonate and dihydro-sulfonate) is achieved. salts are present in solid solutions in polyalkylene glycols and especially in polyvinylpyrrolidone having a molecular weight above 10,000. Said drugs have a solubility in water of more than 0.01% in methanesulfonate form and differ in this respect from the active agents used according to the invention.

According to European application 78430, an increase in the dissolution rate and a maintenance of the absorption of the dihydropyridines, especially of Nifedipine and

Nimodipine is achieved by dissolving these agents together with polyvinylpyrrolidone, for example with a molecular weight of 25,000, in a small amount of liquid organic solvent, such that the solid particles are just dissolved, after which this solution is mixed and granulated with solid carriers with a high absorbency, which leads to evaporation of the organic solvent.

The drug is present in the dissolved state in the solid polyvinylpyrrolidone and exhibits an increased dissolution rate on contact with a water medium. Both aspects distinguish these known products from the compositions of the present invention.

According to Canadian Patent 987588, an increase in the dissolution rate and in the bioavailability of water sparingly soluble drugs is achieved when they are present as solid dispersions in polyethylene glycols and other water soluble matrix materials, for example pentaerythritol tetraacetate or citric acid.

The known drugs, digitoxin-17-methyl-30 testosterone, prednisolone acetate and hydrocortisone acetate are present in the matrix material in concentrations up to 5%, thus obtaining other dispersions of the dispersions of the present invention. The drug griseofulvin, as indicated above, has a water solubility of more than 0.01% and is therefore different from the active agents of the invention.

It has been discovered that when solid dispersions of pharmacologically active agents which are substantially insoluble in water are used in such a matrix material, no expected significant increase in dissolution rate in a water medium is observed. Instead, a decrease is obtained without significant loss of bioavailability.

In addition, it has been discovered that the decrease in dissolution rate can be attributed to a coherent crystalline form of the drug, hereinafter referred to as secondary structure, which form can be maintained even as the water-soluble matrix material on contact with a water medium, eg water , will be removed.

It is preferable to form the secondary structure that the drug is present in the solid dispersion in a concentration above 5% and more than 5% by weight in a crystalline form, preferably as particles with a diameter of less than 5 µm and with a water solubility up to 0.01%, preferably below 0.005% by weight.

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

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

A reduced rate of dissolution was achieved in the following known cases: German Offenlegungsschrift 1,617,362 discloses suspending pharmacologically active agents, in particular theophylline, in molten waxes to prepare galenic at a reduced dissolution rate in a water medium. Polyethylene glycol is used as the wax.

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

German Offenlegungsschrift 3,318,649 discloses a biphasic solid pharmaceutical preparation containing crystalline Nifedipine and separately a solid solution of Nifedipine in a matrix material, in particular in polyvinylpyrrolidone. On contact with a water medium, Nifedipine 15 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, only a solid dispersion of the drug is present, which upon release with a water medium causes release of the drug at a reduced rate.

For the solid dispersion of the invention, the choice of the pharmacologically active agent is not critical, provided the conditions regarding its solubility and crystallization are met.

It is a simple routine matter to test whether a particular active agent meets the required conditions.

The substantially 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 with an optionally substituted 4-phenyl or 4-phenyl derivative group.

For example, a 4-phenyl derivative group is the 4-35 (2,1,3-benzoxadiazol-4-yl) group. An example of a medicine 7 7> yvv * »» i ν '* i - 5 - agent with an optionally substituted 4-phenyl residue is the known 4- (2-nitrophenyl) -1,4- dihydro-2,6-dimethyl-5-methoxy-carbonyl-3-pyridinecarboxylic acid methyl ester (nifedipine).

Examples of drugs with a 4-phenyl-5 derivative group are 4- (2, 1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid ethyl compound (compound A), 4- (2,1,3) -benzoxadiazol-4-yl) -1,4-dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl (compound B) and (- ) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-10 5-methoxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid isopropyl ester (Compound C ).

The dihydropyridines are described extensively in the literature and in particular have a calcium antagonistic effect. They are described, for example, as antihypertonica and as drugs for the treatment of angina pectoris.

The above-mentioned dihydropyridines A and B are known, for example from European Patent Specification 150 and British Patent Specification 2,037,766. Dihydropyridine C is known from British patent application 2,122,192A and is described in particular in example 2c thereof.

It has been found that the dihydropyridines, for example compounds A and B, are substantially insoluble in water and thus have a water solubility of less than 0.01%.

However, processing these compounds into a solid dispersion form did not result in an expected increased dissolution rate, but surprisingly a significantly reduced dissolution rate (see Comparative Trials 1-5), which is advantageous in formulations to be administered once daily.

The retard effect is due to the solid dispersion, for example in granulate form, independent of any excipients present. An advantage is that there is none. burst, "...

The usual drug action occurs and there is no significant decrease in bioavailability (see comparative tests).

