CA1264441A - Galenical retard form - Google Patents
Galenical retard formInfo
- Publication number
- CA1264441A CA1264441A CA000483768A CA483768A CA1264441A CA 1264441 A CA1264441 A CA 1264441A CA 000483768 A CA000483768 A CA 000483768A CA 483768 A CA483768 A CA 483768A CA 1264441 A CA1264441 A CA 1264441A
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- Prior art keywords
- active agent
- matrix
- dispersion
- dispersion according
- dihydro
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Abstract Solid dispersion of a pharmacologically active agent in a crystalline matrix as a carrier , characterized by an agent which a. has a solubility of maximally 0.01% at 37°C in water, b. is present in the matrix at a concentration of more than 5 percent of weight, c. is present in the matrix at a concentration of above 5 percent by weight in a coherent crystalline form.
The secondary active agent structure which results by extracting the matrix material with e.g. water.
The pharmaceutical compositions containing the solid dispersion or the secondary active agent structure, which when taken orally, show a slow release of the active agent.
The secondary active agent structure which results by extracting the matrix material with e.g. water.
The pharmaceutical compositions containing the solid dispersion or the secondary active agent structure, which when taken orally, show a slow release of the active agent.
Description
2 ~j~L~ L
Case 100-6373 NOVEL GALENICAL RETARD FORM
The invention relates to forms of pharmacologically active agents having controlled relea~e properties and espectally to solid dispersion forms of such agents having sustained release properties of the agent in an aqueous medium.
By incorporating an active agent in a solid dispersion or solution up till now merely an accelerated release was realized:
For example solid dispersion ~orms of medicaments are known, e.g.
from the German Offenlegungsschrift Nr. 2.549.740, in which solid dispersions of griseofutvin in polyethylene glycol are described.
The low dissolution rate and accordingly (see page 11, lines 4-5) the low bioavailability of griseofulvin were improved by the preparation of a solid dispersion of griseofulvin in poly-ethylene glycol. In the specifically described medicament formulation, a tablet, a disintegrant had to be added to the solid disoersion granulate since it appeared that a greatly improved dissoluti~n rate of griseofulvin was again receded. The pressure applied in the production of tablets led to considerable cohesion between the tablet particles as a result of the strong cohesion between the polyethylene glycol molecules.
The disintegrant, crosslinked polyvinylpyrrolidone was added, in order to be able to re-form the original granulate particles of the tablet, in which the griseofulvin was present in a faster soluble form.
The water soluble polyethylene glycol, in contact with an aqueous mediumg is extracted from the granulate by diffusion, the finely 24j~fL~L
divided griseofulvin coming into a situation to dissolve quickly.
According to the German Auslegeschrift ~o. 2.546.577 an increase of the dissolution rate and the resorption of salts of difficulty water soluble ergotamine compounds (especially of dihydroer3Ota~ine-methanesulfphonate, of dihydroergocristine-methanesulphonate, of dihydroergocryptine-methanesulphonate and of dihydroergocornine-methane-sulphonate) is obtained when the salts are present in solid solutions in polyalkylene glycols and especlally in polyvinylpyrrolidone of a molecular weight above 10.000, The mentioned drugs have in methanesulphonate salt form a water solubility a~ove 0.01 % and are in this respect distinguished from the active agents used according to the invention.
According to the European application No. 78430 an increase of the dissolution rate and a maintenance of the resorption of dihydro-pyridines, especially of Nifedipine and of Ni~.nodipine is obtained on dissolving these agents together ~ith polyvinylpyrrolidone, e.g. having a molecular weight of 25 000~ in a small quantity of a liquid organic solvent such, that the solid particles are only iust dissolved after which this solution is mixed and granulated with solid carriers having a large capacity to absorbe, leading to evaporation of the organic solvent.
Tne drug is present in the solid polyvinylpyrrolidone in a dissolved state and shows on contact with an aqueous medium an increased dissolution rate. 3Oth these features distinguish these known products from the compositions of the present invention.
According to the Canadian patent No. 987.588 an increase of the dissolution rate and of the bioavailability of difficulty water-soluble drugs is obtained when they are present as solid dis-.
' 2 64~ L
Case 100-6373 NOVEL GALENICAL RETARD FORM
The invention relates to forms of pharmacologically active agents having controlled relea~e properties and espectally to solid dispersion forms of such agents having sustained release properties of the agent in an aqueous medium.
By incorporating an active agent in a solid dispersion or solution up till now merely an accelerated release was realized:
For example solid dispersion ~orms of medicaments are known, e.g.
from the German Offenlegungsschrift Nr. 2.549.740, in which solid dispersions of griseofutvin in polyethylene glycol are described.
The low dissolution rate and accordingly (see page 11, lines 4-5) the low bioavailability of griseofulvin were improved by the preparation of a solid dispersion of griseofulvin in poly-ethylene glycol. In the specifically described medicament formulation, a tablet, a disintegrant had to be added to the solid disoersion granulate since it appeared that a greatly improved dissoluti~n rate of griseofulvin was again receded. The pressure applied in the production of tablets led to considerable cohesion between the tablet particles as a result of the strong cohesion between the polyethylene glycol molecules.
The disintegrant, crosslinked polyvinylpyrrolidone was added, in order to be able to re-form the original granulate particles of the tablet, in which the griseofulvin was present in a faster soluble form.
The water soluble polyethylene glycol, in contact with an aqueous mediumg is extracted from the granulate by diffusion, the finely 24j~fL~L
divided griseofulvin coming into a situation to dissolve quickly.
According to the German Auslegeschrift ~o. 2.546.577 an increase of the dissolution rate and the resorption of salts of difficulty water soluble ergotamine compounds (especially of dihydroer3Ota~ine-methanesulfphonate, of dihydroergocristine-methanesulphonate, of dihydroergocryptine-methanesulphonate and of dihydroergocornine-methane-sulphonate) is obtained when the salts are present in solid solutions in polyalkylene glycols and especlally in polyvinylpyrrolidone of a molecular weight above 10.000, The mentioned drugs have in methanesulphonate salt form a water solubility a~ove 0.01 % and are in this respect distinguished from the active agents used according to the invention.
According to the European application No. 78430 an increase of the dissolution rate and a maintenance of the resorption of dihydro-pyridines, especially of Nifedipine and of Ni~.nodipine is obtained on dissolving these agents together ~ith polyvinylpyrrolidone, e.g. having a molecular weight of 25 000~ in a small quantity of a liquid organic solvent such, that the solid particles are only iust dissolved after which this solution is mixed and granulated with solid carriers having a large capacity to absorbe, leading to evaporation of the organic solvent.
Tne drug is present in the solid polyvinylpyrrolidone in a dissolved state and shows on contact with an aqueous medium an increased dissolution rate. 3Oth these features distinguish these known products from the compositions of the present invention.
According to the Canadian patent No. 987.588 an increase of the dissolution rate and of the bioavailability of difficulty water-soluble drugs is obtained when they are present as solid dis-.