The present invention thus provides a pharmaceutical composition to be administered once a day, which contains a therapeutically effective amount of compound A or B. The matrix materials are preferably pharmaceutically acceptable solid compounds, which are commonly used widely as pharmaceutical excipients.

Since they should preferably be water soluble, they should have polar properties. Thus, most of these matrix materials have polar groups, for example oxy groups, especially hydroxyl groups.

The preferred pharmaceutical preparations contain a solid dispersion of pharmacologically active agents in a polyalkylene glycol, especially in a poly (C 2-8) alkylene glycol, for example in a polyethylene glycol. The polyethylene glycol preferably has a molecular weight of 1000-20,000, in particular of 4000-20,000, most preferably of 4000-8000, for example 6000.

The solid dispersions can be obtained by dissolving the active agents in a concentration above 5% by weight in the liquefied dispersant and allowing the resulting mixture to solidify.

Liquefaction of the dispersant 25 can be accomplished by melting or by adding a liquid organic solvent.

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The present invention thus provides a method for preparing a solid dispersion of a pharmacologically active agent in a crystalline matrix as a carrier, characterized in that an active agent with a maximum solubility of 0.01%, preferably of less than 0.005% in water at 37 ° C in a concentration above 5% by weight dissolves in a liquefied matrix and converts the resulting mixture into a solid form and crystallizes the active agent.

After the solid dispersion is obtained, it can be reduced to a usual particle size to obtain a granulate suitable for further processing.

At least 5% by weight of the drug particles present in the solid dispersion are so small that it is impossible to see them with ordinary optical measurements, since when suspended in water medium for measurement purposes, they are a continuous Brownian seem to have movement.

Thus, it is believed that the particles generally have a diameter of 5 microns or less.

Laser beam scattering tests in suspension in water gave a particle size of even less than 0.5 micron.

Comparison of the 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 a crystalline form.

The concentration of the drug in the matrix can vary from 5-80, especially from 20-50 and especially from 20-40% by weight, and contributes to the effect of the sustained release of the invention.

(higher concentration may cause a greater decrease in dissolution rate, see curves 14-18 in Figure 5 for the amount dissolved in wt% versus time T in hours and increasing concentrations of 10-50 wt% of compound A may cause a decrease of the dissolution rate).

Curves 14-18 in Figure 5 refer to solid dispersion granulates of the same subfraction containing 10, 20, 30, 40 and 50% by weight of compound A.

The correct dose of active agent is up to 250 and preferably up to 200, preferably up to 100 mg, for compound A and up to 50, preferably up to 30, and most preferably 10-25 mg, for compound B per day. For a reasonably administrable dispersion amount of c5015 / 8-8, a concentration of 10-80 wt% active agent in the matrix at an average of 50 wt%, e.g. 40 wt% compound A and 20 wt% compound B is indicated .

If the chemical stability of the active agent is not high, the temperature of the molten matrix material, for example of the polyalkylene glycol, must be kept correspondingly low. If more active agent is added to the polyalkylene glycol, it can be dissolved at the maximum allowable temperature; the excess is not dissolved, but 10 is taken up as a suspension.

The undissolved fraction particles preferably have a particle size of at most 100 micrometers.

these particles

After cooling of the suspension 7 of a similar size in the dispersion are found next to the fraction of active agent, which was dissolved and after cooling can be found again in the form of crystals with a diameter of at most 5 micrometers.

In the granulation process discussed briefly above, the solid dispersion is preferably reduced to a particle size of 50-2000 microns, especially 90-1000 microns, especially 125-500 microns.

The particle size of the granulate contributes to the controlled release effect of the invention (larger particles cause a greater decrease in the dissolution rate, see curves 19-22 in Figure 6; dissolved amount in weight% versus time T; increasing particle size causes decrease in dissolution rate, curves 19-22 relate to sieve factors of 90-180, 180-355, 355-500 and 500-710 micrometers, respectively, 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 controlled by changing the concentration of the active agent in the solid dispersion, as well as by changing the particle size of the solid dispersion granulate.

8501578 t, -9-

It has surprisingly been found that when the dispersion granulate particles, for example those of Example 1, are placed in water, a matrix fraction is rapidly and quantitatively dissolved. The active agent particles, which in the dispersion have, for example, a size of up to 5 micrometers, form coherent secondary structures, their density and diameter varying with the concentration of the active agent in the matrix and the diameter of the granulate particles.

The present invention thus provides a secondary active agent structure, which is formed from the solid dispersion after selective extraction of the matrix material, for example in a water medium. This secondary structure can have a diameter comparable to that of the dispersion granulate. It exhibits a delayed dissolution rate in water. It can be partially restored to the original particles by intensive ultrasonic treatment. to * 5 μm.