' 2 64~ L
- 3 - 100-6373 persions in polyethylene glycols and in other water-soluble matrix materials, e.g. pentaerytnritol~ pentaerythritol 1;etraacetate or citric acid.
The known drugs di~itoxin 17-methyltestosterone,prednisolone acetate and hydrocortisone acetate are present at concentrations up to ~ % in the matrix material, thus giving disperstons which are different from the dtspersions according to the present Invention. The drug griseofulvin has, as indicated above, a water-solubility of more than 0.01 % and is therefore distingutshed from the active agents used according to the invention.
We have discovered that if solid dispersions of pharmacologically active agents, practically insoluble in water are employed in such a matrix material, no signif~cant expected increase of the dissolution rate in anaqueous medium is observed. Instead a l~ decrease is obtained,without a material loss of ~ioavail-ability.
We have additionally discovered, that the decrease of the dissolution rate may be attributed to a coherent crystalline form o~ the drug, hereinafter referred to 2S a secondary structure, which form may be maintained even if the water-soluble matrix material is removed on contact with an aqueous medium, e.g, water.
To permit the secondary structure to be formed, it is preferred to have the drug in the solid dispersion present in a concentration above 5 %, and for more than 5 percent by weight in a crystalline form preferably as particles of a diameter below 5 mIcrometer and having a water-solubility up to 0,01 %, preferably below 0.005 percent by weight.
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The known drugs di~itoxin 17-methyltestosterone,prednisolone acetate and hydrocortisone acetate are present at concentrations up to ~ % in the matrix material, thus giving disperstons which are different from the dtspersions according to the present Invention. The drug griseofulvin has, as indicated above, a water-solubility of more than 0.01 % and is therefore distingutshed from the active agents used according to the invention.
We have discovered that if solid dispersions of pharmacologically active agents, practically insoluble in water are employed in such a matrix material, no signif~cant expected increase of the dissolution rate in anaqueous medium is observed. Instead a l~ decrease is obtained,without a material loss of ~ioavail-ability.
We have additionally discovered, that the decrease of the dissolution rate may be attributed to a coherent crystalline form o~ the drug, hereinafter referred to 2S a secondary structure, which form may be maintained even if the water-soluble matrix material is removed on contact with an aqueous medium, e.g, water.
To permit the secondary structure to be formed, it is preferred to have the drug in the solid dispersion present in a concentration above 5 %, and for more than 5 percent by weight in a crystalline form preferably as particles of a diameter below 5 mIcrometer and having a water-solubility up to 0,01 %, preferably below 0.005 percent by weight.
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4 100-6373 The present invention therefore provides in one aspect a solid dispersion of a pharmacologically active a3ent in a water-soluble crystalline matrix as a carrier, in which the active agent a) has a maximum solubility of 0.01 % at 37C in water, b) is present in the matrix at a concentration of above 5 percent ~y weight and c) is present in the matrix at a concentration of above 5 percent ~y weight in a coherent crystalllne form.
This solid dispersion has in an aqueous medium a decreased dissolution rate.
A decreased dissoluti~on rate was established in the following cases in the art:-Ger,~an Offenlegungsschrift No. 1.617.362 describes suspendingpharmacologically active agents, particularly theophylline.in molten waxes for the preparation of galenical forms having a decreased dissolution rate in ana~ueous medium. As a wax poly-ethylene glycol is used.
However, the solubllity of theophylline is not low enough (above 0.01 ~) and only the additional incorporation of conventional retardation excipients, like beeswax or stearic acid can cause a satisfactory decrease of the dissolution rate of the drug.
According to German Offenlegungsschrift No. 3.318.549 a two phasic solid pharmaceutical composition is described which contains crystalline Nifedipine and separately a solid solution of Nifedipine in a matrix material, particularly in polyvinylpyrrolidone. On contact with an aqueous medium, Nifedipine is dissol~ed from the .., ., ~ -. , .
This solid dispersion has in an aqueous medium a decreased dissolution rate.
A decreased dissoluti~on rate was established in the following cases in the art:-Ger,~an Offenlegungsschrift No. 1.617.362 describes suspendingpharmacologically active agents, particularly theophylline.in molten waxes for the preparation of galenical forms having a decreased dissolution rate in ana~ueous medium. As a wax poly-ethylene glycol is used.
However, the solubllity of theophylline is not low enough (above 0.01 ~) and only the additional incorporation of conventional retardation excipients, like beeswax or stearic acid can cause a satisfactory decrease of the dissolution rate of the drug.
According to German Offenlegungsschrift No. 3.318.549 a two phasic solid pharmaceutical composition is described which contains crystalline Nifedipine and separately a solid solution of Nifedipine in a matrix material, particularly in polyvinylpyrrolidone. On contact with an aqueous medium, Nifedipine is dissol~ed from the .., ., ~ -. , .
- 5 - 100-6373 solid solution at an increased dissolution rate and from the solid Nifedipine crystals at a decreased dissolution rate, According to the present invention only a solid dispersion of the drug is present, which on contact ~ith an aqueous medium causes the release of the drug at a decreased rate.
For the solid dispersion according to the invention the choice of the pharmacologicàlly active agent ls not critical,provided t~at its solubility and crystallisation conditions are met.
It is a simple and routine matter to test whether a given active agent complies with the required conditions.
The practically insoluble pharmacologically active agents in the dispersion according to the invention are e.g. dihydropyridines, particularly the 1,4-dihydro-3,5-dicarboxylic acid diester-2,6 dimethylpyridines, especially such having an optionally substituted 4-phenyl ~ a 4-phenyl derivative group.
A 4 phenyl derivative group is e.g. the 4-(2,1,3-benzoxadiazol-4-yl) group. An example of a drug having an optionally substituted 4-phenyl residue is the known 4-(2-nitrophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridine carboxylic acid methylester (nifedipine).
Examples of drugs having a 4-phenyl derivative group are 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5 ethoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid ethyl ester (compound A), 4-~2,1,3)- -benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6~dimethyl-3-pyridine carboxylic acid isopropylester (compound B) and ~ S)-4-(2~1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridine carboxylic acid isopropylester (compound C).
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For the solid dispersion according to the invention the choice of the pharmacologicàlly active agent ls not critical,provided t~at its solubility and crystallisation conditions are met.
It is a simple and routine matter to test whether a given active agent complies with the required conditions.
The practically insoluble pharmacologically active agents in the dispersion according to the invention are e.g. dihydropyridines, particularly the 1,4-dihydro-3,5-dicarboxylic acid diester-2,6 dimethylpyridines, especially such having an optionally substituted 4-phenyl ~ a 4-phenyl derivative group.
A 4 phenyl derivative group is e.g. the 4-(2,1,3-benzoxadiazol-4-yl) group. An example of a drug having an optionally substituted 4-phenyl residue is the known 4-(2-nitrophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridine carboxylic acid methylester (nifedipine).