Active agent particles, which may have, for example, a diameter of up to 100 microns in the dispersion granulate, are in the secondary structure created from the particles. up to 5 micrometers enclosed unchanged.

Since the original particles of the agent up to 5 micrometers and the subsequently enclosed particles of the agent up to 100 micrometers contribute to the controlled release effect, both their solid dispersions and their secondary active agent structures are included in the present invention.

The diameter and area of the secondary structural particles of the active agent were examined. They have irregular, fracture-like channels and have an external and internal surface.

Both the size and the structure of the external surface influence the dissolution rate in an eg aqueous solvent medium. The internal surface exhibits narrow pores of up to 1 micron that hardly contribute to the release of active agent, since if they still contain solvent medium their motility is greatly reduced.

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

After removal of the solvent medium, for example until drying, the specific surface area and the pore volume can be measured.

The present invention provides the secondary structure of an active agent having a diameter of preferably 50-2000, more preferably 90-1000, most preferably 125-500 microns with a porous structure, characterized by a specific surface area of 1-15 m / g, preferably from 2-12 ta / g, measured by the BET method and with a pore volume of 25-95%, measured by mercury porosimetry.

The solid dispersion particles and the secondary structure particles can be used for the preparation of pharmaceutical preparations.

Thus, the present invention also provides pharmaceutical compositions containing the solid dispersion granulate or the secondary structure particles.

Pharmaceutical preparations containing the solid dispersion granulate can be considered as galenic precursor forms of corresponding preparations containing the secondary structural particles, since their behavior in the body is comparable to that of prodrugs.

For the preparation of the pharmaceutical oral dosage forms containing the solid dispersions, the granulate of the solid dispersion can be mixed in the usual manner with suitable pharmaceutical excipients, for example a filler such as lactose, a lubricant, for example silicon dioxide and a lubricant, for example magnesium stea 35 (see, for example, Examples II, V, VI and IX) and optionally §501578 -11- a disintegrant, such as cross-linked polyvinylpyrrolidone, for example crosspovidone (see for example Examples II, III, V and VI), or sodium carboxymethylcellulose (see for example example IX) and processing into the usual solid oral administration forms, such as tablets or capsules.

For the manufacture of tablets, the solid dispersion granulate can preferably be mixed with, for example, lactose, silicon dioxide and magnesium stearate (see examples IV, V, VI and IX).

The porous secondary structural particles of the agent are preferably used in capsules, since they are less resistant to the pressure during tablet molding.

For the manufacture of capsules, the solid dispersion granulate of the secondary structural particles of the agent can be mixed in the usual manner, preferably with a placebo granulate from suitable excipients such as lactose, starch and polyvinylpyrrolidone and with a mixture of crosspovidone, silicon dioxide and magnesium stearate (see examples II). and III). The disintegrant can be used to suspend the capsule contents.

In general, pharmaceutical dosage forms, especially capsules and, to a lesser extent, also tablets, exhibit a drug burst during gastric transit, which can be largely prevented by application of an enteric coating. Suitable enteric coatings are hydroxypropylmethylcellulose phthalate (see examples III, V, VI and XII). If the active agent is absorbed in the upper part of the intestines - dihydropyridines are such agents - such a coating is very favorable and does not interfere with the absorption process.

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

5301578 -12-

It has been found that capsules or tablets can be made without an enteric coating if a hydrophobic excipient, such as a fatty acid glyceryl ester, is added to the solid dispersion (see Examples 111 111 and IX and Comparative Test 4). This hydrophobic ester reduces the drug burst in the stomach and cannot significantly interfere with the absorption process in the intestines. Such preparations can be prepared by dissolving the pharmacologically active agent in the liquid matrix and emulsifying the resulting mixture as much as possible with the hydrophobic substance, for example the fatty acid glyceryl ester, after which the resulting mixture can be allowed to solidify by cooling.

Preferred fatty acid glyceryl ester are physiologically acceptable esters such as (Cqq2q) fatty acids, eg palmitic acid and / or stearic acid glyceryl esters.

These esters can be, for example, mono-, di- and / or triesters of glycerol.

The amount of fat is preferably up to 60% of the total weight of the solid dispersion, for example 20-60%, in particular 15-25%, for example 20%.

The sustained-release compositions of the invention can be used to administer very different classes of substantially insoluble water agents. They can be used for their known mutations.

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

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

The pharmaceutical preparations of, for example, compounds A and B can be used for, for example, the same 8501578 -13 indications as described in European patent 150 and British patent 2,037,766.

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

In particular, the present invention provides a pharmaceutical composition for plasma levels of 2-8 mg of compound A per ml for at least 22 hours if / a dose contains 50 mg of active agent. The basis for this observation is the plasma mirror curves 1, 3, 4, 5 and 6-13 in figure 1-3.

The present invention also provides a pharmaceutical composition for plasma levels of 1-2.5 mg of compound B per ml for at least 22 hours, when it contains a dose of 10 mg of active agent. The basis for these observations are the plasma mirror curves 23 and 26 in Figures 7 and 8.

The plasma level of compound A can be determined by gas chromatography for curves 1-13 in Figure 1-4 (concentrations versus time).

A 1 ml plasma sample, adjusted to pH 13 with NaOH, was extracted with toluene, the toluene evaporated and the residue dissolved in 0.5 ml toluene. 2 microliters of the formed solution were separated at 300 ° C in a 0V 17 column (6% on Gaschrom Q 100-120 mesh) using an argon / methane gas (volume ratio 95: 5) mixture as carrier gas (rate 60 ml / minute). The analysis can be performed using an electron capture detector. The retention time of compound A was 3.1 minutes.

The compound concentration was calculated by peak measurement as compared to the peak of an internal standard. The observers limit is 0.5 mg of active agent per ml of plasma.

The dissolution rate of compound A in vitro for curves 14-22, of compound C in example XIII and of nifedipine in example XIV (dissolved amounts in wt% £ S r * K 7 C £ Lv c 3 / v -14- versus time) was determined in 1000 ml of solvent medium at 37 ° C by the rotary scrub method (USP XX) at 30 rpm. A 0.1 HCl solution in water or solvent medium was used for compound A and for nifedipine. After 2 hours, the pH was adjusted by adding a pH 6.8 surfactant-containing buffer solution. Compound G was tested in a neutral surfactant-containing solution in water.

20 microliters of a filtered sample of the solution of active agent and a comparison solution were separated chromatographically into two columns of 10 cm length and 4.6 mm diameter, containing substance EP.18, at 5 micrometers as stationary phase and with methanol / water (volume ratio 85:15) as the mobile phase and at a pressure of 150 bar at room temperature and measured at a wavelength of 326 mm.

The plasma levels of compound B were also chromatographed for curves 23-26 in Figures 7 and 8. A 2 ml plasma sample, adjusted to pH 13 with NaOH, was extracted with toluene. The toluene was evaporated and the residue dissolved in 25 microliters of toluene. 2 Microliters of the formed solution were separated at a temperature of 300 ° C into a 0V 17 capillary column (internal diameter 0.3mm and 25m long) using helium as the carrier gas (inlet pressure: 0, 7 atmospheric overpressure) ..

The analysis was performed at a temperature of 300 ° C using an electron capture detector and an argon / methane (90:10 volume ratio) gas mixture (rate 30 ml / minute) as the added 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 picograms of active agent per ml of plasma.

35 850 1 57 8 \ -15-

Example I: 4- (2,1,3-Benzoxadiazol-4-yl) -3,4-dihydro-5-carboxy-carbonyl-2,6-dimethyl-3-pyridinecarboxylic acid ethyl ester (Compound A). solid dispersion: 4 parts by weight of polyethylene glycol 6000 flakes are melted at 55-63 ° C and heated to 85 ° C with stirring.

While stirring at constant temperature, a part by weight of compound A is added and completely dissolved. The solution is then quickly cooled by pouring it onto a metal plate, on which it solidifies in a layer thickness of 2 mm. After cooling to room temperature, the solidified layer is torn from the plate, reduced to coarse particles, and then passed in stages through sieves of decreasing mesh size (2, 5, 1.0 and 0.5 mm) or in a hammer mill to small particles are crushed to obtain a granulate which can be used to prepare a mixture for the manufacture of tablets or capsules.

20

Example II:

Hard gelatin capsules.

25 Components: Amounts in mg 1. Compound A - polyethylene glycol 6000 granules (20%), prepared according to Example I. 250.0 2. Placebo granules of Lactose 83 parts

Corn starch 10 parts

Polyvinylpyrrolidone 6 parts 41.0 3. Cross-linked polyvinylpyrrolidone 6.0 4. Silicon dioxide 1 »5 35 8501578 -16- 5. Magnesium stearate 1.5 300.0

Both granules 1 and 2 are mixed. Components 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 III: 10

The hard gelatin capsule of Example II is enterically coated in a Wurster column enterically with a mixture of hydroxypropylmethylcellulose phthalate 33.3 mg and diethyl phthalate 3.3 mg in a usual manner.

Example IV

20

Tablet

Components: Amount in mg 25 1. Compound A - polyethylene glycol 6000 granules (20%) prepared according to example I 250.0 2. Lactose, anhydrous 188.5 3. Silicon dioxide 2.5 4. Magnesium stearate 9.0 30 450.0

Components 1-4 are briefly mixed and the mixture is sieved (screen size 630 micrometers), mixed again and processed into tablets in the usual manner.