Examples of drugs having a 4-phenyl derivative group are 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5 ethoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid ethyl ester (compound A), 4-~2,1,3)- -benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6~dimethyl-3-pyridine carboxylic acid isopropylester (compound B) and ~ S)-4-(2~1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridine carboxylic acid isopropylester (compound C).
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- 6 - 100-6373 The dihydropyridines are extensively described in the literature and have parti~cularly a calciumantagonistic activity. They are described e.g. as antihypertonics and as medicaments to treat angina pectoris.
The a6Ove-mentioned dihydropyyjdtnes A and B are known, e g.
From the European patent No. 150 and the British patent No, 2.037.766. The dihydropyridine C is known ~rom the Brttish patent application GB 2.122 1q2 A, and is specifically described in Example 2c thereof.
It has ~een establtshed, that the dihydropyrid~nes, e.g. the compounds A and B are practically water-insoluble and thus have a water solubility of `less than 0.01 %.
Processing of them into a solid dispersion form however did not, as expected, result in an increased dissolution rate but surprisingly in a significantly decreased dissolution rate (see the comparative tests 1 to 5), advantageous in compositions which are to be administered once a day.
This retard effect is attributed to the solid dispersio~ e.g.
in granulate form, independent of optionally present excipients.
An advantage is that no customary drug burst appears and that there is not significant decrease of the bioavailability (see the comparative tests).
The present invention thus provides a pharmaceutical composition for administration once a day~ containing a therapeutical effective amount of the compounds A or B. The matrix materials are .. .,. :
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_ 7 100-6373 preferably pharmaceutical acceptable solid compounds conventionally widely used as pharmaceutical excipients.
Since they must preferably be ~ater-soluble, they should have polar properties. Most of these matrix materials thus have polar groups, e.g. oxy groups~ especially hydroxy groups.
The preferred pharmaceutical compositions contain a solid dispersion of pharmacologially active agents in a polyalkylene glycol, particularly in a poly(C2 3)alkylcne glycol, e.g. in a polyethylene glycol. The polyethylene glycol preferably has a molecular weight from 1000 to 20.000, espectally from 4.000 to 20.000, particularly from 4.000 to 8.000, e.g. 6.000.
The solid dispersions may be obtained by dissolving the active agents at a concentration a6Ove 5 percent by weight, in the liquified dispersing agent and solidifying the obtained mixture.
- 15 Liquifying the dispersing agent may occur by melting or by addition of a liquid organic solvent.
Solidifying of the liquid active agent containing dispersing agent may occur e,g. by cooling or by evaporating the liquid organic solvent.
The present invention thus also provides a process for the prepara~
tion of a solid dispersion of a pharmacologically active agent in a crystalline matrix as a carrier, characterized in that an active agent,having a maximum solubility of 0.01 %, preferably below 0.005 %, in water at 37C, is dissolved at a concentration of above 5 percent by weight in a liquified matrix and the obtained mixture is transformed to a solid form and the active agent is crystallized.
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After obtaining ~he solid dispersjon it may be reduced to a conventional particle size, giving a granulate useful for further processing.
At least 5 percent of weight of the drug particles present in the solid dispersion are so small, that ~t is impossi~le to see them by conventional optical measurements, since if suspended for measurement purposes in an aqueous medium, they appear to have a Brownian perpetual mot~on.
Hence the particles are assumed generally to have a diameter of 5 micrometres or less.
Laserlight scattering tests in the aqueous suspension established a particle size of even less than 0.5 micrometer.
Comparison of the Guinier-de Wolff-spectra of the solid dis-persion and of a corresponding mechanical mixture showed no significant difference.
The spectra show further that both drug and matrix material in the dispersion are in a crystalline Form.
The concentration of the drug in the matrix may vary from 5 to 80 %, especially from ~0 to 50 %, and particularly ~rom 20 zo to 40 percent of weight and contributes to the sustained release effect according to the tnvention. (Greater concentration may cause a greater decrease of the dtssolution rate, see curves 14 to 1~ in flg. 5 for the dissolved quantity in percent of weight versus time T in hours, increasing concentratîons of 10 to 50 percent by weight of compound A may cause a decrease of the dissolution rate).
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- ~ - 100-6373 Curves 14 to 18 in fig. 5 relate to solid dispersion granulates of the same su~Fracti~on, containing lO, 20, 30, 40 and 50 percent by weight of compound A .
The appropriate dose of the active agent amounts preferably up to 250 mg and preferaBl~ up to 200, especially up to lO0 mg for compound A and up to S0, prefera~ly up to 30, especially lO to 25 mg for compound B per day. For a rationally administrable dispersion quantity a concentration from lO to 80% of active agent in the matrlx~on the average up to 50%, e.g. 40% of compound A and 20 percent By weight of compound B are indicated.
If the chemical stability of the act~ve agent is not high, then the tempera~ure of the molten matrix material, e.g, of the polyalkylene glycol, should be kept appropriately low. If more active agent is added to the polyalkylene glycol, then can be dissolved at the maximum allowable temperature; the excess will not be dissolved, but will be incorporated as a suspension.
The undissolved fraction particles preferably should have a particle size of at most 100 micrometres.
After cooling of the suspension these particles may be found in the dispersion with an similar size in addition to the fraction of active agent, that was dissolved and after cooling can be found again in the form of crystals hav1ng a diameter of at most S micro-metres.
In the granulating process, briefly described above, the solid dispersion is preferably reduced to a particle size from 50 to 2000 micrometer, especially from 90 to lOOQ, mor particularly from 125 to 500 micrometer.
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The particle size of the granulate contributes to the controlled release effect according to the invention (larger narticles cause a greater decrease of the d~ssolution rate, see curves 19 to 22 in fig. 6; dissolved quantity in percent by weight versus time T;
an increasing particle size causes a decrease of the dissolution rate, curves 19 to 22 relate to sieve factors oF ~0 to 1~0, of 180 to 355, of 355 to 500 and of 500 to 710 micrometre respectively of the dispersion granulate of a 40% dispersion of compound A in polyethylene glycol 6000.
Summarizing, it may be concluded that the releaseof the ~harmaco-logically active agent can be controlled by changing the concen-tration of the active agent in the solld dispersion as well as by varying the particle size of the solid dispersion granulate.
Surprisingly, it has been established that when the dispersion granulate particles, e.g. those of Example 1, are brought into water, their matrix fraction is dissolved quickly and quantitatively.
The active agent particles which in the dispersion have for example a size of up to 5 micrometre, form coherent secondary structures, their density and diameter varying according to the concentration of the acttve agent in the matrix and the diameter of the granulate particles.
The present invention thus provides an secondary active agent structure, formed from the solid dispersion after selective extraction of the matrix material, e.g. in an aqueous medium.
This secondary structure may have a diameter comparable to that of the dispersion granulate. It shows in water a retarded disso-lution rate. It can ~e partially restored to its original particles of up to 5 micrometre by intensive ultrasonic treatment.
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Particles of active agent which in the dispersion granulate may have for example a diameter of up to lO0 micrometre are in the secondary structure, which has 6een proceeded from the particles of up to 5 micrometre, enclosed in an unchanged state.
S Since the original agent particles up to 5 micrometre and the additionally enclosed agent particles up to lO0 micrometre contribute to the controlled release effect, both their solid dispersions and secondary active agent structures belong to the present invention.
The diameter and the surface of the secondary structure particles of the active agent have been investigated~ They show irregular fissurelike channels and have an external and an internal surface.
Both the size and the structure of the external surface influence the dissolution rate in an,e.g. aqueous,solvent medium. The internal surface shows narrow pores up to l micrometre which hardly contribute to the release of active agent~ since if they contain a solvent medium, its mobi1ity is strongly reduced.
The size of the seconda~y structure corresponds to the size of the solid dispersion granulate particles, from which they originate.
After removal of the solvent medium, e.g. by drying, the speciFic surface and the pore volume are measurable.
The present invention provides the secondary structure of an active agent of a diameter of preferably from 50 to 2000, more particu-larly from 90 to 1000, especially from 125 to 500 micrometre, having a porous structure, characterized by a speciflc surface .~ ,, ~2~4~L
- 12 ~ 100-6373 of l to lS m2lg, preferably from 2 to 12 m2/g, measured according to the BET-method and by a pore volume of 20 to 95%, measured by mercury~porosimetry The solid dispersion particles as well as the secondary structure particles are usable for the preparation of pharmaceutical compounds.
The present invention thus provides also pharmaceutical compositions containing the solid dispersion granulate or the secondary structure particles.
Pharmaceutical compositions containing the solid dispersion yranulate can be considered as galenical precursor forms of corresponding compositions containing the secondary structure particles, since their beha~iour in the body-is comparable with that of pro-drugs.
For the preparation of the pharmaceutical oral administration forms containing the solid dispersion7 the granulate of the solid dispersion may be mixed in a conventional manner with suitable pharmaceutical excipients, e.g. a filling agent, such as lactose, a glidant, e.g. silicon dioxide and a lubricant, e.g. magnesium stearate (see. e.g. examples 2, 5 , 6 and 9) and optionally a desintegrant, such as crosslinked polyvinylpyrrolidone, e.g.
crosspovidone (see. e.g. examples 2, 3, 5 and 6), or sodium carboxymethylcellulose (see example 9) and may be manufactured to conventional solid oral administration forms, such as tablets or capsules.
For the preparation of tablets the solid dispersion granulate may preferably be mixed with e.g. lactose9 silicon7 dioxide and magnesium stearate (see example 4, 5, ~ and 9).
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The porous secondary structure agent particles are preferably used in capsules, since they are less able to resist the pressure for tabletting.
For the preparation of capsules, the solid dispersion granulate of the secondary structure agent particles may be mixed in conventional manner preferably with a placebo granulate from suitable exci pi ents like lactose, starch and polyvinylpyrrolidone and with a mixture of crospovidone,silicone dioxide and magnesium stearate (see examples 2 and 3). The desintegrant may be used for suspending the capsule content.
Generally pharmaceutical administration forms, especially capsules and to a lower extent tablets as well show, during the passage through the stomach, a drug burst, which can to a large extent be prevented by applying an enteric coating on it.Suitable enteric coatings include hydroxypropylmethylcellUloSephthalate (see example 3,5, 6 and 12). I~ the active agent is resorbed in the upper part of the intestin~s - dihydropyridines are such agents - then such a coating is very benefictal and does not impair the resorption process.
Tablets, which contain the components in compressed state, may need this coating to a lower extent, but then the desintegrant should be omitted (see the tablet of example 4, which contains no crosslinked polyvinylpyrrolidone).
We have established, that capsules or tablets without an enteric coating may be made if a hydrophobic excipient, such as a fatty acid glyceryl ester, is added to the solid dispersion ~see examples 8 and 9 and comparative test No. 4). This hydro-, ~
": , ` :
, phobic ester reduces the drug burst in the stomach and may not significantly disturb the resorption process in the intestines.
Such compositions may ~e prepared ~y dissolving the pharmacolo-gically active agent in the liquid matrix and emulgating the obtained mixture wi~h the hydrophobic substance, e.g. the fatty acid glyceryl ester, as much as possible, after which the obtained mixture may be solidified by cooling.
Preferred fatty acid glyceryl esters are physiologically acceptable esters~ like (Cl0~20)fatty acid, e.g, palmitic and/or stearid acid glyceryl esters. These esters may ~e, e.g. mono-, di- and/or triesters of glycerin.
The amount of fat is preferably up to 60 percent of the total weight of the solid dispersion, e.g. 5 to 60%, and is particularly up to 15 to 25%, e.g. 20%.
The sustained release compositions according to the invention may be used to administer very different, practically water insoluble classes of active agents. They may be used for their known indications.
The quantities of active agents to be administered may be dependent on various factors, e.g. the conditions to be treated, the duration of treatment desired and the rate of release of the active agents.
The amount of each active agent required and the rate of release may be determined using in vivo techniques, e.g. mea-suring the concentration of active agent in the blood serum.
The pharmaceutical compositions of e.g. the compounds A and B
may be used e.g. for the same indications as described in the European patent No. 150 and in the Brltish patent No. 2037766.
A~
2 6~ L
For the antihypertonic use e.g. up to 250, especially up to 200, particularly 50 to 100 mg of compound A and up to 50~ especially up to 25, particularly 10 to 20 mg of compound B are used per day.
In the drawings:
Figures 1-4 show conce~trations vs. time for compound A;
Figures 5 and 6 show the dissolution rate of compound A in vitro; and Figures 7 and 8 show concentrations vs. time for compound B.
lU The present invention provides especially a pharmaceutical compo-sition for plasma levels of 2 to ~ mg of compound A per ml during at least 22 hours, in the event that it contains one dosis of 50 mg of the active agent. Basis for this observation are the plasma level curves 1, 3, 4, 5 and 6 to 13 in fig. 1 to 4.
The present invention also provides a pharmaceutical composition for plasma levels of 1 to 2,5 mg of compound B) per ml, during at least 22 hours~ in the event that it contains one dosis of 10 mg of the active agent. Basis for this observation are the plasma level curves 23 and 26 in fig. 7 and 8.
The plasma level of compound A for curves 1 to 13 in fig. 1 to 4 ~concentrations vs. time) may be determined gaschromatographically.
A plasma sample of 1 ml, adjusted with NaOH to pH 13,was extracted with toluene, the toluene was evaporated and the residue dissolved in 0.5 ml of toluene. 2 microlitres of the formed solution were separated at 300C in a OV 17 column(6~ on Gaschrom Q 100-120 mesh) using a argon/methane gas (95:5 volume/
volume)mixture as a carrier gas(rate 60 ml/min). The analysis may be carried out using an electron capture detector. The retention time of compound A was 3.1 min.