35 850 1 57 3 -17-

Example V Tablet 5 Components: Amounts in mg 1. Compound A - polyethylene glycol 6000 - granulate (20%), prepared according to example I. 250.00 2. Lactose, anhydrous · 177.25 ^ 3. Cross-linked polyvinylpyrrolidone 11.25 4. Silicon dioxide 2.50 5. Magnesium stearate 9.00

Components 1-5 are mixed and made into tablets as described in Example IV.

The tablet is enteric coated as described in Example III with a mixture of hydroxypropylmethylcellulose phthalate 9% 20 and diethyl phthalate 9% 50.00 500.00

Example VI 25

In an analogous manner as described in example I.

a 40% dispersion of compound A in polyethylene glycol 6000 is prepared at a temperature of 125 ° C. The dispersion granulate was pressed into tablets containing 50 and 100 mg of the active agent in the manner described in Example V.

Tablets: 35 S5fl157 8 -18-

Components! Amounts in mg 1. 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 4. Silicon diodyde 1.0 2, 0 5. Magnesium stearate 4.0 8.0 enteric coating * · 20.0 40.0 10 220.0 440.0

a

A coating of hydroxypropylmethylcellulose phthalate 93 titanium dioxide 3.5 ^ iron oxide, yellow „3.5

The coating is applied in a Wurster column in the usual manner.

20

Comparative Test No. 1

A plain uncoated hard gelatin capsule containing a granulate of components 1-5 and an external phase of 25 a mixture of components 6-9.

amount in mg 1. Compound A 50.0 2. Lactose 216.0 30 3. Cross-linked polyvinylpyrrolidone 6.0 4. Polyoxyethylene-polyoxypropylene polymer * 5. Polyvinylpyrrolidone 7.5 6. Cross-linked polyvinylpyrrolidone 5.5 7. Polyethylene glycol 6000 (sol bilising agent) * 850 1 57 8 -19- 8. Corn starch 52.0 9 4 Magnesium tearate 3.0 360.0 5 was compared with the enteric coated delayed capsule of Example III and with the uncoated delayed capsule of example II.

In 8 healthy fasted male volunteers aged 19-40 years, the enteric coated delayed 10 capsules of Example III produced almost constant plasma levels of Example A (approximately 5 nano.grams / ml) for 3-28 hours after administration (mean curve 1 in Figure 1 ).

Ordinary hard gelatin capsules produced the usual image of mean curve 2 in Figure 1 in the same volunteers, with the active agent for the •.

the majority is issued within 6 hours. The areas under both curves 1 and 2 are almost the same: AUC * = 210 and 196.2 nanograms / ml / h, respectively. This indicates that the capsule of the invention does not show a significant loss of bioavailability.

In the second trial, the uncoated delayed capsule of Example II was administered to 8 healthy male volunteers. 4 of these volunteers also participated in the first enteric coated delayed cap-25 test. Compared to the regular capsule (curve 2), a delay effect is obtained (mean curve 3, in Figure 1).

However, the uncoated delayed capsule of Example II tends to cause drug burst (Curve 3).

It can now be determined from both tests that the combination of the new solid dispersion granulate with the enteric coating has an excellent controlled release effect.

The delayed capsules of examples II and III, * 5 "/ 5, b, vv, j-20- especially the enteric coated of example III, allow administration once a day, while the regular form 2-3 capsules should be taken at regular intervals.

^ * = AUC 00 = Area under curve (extrapolated o to infinity).

Comparative Test No. 2 10

The regular uncoated hard gelatin capsule of Comparative Trial No. 1 was again compared, but now with the enteric coated delayed tablet of Example V and the trial in another group of 8 healthy male volunteers.

O

The enteric coated delayed tablet of Example V gave plasma levels of the mean curve 4 in Figure 2 and the regular capsule of Comparative Test No. 1 gave an average result comparable to curve 2. The enteric coated delayed tablet of Example 2 V gave substantially constant plasma levels of compound A (about 6-7 nanograms / ml) for 5-32 hours after administration (curve 4).

Again, there is no significant loss in (relative) bioavailability using the enteric coated delayed tablet. This allows for once daily administration. A regular hard gelatin capsule should be taken 2-3 times a day.

Comparative Test No. 3 30

In a further human study with 8 healthy male subjects, the normal uncoated capsule described in Comparative Trial No. 1 was compared with three other preparations, including the enteric coated delayed tablet of Example VI, which was 50 mg of compound A contained in a 40% fl 3 1 1 57 8 62 62 / -ii '-21 solid dispersion in polyethylene glycol 6000.

In this study, all preparations were administered to the fasted subjects with 150 ml of water. a standard breakfast was given an hour later.

The mean curve 5 in Figure 3 shows the plasma levels of the enteric coated delayed tablet up to 72 hours.

Concentrations between 3 and 5 nanograms / ml are obtained • 7-36 hours after ingestion, so that the absorption lasts 29 hours.

Compared to the normal capsule, the relative bioavailability of the delayed tablet was 88% with a standard deviation of 36%. This value does not statistically differ from 100% based on a paired t-test, indicating no loss of bioavailability.

A remarkable aspect of the pharmacokinetic behavior of this delayed tablet is the relatively low intra-individual variability, given the individual kinetic profile curves 6-13 in Figure 4.

In all cases, plasma levels appear to drop to 20 in the range of 2-8 nanegram / ml without significant drug outbreaks occurring in any person.

Furthermore, the presence of the gastroresistant coating gave a very reproducible time course for absorption (2.6 - + 0.8 hours) when the tablets were administered during the fasting period.

These results demonstrate that an enteric coated tablet containing a 40% solid dispersion is an excellent form for admitting a 50 mg once daily administration and potentially higher doses, for example 100 mg of drug.

35

850 1 57 S

-22-

Example VII: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester (Compound B).

Preparation of the solid dispersion and of the dispersion granulate: 6 parts by weight of polyethylene glycol 6000 are mixed with 2 parts by weight of a commercial mixture containing mono-, di- and 10-triesters of palmitic acid and stearic acid and glycerol (Precirol *) and with 2 parts by weight of compound B, then melted at a temperature of 75-85 ° C and dissolved as much as possible with intensive stirring at a constant temperature of 70 ° C.

The mixture is then quickly cooled to room temperature by pouring it onto a pre-cooled metal plate and kept at 4 ° C for 3 hours. It solidifies as a layer about 4mm thick.

The solidified layer is reduced to coarse particles which are passed through a hammer mill (Fitzpatrick type, USA) to obtain a granulate suitable for the preparation of a mixture for the manufacture of tablets or capsules.

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

25 n a ca 3 (reciprocamate for the distribution range) (H. Sucker, et al. Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart 1978, p. 110).

s Gattefosse trademark 30

Example VIII Tablet 35 8501578 e -23-

Components: Amounts in mg 1. Compound B - polyethylene glycol 6000 - fatty acid glyceryl ester mixture / granulate (prepared according to Example 5) 50.0 2. Lactose, anhydrous 68.8 3. Magnesium stearate 1.2 120.0 10 Components 1 and 2 are mix briefly (5 minutes). The mixture is sieved (sieve size: 800 micrometers), sieved again (10 minutes), mixed with component 3 (5 minutes) and pelleted in a conventional manner on a rotary tabletting machine.

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

Example IX

2a Tablet

Components: Amounts in mg 1. Compound B - polyethylene glycol.

6000 - fatty acid glyceryl ester mixture / granulate (according to example VII) 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

Components 1, 2 and 4 are briefly mixed (5 minutes), the mixture is sieved (mesh size: 800 micrometers) and mixed again (10 minutes).

«Fe tf * '* · Λ. ; : 9 \ r -i ‘« c V * »^ -24-

Components 3 and 5 are mixed together with a portion of the mixture of 1, 2 and 4, sieved (800 µm) and mixed with the rest of the mixture of 1, 2 and 4 (5 minutes).

5

Comparative test no. 4

A plain uncoated hard gelatin capsule, containing a mixture of components 1-6 10 amounts in mg 1. Compound B 10.0 2. Lactose (filler) 167.0 15 3. Sodium lauryl sulfate (solubilizer) * 4. Silicon dioxide (lubricant) 1.5 5. Corn starch (disintegrant) 128.0 6. Polyethylene glycol 6000 (solubilizer) 8.0 20 320.0 was compared with the delayed tablet of Example VIII.

In 8 fasted healthy male volunteers aged 19-40 years, the delayed tablet of Example 25 VIII showed substantially constant drug plasma levels between 2.3 and 1 nanogram / ml and on average between 1.5 and 1 nanogram / ml for 2-24 hours after administration (see mean curve 23 in Figure 7). The undelayed regular capsule exhibited the usual image of mean curve 24 and drug release within 6 hours in the same volunteers.

The areas under both curves 23 and 24 are substantially the same. By comparing the AUCq of curves 23 and 24, a relative bioavailability of up to 96.2% for the delayed tablet of Example VIII could be determined.

3501578 -25-

The delayed tablet of Example VIII, compared to the ordinary uncoated hard gelatin capsule, produced a barely perceptible drug burst.

While one had to administer 2-3 regular capsules over a period of 5 time periods, the delayed tablet allows for once-daily administration.

Example X.

Preparation of the solid dispersion of the dispersion granulate: 10 parts by weight of compound B are dissolved in liquefied polyethylene glycol 15 6000 at a temperature of 125 ° C.

The mixture is quickly cooled to room temperature by pouring it onto a pre-cooled metal plate and storing overnight.

The solidified layer is reduced to coarse particles and passed through a hammer mill (type Fitzpatrick, USA) to obtain a granulate which can be used for the preparation of a mixture for the manufacture of tablets or capsules.