The concentration of the compound was calculated by peak measure-ment in comparison to the peak of an internal standard. The detection limit is 0.5 mg of active agent per ml of plasma.
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The dissolution rate of compound A in vitro for curves 14 to 22, of compound C in example 13 and of nifedipine in example 1~
(dissolved quantities in percent ~y weight vs. time) was determined in 10~0 ml of solvent medium at 37C according to the Rotation Paddle-,~ethod (USP XX) at 30 rotations per min. For compound A
and for nifedipine an aqueous 0.1 HCl soluticn was used as the solvent medium. After 2 hours the pH was adjusted by addition of a tenside containing 6uffer solution of pH 6.8. Compound C was tested in a neutral tenside containing aqueous solution.
20 microlitres of a filtered sample of the solution of active agent and of a reference solution were separated chromatographically in 2 columns of a length of 10 cm and a diameter of ~.6 mm,contai-ning substance RP.18; 5 micrometre as a stationary phase and with methanollwater 85:15(v/v)as a mobile phase and at a pressure of 150 bar at room temperature and were measured at a wave length of 326 mm.
The plasma levels of compound B for curves 23 to 26 in fig. 7 and 8 were chromatographically determined as well. A plasma sample of 2 ml, adjusted with NaOH to a pH 13, was extracted with toluene. The toluene was evaporated and the residue dissolved in 25 microlitre of toluene. 2 microlitre of the formed solution were separated at a temperature of 300C in a OV 17 capillary column (internal diameter of 0.3 mm and a length of 25 m), using helium as a carrier gas; (pressure at the input: 0.7 atm. of excess pressure).
The analysis was carried out at a temperature of 300C using an electron capture detector and with an argonlmethane (90:10 vol/vol) gas mixture (rate 30 ml/min) as additional gas. The retension time of compound B) was 11.5 min.
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The calculation of tKe concentration of compound B was carried out analogously as described for compound A . The detection limit is 50 picogram of active agent per ml of plasma.
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Example 1: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-carboxy-carbonyl-2,6-dimethyl-3-pyridincarboxylic acid ethylester (compound A) Preparation of the solid dispersion:
4 parts by weight of scaly polyethylene glycol 6000 are melted at 55 to 63C and heated to about 85C while stirring.
One part by weight of compound A are added and dissolved completely while stirring at a constant temperature. The solution is then rapidly cooled by pouring it into a metal sheet, where it solidifies in a layer thickness of about 2 mm. After cooling to room temperature the solidified layer is detached from the sheet, reduced to coarse pieces and then passed in stages through sieves of decreasing mesh (2.5, 1.0 and 0.5 mm~ or reduced to small pieces in a hammer-mill so that a granulate is produced, usable fo~the preparation of a tabletting or capsulating mixture.
Example 2-Hart gelatine capsule Components: quantities in mg 23 1. Compound A - polyethylene glycol 6000 granulate g20%), prepared according to example 1 250.0 2. Placebo granulate of Lactose 83 parts Cornstarch 10 parts Polyvinylpyrrolidon6 parts 41.Q
3. Crosslinked polyvinylpyrrolidone 6.0 4. Silicon dioxide 1.5 5. ~agnesium stearate 1.5 300.0 ., :
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19 _ 100-6373 Both granulates l.and 2 are mixed. Components 3.to 5.are mixed as well, after which the mixture of 1. and 2. is mixed with the mixture of 3. to 5. and is filled in gelatinecapsules of a suitable capacity.
Example 3:
The hard gelatine capsule of example 2 is enteric coated in conventional manner in Wurster column with a mixture of hydroxypropylmethylcellulosephthalate 33.3 mg and diethylphthalate 3.3 mg Example 4:
Tablet Components: quantity in mg 1. Compound A - polyethylene glycol 6000 granulate (20%), prepared according to example 1 250.0 2. Lactose, anhydrous 188.5 3. Silicon dioxide 2.5 4. Magnesium stearate 9.0 450.0 The components 1. to 4. are briefly mixed, the mixture is sieved (630 mikrometre mesh), mixed again and tabletted in conventional manner.
.. , _ mple 5:
Table Components: quantities in mg l. Compound A - polyethylene glycol 6000 ~ granulate (20%), prepared according to example l 250.00 2. Lactose, anhydrous 177.25 3. Crosslinked polyvinylpyrrolidone 11.25 4. Silicon dioxide 2.50 5. ~agnesium stearate 9.00 The components 1. to 5. are mixed and tabletted as described in example 4.
The kablet is enteric coated as described in example 3 with a mixture of hydroxypropylmethylcellulosephthalate 9 %
and diethylphthalate 9 % 50.00 500.00 Example 6:
In an analogous manner as described in example 1, a 40% dispersion of compound A in polyethylene glycol 6000 is prepared at a temperature of 125C. The dispersion granulate is,in a manner as described in examp1e 5, compressed t~ tablets containing 50 and 100 mg o~ active agent.
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2 ~ 9L
Tablets Components: quantities in mg 1. Compound A - polyethylene glycol 6000 granulate (40~) 125.0 250.0 2. Lactose, anhydrous 65.0 130.0 3. Cross-linked polyvinylpyrrolidone 5.0 lO.0 4. Silicon dioxide 1.0 2.0 5. i~agnesium stearate 4.0 8.0 enteric coating * 20.0 40.0 220.0 440.0 * A coating of percents by weight hydroxypropylmethylcellulosephthalate 93 Titanium dioxide 3.5 Iron oxide, yellow 3.5 The coating is applied to in conventional manner in a Wurster column Comparative test No. 1 A conventional uncoated hard gelatinecapsule containing a granulate of components 1. to 5~ and an external phase of a mixture of components 6. to 9.
quantities in mg l. Compound A 50 0 2. Lactose 216.0 3. Cross-linked polyvinylpyrrolidone 6.0 4. Polyoxyethylene-polyoxypropylene polymer 10.0 5. Polyvinylpyrrolidone 7.5 6. Cross-linked polyvinylpyrrolidone 5.5
The a6Ove-mentioned dihydropyyjdtnes A and B are known, e g.
From the European patent No. 150 and the British patent No, 2.037.766. The dihydropyridine C is known ~rom the Brttish patent application GB 2.122 1q2 A, and is specifically described in Example 2c thereof.
It has ~een establtshed, that the dihydropyrid~nes, e.g. the compounds A and B are practically water-insoluble and thus have a water solubility of `less than 0.01 %.
Processing of them into a solid dispersion form however did not, as expected, result in an increased dissolution rate but surprisingly in a significantly decreased dissolution rate (see the comparative tests 1 to 5), advantageous in compositions which are to be administered once a day.
This retard effect is attributed to the solid dispersio~ e.g.
in granulate form, independent of optionally present excipients.
An advantage is that no customary drug burst appears and that there is not significant decrease of the bioavailability (see the comparative tests).