Example XI

Tablet

Components: Amounts in mg 30 1. Compound B - Polyethylene glycol 6000 - granulate (20%, prepared according to example X) 50.00 2. Lactose, anhydrous 63.85 3. Magnesium stearate 1.15 35 115.00 e5t * 10 / c <* -26-

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

Tablets: diameter 7 mm 5 compression strength: 40 Newton.

Example XII

The tablet of Example XI is conventionally coated in a Wuster column with a mixture of amounts in mg of hydroxypropylmethylcellulose phthalate 13.8 iron oxide pigment, red 0.6 titanium oxide 0.6 15.0

Comparative Test No. 5 20

Two regular, non-delayed capsules, each containing a mixture of components 1-6 in mg 25 1. Compound B 5.0 2. Lactose 172.0 3. Sodium lauryl sulfate 5.5 4. Silicon dioxide 1.5 30 5. Corn starch 128.0 6. Polyethylene glycol 6000 (solubilizing agent) 8.0 320.0 22 were compared to the enteric coated delayed tablet of

850 1 57 S

-27- example XII.

The test was performed as described in comparative test No. 4, except that the number of volunteers was increased to 11.

The plain, undelayed capsules both showed the usual image of the mean curve 25 in Figure 8 and the drug was released within 10 hours.

The enteric coated delayed tablet of Example 12 gave a mean plasma level between 2.5 and 0.8 nanograms / ml of compound B (mean curve 26) for 3-28 hours after administration and had an undiminished relative bioavailability compared to the ordinary capsule.

The enteric coated delayed tablet of Example XII allows for once daily administration, while the regular capsule is to be taken two to three times daily.

Example XIII: (-) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridine car -20 carboxylic acid isopropyl ester (compound C).

In a manner analogous to that described in Examples I and VII, a 20, 30, 40 and 50% dispersion of compound G in polyethylene glycol 6000 was prepared. 25 Of the obtained dispersion granulates, containing 50 mg of compound C, the dissolution rate in a water medium was determined according to the rotary vane method (USP XX).

30 35

* 2 Λ ·: · - Λ. · 'V

Si ^ V * w - ^ -28-

Dispersion granulate

Time in hours 20% 30% 40% 50% 0 0 0 0 0 52 100 86 54 27 3 88 60 33 4 88 63 38 5 89 68 44 6 90 72 48 10

Nifedipine

Example XIV 15

Analogously as described in Examples I and VII, a 20% and a 40% dispersion of Nifedipine in polyethylene glycol 6000 was prepared.

The dissolution rates in a water medium of the dispersion granulates obtained, which contained 50 mg of Nifedipine, were determined by the rotary vane method (USP XX).

Dispersion granules

Time in hours 20% 40% 25 —--- 0 0 0 2 5 0 3 29 1 1 4 56 20 30 5 77 31 6 90 41 7 96 '46 8 97 51 12 98 63 35 16 99 72 20_101_79_ s7 8 < v W w - J fv

Claims (5)

Solid dispersion of a pharmacologically active agent in a crystalline matrix as a carrier, characterized in that the active carrier a) has a maximum solubility of 0.01% at 37 ° C in water, b) in the matrix in a concentration is present above 5% by weight and c) is present in the matrix in a concentration above 5% by weight in a coherent crystalline form. Dispersion according to claim 1, characterized in that the active agent is dihydropyridine. Dispersion according to claim 2, characterized in that the active agent is a 1,4-dihydro-3,5-dicarboxylic acid diester-2,6-dimethylpyridine. Dispersion according to claim 1, characterized in that the active agent has an optionally substituted 4-phenyl or 4-phenyl derivative group. Dispersion according to claim 4, characterized in that the active agent has a 2,3,3-benzoxadiazol-4-yl group. Dispersion according to claim 5, characterized in that it contains 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-ethoxy-2,6-dimethyl-3-pyridinecarboxylic acid ethyl ester as active agent contains. Dispersion according to claim 5, characterized in that it contains 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester as an active agent. Dispersion according to any one of claims 1 to 7, characterized in that the matrix is a polyalkylene glycol. 9. Dispersion characterized in that it contains 4- (2,1,3-30-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid ethyl ester in an active agent polyalkylene glycol matrix. v f o7 S -30- Dispersion characterized in that it contains 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester in a poly -alkylene glycol matrix. Dispersion according to any one of claims 1 to 10, characterized in that the matrix is a poly (C 1-4 alkylene glycol). Dispersion according to claim 11, characterized in that the matrix is a polyethylene glycol. Dispersion according to claim 12, characterized in that the matrix is a polyethylene glycol with a molecular weight of 100-20,000. Dispersion according to any one of claims 1 to 13, characterized in that it contains more than 5% by weight of crystalline active agent particles with a diameter of up to 5 micrometers. Dispersion according to claim 14, characterized in that it additionally contains entrapped active agent particles with a diameter of up to 100 micrometers. Dispersion according to any one of claims 1-15, characterized in that it contains up to 80% by weight of active agent. Dispersion according to any one of claims 1 to 16, characterized in that it is in granulate form. Dispersion granulate according to claim 17, characterized in that the granulate particles have a diameter of up to 2000 micrometers. Secondary active agent structure, characterized in that it is obtained by selective removal of matrix material from a solid dispersion according to any one of claims 1-18. Secondary active agent structure 30, characterized in that it is obtained after removal of the matrix material with a water medium from a solid dispersion according to any one of claims 1-18. 21. Secondary active agent structure according to claim 19 or 20, characterized in that it is irregularly penetrated through fracture-like channels and contains small 35C1578 Λ -31 pores with a diameter of less than 5 micrometers. 22. Secondary active agent structure 2, characterized in that it has an area of 1-15 m / g measured by the BET method and a pore volume of 20-95% measured by mercury porosimetry. Pharmaceutical preparation, characterized in that it contains a dispersion or structure according to any one of claims 1-22. Pharmaceutical preparation according to any one of claims 1-18, characterized in that it has the tablet form. Pharmaceutical preparation according to any one of claims 1-23, characterized in that it has the capsule form. 26. Pharmaceutical preparation according to any one of claims 23-25, characterized in that it is in enteric coated form. Pharmaceutical preparation according to any one of claims 23-25, characterized in that it contains a solid dispersion containing a fatty acid glycerol ester. 28. A pharmaceutical composition according to any one of claims 23-27 for once-daily oral administration, characterized in that it is in dosage unit form containing up to 250 mg of active agent. 29. Pharmaceutical composition for once-daily oral administration, characterized in that it contains a therapeutically effective amount of 4- (2,3-benzoxadiazol-4-yl) -1,4-dihydro-5-ethoxycarbonyl-2,6 dimethyl-3-pyridinecarboxylic acid ethyl ester as the active agent. 30. Pharmaceutical composition for once-daily oral administration, characterized in that it has a therapeutically effective amount of 4- (2,3-benzoxadiazol-4-yl) -1,4-di-hydro-5-methoxycarbonyl-2, 6-dimethyl-3-pyridinecarboxylic acid isopropyl ester as active agent. 31. Pharmaceutical composition according to claim 29, characterized in that, when administered orally, it has a plasma level of 2-8 nanograms of active agent / ml for at least 22 hours. * »I -32- if given a dose of 50 mg 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-3-pyridine -carboxylic acid ethyl ester as the active agent. Pharmaceutical preparation according to claim 30, characterized in that, when administered orally, it can give a plasma level of 1-2.5 nanograms of active agent / ml for at least 22 hours, if it is a dose of 10 mg of 4- (2 1,3-benzoxa-diazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6,6-dimethyl-3-pyridine-carboxylic acid isopropyl ester as active agent. 33. Dispersion, secondary active agent structure or preparation thereof, substantially as described in the description and / or the examples. 34. A method of sustained release of an active agent from a pharmaceutical preparation, characterized in that a pharmaceutical preparation according to any one of claims 23-32 is administered. 35. A process for preparing a solid dispersion of a pharmacologically active agent in a crystalline matrix as a carrier, characterized in that an active agent with a maximum solubility of 0.01% in water at 37 ° C in a concentration is used. dissolves above 5% by weight in a liquefied matrix and converts the resulting mixture into a solid form and crystallizes the active agent. 36. A process for the preparation of a pharmaceutical preparation, characterized in that the product of the process of claim 35 is reduced to granulate particulate forms and processed as dosage unit forms in tablets or capsules. 37. A process for the preparation of a secondary structure of an active agent, characterized in that the product of the process according to claim 35 is reduced to granulate particle form and the matrix material is selectively removed. 38. A process for the preparation of a pharmaceutical composition, characterized in that the product of the 850157 process according to claim 37 is encapsulated in capsules. -33- - l r “* - -; i * 8. y1 n ': f c V}, r. d I. Έ. TOJUNIVbS Improvement of errata in the specification associated with patent application No. 8501578 Ned. proposed by applicant dated June 10, 1985._____________________________________________________________ Page 3, line 27 and page 29, line 6 are to read "b) in the matrix at a total concentration greater than 5% by weight of the matrix". 5 Page 3, line 29 and page 29, line 8 are replaced by the following: "(c) in the matrix at a concentration exceeding 5% by weight of the matrix". On page 13, lines 8, 13 and 31, "mg" 10 is replaced by "ng". On page 14, line 2, "30" is changed to "50". On page 24, line 23, it reads "00" instead of "28". 15 "f5 * 115 7 8 • <Atf