The present invention thus provides a pharmaceutical composition for administration once a day~ containing a therapeutical effective amount of the compounds A or B. The matrix materials are .. .,. :
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_ 7 100-6373 preferably pharmaceutical acceptable solid compounds conventionally widely used as pharmaceutical excipients.
Since they must preferably be ~ater-soluble, they should have polar properties. Most of these matrix materials thus have polar groups, e.g. oxy groups~ especially hydroxy groups.
The preferred pharmaceutical compositions contain a solid dispersion of pharmacologially active agents in a polyalkylene glycol, particularly in a poly(C2 3)alkylcne glycol, e.g. in a polyethylene glycol. The polyethylene glycol preferably has a molecular weight from 1000 to 20.000, espectally from 4.000 to 20.000, particularly from 4.000 to 8.000, e.g. 6.000.
The solid dispersions may be obtained by dissolving the active agents at a concentration a6Ove 5 percent by weight, in the liquified dispersing agent and solidifying the obtained mixture.
- 15 Liquifying the dispersing agent may occur by melting or by addition of a liquid organic solvent.
Solidifying of the liquid active agent containing dispersing agent may occur e,g. by cooling or by evaporating the liquid organic solvent.
The present invention thus also provides a process for the prepara~
tion of a solid dispersion of a pharmacologically active agent in a crystalline matrix as a carrier, characterized in that an active agent,having a maximum solubility of 0.01 %, preferably below 0.005 %, in water at 37C, is dissolved at a concentration of above 5 percent by weight in a liquified matrix and the obtained mixture is transformed to a solid form and the active agent is crystallized.
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After obtaining ~he solid dispersjon it may be reduced to a conventional particle size, giving a granulate useful for further processing.
At least 5 percent of weight of the drug particles present in the solid dispersion are so small, that ~t is impossi~le to see them by conventional optical measurements, since if suspended for measurement purposes in an aqueous medium, they appear to have a Brownian perpetual mot~on.
Hence the particles are assumed generally to have a diameter of 5 micrometres or less.
Laserlight scattering tests in the aqueous suspension established a particle size of even less than 0.5 micrometer.
Comparison of the Guinier-de Wolff-spectra of the solid dis-persion and of a corresponding mechanical mixture showed no significant difference.
The spectra show further that both drug and matrix material in the dispersion are in a crystalline Form.
The concentration of the drug in the matrix may vary from 5 to 80 %, especially from ~0 to 50 %, and particularly ~rom 20 zo to 40 percent of weight and contributes to the sustained release effect according to the tnvention. (Greater concentration may cause a greater decrease of the dtssolution rate, see curves 14 to 1~ in flg. 5 for the dissolved quantity in percent of weight versus time T in hours, increasing concentratîons of 10 to 50 percent by weight of compound A may cause a decrease of the dissolution rate).
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- ~ - 100-6373 Curves 14 to 18 in fig. 5 relate to solid dispersion granulates of the same su~Fracti~on, containing lO, 20, 30, 40 and 50 percent by weight of compound A .
The appropriate dose of the active agent amounts preferably up to 250 mg and preferaBl~ up to 200, especially up to lO0 mg for compound A and up to S0, prefera~ly up to 30, especially lO to 25 mg for compound B per day. For a rationally administrable dispersion quantity a concentration from lO to 80% of active agent in the matrlx~on the average up to 50%, e.g. 40% of compound A and 20 percent By weight of compound B are indicated.
If the chemical stability of the act~ve agent is not high, then the tempera~ure of the molten matrix material, e.g, of the polyalkylene glycol, should be kept appropriately low. If more active agent is added to the polyalkylene glycol, then can be dissolved at the maximum allowable temperature; the excess will not be dissolved, but will be incorporated as a suspension.
The undissolved fraction particles preferably should have a particle size of at most 100 micrometres.
After cooling of the suspension these particles may be found in the dispersion with an similar size in addition to the fraction of active agent, that was dissolved and after cooling can be found again in the form of crystals hav1ng a diameter of at most S micro-metres.
In the granulating process, briefly described above, the solid dispersion is preferably reduced to a particle size from 50 to 2000 micrometer, especially from 90 to lOOQ, mor particularly from 125 to 500 micrometer.
' .
The particle size of the granulate contributes to the controlled release effect according to the invention (larger narticles cause a greater decrease of the d~ssolution rate, see curves 19 to 22 in fig. 6; dissolved quantity in percent by weight versus time T;
an increasing particle size causes a decrease of the dissolution rate, curves 19 to 22 relate to sieve factors oF ~0 to 1~0, of 180 to 355, of 355 to 500 and of 500 to 710 micrometre respectively of the dispersion granulate of a 40% dispersion of compound A in polyethylene glycol 6000.
Summarizing, it may be concluded that the releaseof the ~harmaco-logically active agent can be controlled by changing the concen-tration of the active agent in the solld dispersion as well as by varying the particle size of the solid dispersion granulate.
Surprisingly, it has been established that when the dispersion granulate particles, e.g. those of Example 1, are brought into water, their matrix fraction is dissolved quickly and quantitatively.
The active agent particles which in the dispersion have for example a size of up to 5 micrometre, form coherent secondary structures, their density and diameter varying according to the concentration of the acttve agent in the matrix and the diameter of the granulate particles.
The present invention thus provides an secondary active agent structure, formed from the solid dispersion after selective extraction of the matrix material, e.g. in an aqueous medium.
This secondary structure may have a diameter comparable to that of the dispersion granulate. It shows in water a retarded disso-lution rate. It can ~e partially restored to its original particles of up to 5 micrometre by intensive ultrasonic treatment.
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Particles of active agent which in the dispersion granulate may have for example a diameter of up to lO0 micrometre are in the secondary structure, which has 6een proceeded from the particles of up to 5 micrometre, enclosed in an unchanged state.
S Since the original agent particles up to 5 micrometre and the additionally enclosed agent particles up to lO0 micrometre contribute to the controlled release effect, both their solid dispersions and secondary active agent structures belong to the present invention.
The diameter and the surface of the secondary structure particles of the active agent have been investigated~ They show irregular fissurelike channels and have an external and an internal surface.
Both the size and the structure of the external surface influence the dissolution rate in an,e.g. aqueous,solvent medium. The internal surface shows narrow pores up to l micrometre which hardly contribute to the release of active agent~ since if they contain a solvent medium, its mobi1ity is strongly reduced.
The size of the seconda~y structure corresponds to the size of the solid dispersion granulate particles, from which they originate.
After removal of the solvent medium, e.g. by drying, the speciFic surface and the pore volume are measurable.
The present invention provides the secondary structure of an active agent of a diameter of preferably from 50 to 2000, more particu-larly from 90 to 1000, especially from 125 to 500 micrometre, having a porous structure, characterized by a speciflc surface .~ ,, ~2~4~L
- 12 ~ 100-6373 of l to lS m2lg, preferably from 2 to 12 m2/g, measured according to the BET-method and by a pore volume of 20 to 95%, measured by mercury~porosimetry The solid dispersion particles as well as the secondary structure particles are usable for the preparation of pharmaceutical compounds.
The present invention thus provides also pharmaceutical compositions containing the solid dispersion granulate or the secondary structure particles.
Pharmaceutical compositions containing the solid dispersion yranulate can be considered as galenical precursor forms of corresponding compositions containing the secondary structure particles, since their beha~iour in the body-is comparable with that of pro-drugs.
For the preparation of the pharmaceutical oral administration forms containing the solid dispersion7 the granulate of the solid dispersion may be mixed in a conventional manner with suitable pharmaceutical excipients, e.g. a filling agent, such as lactose, a glidant, e.g. silicon dioxide and a lubricant, e.g. magnesium stearate (see. e.g. examples 2, 5 , 6 and 9) and optionally a desintegrant, such as crosslinked polyvinylpyrrolidone, e.g.
crosspovidone (see. e.g. examples 2, 3, 5 and 6), or sodium carboxymethylcellulose (see example 9) and may be manufactured to conventional solid oral administration forms, such as tablets or capsules.
For the preparation of tablets the solid dispersion granulate may preferably be mixed with e.g. lactose9 silicon7 dioxide and magnesium stearate (see example 4, 5, ~ and 9).
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The porous secondary structure agent particles are preferably used in capsules, since they are less able to resist the pressure for tabletting.
For the preparation of capsules, the solid dispersion granulate of the secondary structure agent particles may be mixed in conventional manner preferably with a placebo granulate from suitable exci pi ents like lactose, starch and polyvinylpyrrolidone and with a mixture of crospovidone,silicone dioxide and magnesium stearate (see examples 2 and 3). The desintegrant may be used for suspending the capsule content.
Generally pharmaceutical administration forms, especially capsules and to a lower extent tablets as well show, during the passage through the stomach, a drug burst, which can to a large extent be prevented by applying an enteric coating on it.Suitable enteric coatings include hydroxypropylmethylcellUloSephthalate (see example 3,5, 6 and 12). I~ the active agent is resorbed in the upper part of the intestin~s - dihydropyridines are such agents - then such a coating is very benefictal and does not impair the resorption process.
Tablets, which contain the components in compressed state, may need this coating to a lower extent, but then the desintegrant should be omitted (see the tablet of example 4, which contains no crosslinked polyvinylpyrrolidone).
We have established, that capsules or tablets without an enteric coating may be made if a hydrophobic excipient, such as a fatty acid glyceryl ester, is added to the solid dispersion ~see examples 8 and 9 and comparative test No. 4). This hydro-, ~
": , ` :
, phobic ester reduces the drug burst in the stomach and may not significantly disturb the resorption process in the intestines.
Such compositions may ~e prepared ~y dissolving the pharmacolo-gically active agent in the liquid matrix and emulgating the obtained mixture wi~h the hydrophobic substance, e.g. the fatty acid glyceryl ester, as much as possible, after which the obtained mixture may be solidified by cooling.
Preferred fatty acid glyceryl esters are physiologically acceptable esters~ like (Cl0~20)fatty acid, e.g, palmitic and/or stearid acid glyceryl esters. These esters may ~e, e.g. mono-, di- and/or triesters of glycerin.
The amount of fat is preferably up to 60 percent of the total weight of the solid dispersion, e.g. 5 to 60%, and is particularly up to 15 to 25%, e.g. 20%.
The sustained release compositions according to the invention may be used to administer very different, practically water insoluble classes of active agents. They may be used for their known indications.
The quantities of active agents to be administered may be dependent on various factors, e.g. the conditions to be treated, the duration of treatment desired and the rate of release of the active agents.
The amount of each active agent required and the rate of release may be determined using in vivo techniques, e.g. mea-suring the concentration of active agent in the blood serum.
The pharmaceutical compositions of e.g. the compounds A and B
may be used e.g. for the same indications as described in the European patent No. 150 and in the Brltish patent No. 2037766.
A~
2 6~ L
For the antihypertonic use e.g. up to 250, especially up to 200, particularly 50 to 100 mg of compound A and up to 50~ especially up to 25, particularly 10 to 20 mg of compound B are used per day.
In the drawings:
Figures 1-4 show conce~trations vs. time for compound A;
Figures 5 and 6 show the dissolution rate of compound A in vitro; and Figures 7 and 8 show concentrations vs. time for compound B.
lU The present invention provides especially a pharmaceutical compo-sition for plasma levels of 2 to ~ mg of compound A per ml during at least 22 hours, in the event that it contains one dosis of 50 mg of the active agent. Basis for this observation are the plasma level curves 1, 3, 4, 5 and 6 to 13 in fig. 1 to 4.
The present invention also provides a pharmaceutical composition for plasma levels of 1 to 2,5 mg of compound B) per ml, during at least 22 hours~ in the event that it contains one dosis of 10 mg of the active agent. Basis for this observation are the plasma level curves 23 and 26 in fig. 7 and 8.
The plasma level of compound A for curves 1 to 13 in fig. 1 to 4 ~concentrations vs. time) may be determined gaschromatographically.
A plasma sample of 1 ml, adjusted with NaOH to pH 13,was extracted with toluene, the toluene was evaporated and the residue dissolved in 0.5 ml of toluene. 2 microlitres of the formed solution were separated at 300C in a OV 17 column(6~ on Gaschrom Q 100-120 mesh) using a argon/methane gas (95:5 volume/
volume)mixture as a carrier gas(rate 60 ml/min). The analysis may be carried out using an electron capture detector. The retention time of compound A was 3.1 min.
The concentration of the compound was calculated by peak measure-ment in comparison to the peak of an internal standard. The detection limit is 0.5 mg of active agent per ml of plasma.
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The dissolution rate of compound A in vitro for curves 14 to 22, of compound C in example 13 and of nifedipine in example 1~
(dissolved quantities in percent ~y weight vs. time) was determined in 10~0 ml of solvent medium at 37C according to the Rotation Paddle-,~ethod (USP XX) at 30 rotations per min. For compound A
and for nifedipine an aqueous 0.1 HCl soluticn was used as the solvent medium. After 2 hours the pH was adjusted by addition of a tenside containing 6uffer solution of pH 6.8. Compound C was tested in a neutral tenside containing aqueous solution.
20 microlitres of a filtered sample of the solution of active agent and of a reference solution were separated chromatographically in 2 columns of a length of 10 cm and a diameter of ~.6 mm,contai-ning substance RP.18; 5 micrometre as a stationary phase and with methanollwater 85:15(v/v)as a mobile phase and at a pressure of 150 bar at room temperature and were measured at a wave length of 326 mm.
The plasma levels of compound B for curves 23 to 26 in fig. 7 and 8 were chromatographically determined as well. A plasma sample of 2 ml, adjusted with NaOH to a pH 13, was extracted with toluene. The toluene was evaporated and the residue dissolved in 25 microlitre of toluene. 2 microlitre of the formed solution were separated at a temperature of 300C in a OV 17 capillary column (internal diameter of 0.3 mm and a length of 25 m), using helium as a carrier gas; (pressure at the input: 0.7 atm. of excess pressure).
The analysis was carried out at a temperature of 300C using an electron capture detector and with an argonlmethane (90:10 vol/vol) gas mixture (rate 30 ml/min) as additional gas. The retension time of compound B) was 11.5 min.
~2~4~
The calculation of tKe concentration of compound B was carried out analogously as described for compound A . The detection limit is 50 picogram of active agent per ml of plasma.
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Example 1: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-carboxy-carbonyl-2,6-dimethyl-3-pyridincarboxylic acid ethylester (compound A) Preparation of the solid dispersion:
4 parts by weight of scaly polyethylene glycol 6000 are melted at 55 to 63C and heated to about 85C while stirring.
One part by weight of compound A are added and dissolved completely while stirring at a constant temperature. The solution is then rapidly cooled by pouring it into a metal sheet, where it solidifies in a layer thickness of about 2 mm. After cooling to room temperature the solidified layer is detached from the sheet, reduced to coarse pieces and then passed in stages through sieves of decreasing mesh (2.5, 1.0 and 0.5 mm~ or reduced to small pieces in a hammer-mill so that a granulate is produced, usable fo~the preparation of a tabletting or capsulating mixture.
Example 2-Hart gelatine capsule Components: quantities in mg 23 1. Compound A - polyethylene glycol 6000 granulate g20%), prepared according to example 1 250.0 2. Placebo granulate of Lactose 83 parts Cornstarch 10 parts Polyvinylpyrrolidon6 parts 41.Q
3. Crosslinked polyvinylpyrrolidone 6.0 4. Silicon dioxide 1.5 5. ~agnesium stearate 1.5 300.0 ., :
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19 _ 100-6373 Both granulates l.and 2 are mixed. Components 3.to 5.are mixed as well, after which the mixture of 1. and 2. is mixed with the mixture of 3. to 5. and is filled in gelatinecapsules of a suitable capacity.
Example 3:
The hard gelatine capsule of example 2 is enteric coated in conventional manner in Wurster column with a mixture of hydroxypropylmethylcellulosephthalate 33.3 mg and diethylphthalate 3.3 mg Example 4:
Tablet Components: quantity in mg 1. Compound A - polyethylene glycol 6000 granulate (20%), prepared according to example 1 250.0 2. Lactose, anhydrous 188.5 3. Silicon dioxide 2.5 4. Magnesium stearate 9.0 450.0 The components 1. to 4. are briefly mixed, the mixture is sieved (630 mikrometre mesh), mixed again and tabletted in conventional manner.
.. , _ mple 5:
Table Components: quantities in mg l. Compound A - polyethylene glycol 6000 ~ granulate (20%), prepared according to example l 250.00 2. Lactose, anhydrous 177.25 3. Crosslinked polyvinylpyrrolidone 11.25 4. Silicon dioxide 2.50 5. ~agnesium stearate 9.00 The components 1. to 5. are mixed and tabletted as described in example 4.
The kablet is enteric coated as described in example 3 with a mixture of hydroxypropylmethylcellulosephthalate 9 %
and diethylphthalate 9 % 50.00 500.00 Example 6:
In an analogous manner as described in example 1, a 40% dispersion of compound A in polyethylene glycol 6000 is prepared at a temperature of 125C. The dispersion granulate is,in a manner as described in examp1e 5, compressed t~ tablets containing 50 and 100 mg o~ active agent.
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Tablets Components: quantities in mg 1. Compound A - polyethylene glycol 6000 granulate (40~) 125.0 250.0 2. Lactose, anhydrous 65.0 130.0 3. Cross-linked polyvinylpyrrolidone 5.0 lO.0 4. Silicon dioxide 1.0 2.0 5. i~agnesium stearate 4.0 8.0 enteric coating * 20.0 40.0 220.0 440.0 * A coating of percents by weight hydroxypropylmethylcellulosephthalate 93 Titanium dioxide 3.5 Iron oxide, yellow 3.5 The coating is applied to in conventional manner in a Wurster column Comparative test No. 1 A conventional uncoated hard gelatinecapsule containing a granulate of components 1. to 5~ and an external phase of a mixture of components 6. to 9.
quantities in mg l. Compound A 50 0 2. Lactose 216.0 3. Cross-linked polyvinylpyrrolidone 6.0 4. Polyoxyethylene-polyoxypropylene polymer 10.0 5. Polyvinylpyrrolidone 7.5 6. Cross-linked polyvinylpyrrolidone 5.5
7. Polyethylene glycol 6000 (solubilizing agent) lO.0
8. Corn starch 52.0
9. Magnesium stearate 3.0 360.0 ' ' ' "' .
~2~
was compared with the enteric coated retarded capsule of example 3 and with the uncoated retarded capsule of example 2.
In 8 healthy fasted male volunteers of 19 to 40 years the enteric coated retarded capsules of example 3 produced almost constant plasma levels of compound A (about 5 nanogram/ml) from 3 hours till 28 hours after administration (mean curve 1 in fig. 1).
Conventional hard gelatin capsules caused in the same volunteers the conventional picture of mean curve 2 in fig. 1, the active agent for the most part being released within 6 hours. The areas under both curves 1 and 2 are almost the same: AUCoC~ * = 210 and 196.2 nanograms/ml/h respectively. This indicates that the capsule of the invention has no significant loss of bioavailability.
In a second test the uncoated retarded capsule of example 2 was administered to 8 healthy male volunteers. 4 of the volunteers were also participants in the first test with the enteric coated retarded capsule. In comparison to the conventional capsule (curve 2) a retard effect is obtained (mean curve 3, in fig. 1).
However, the uncoated retarded capsule of example 2 has a tendency to cause a drug burst (curve 3).
From both tests it can now be established, that the combination of the new solid dispersion granulate with the enteric coating has an excellent controlled release effect.
The retarded capsules of examples 2 and 3, particularly the enteric coated of example 3, make a once-a-day-administration possible;
of the conventional ~orm 2 to 3 capsules have to be taken a day in regular periods of time.
* = AUCG~ = Area under the curve (extrapolated to infinite) . ~
fl~L
Comparative test No. 2 The conventional uncoated hard gelati~ capsule of comparative test No. 1 was compared again, but instead with the enteric coated retarded tablet of example 5,and tested in another group of healthy male volunteers.
The enteric coated retarded tablet of example 5 produced plasma levels of the mean curve 4 in fig. 2 and the conventional capsule of comparative test No. 1 produced a mean result, comparable with curve 2. The enteric coated retarded tablet of example 5 produced practically ccnstant plasma levels of compound A (about 6 to 7 ng/ml), from 5 and till 32 hours after administration (curve 4).
Again, there ;s no significant loss in (relative) bioavailability, using the enteric coated retarded tablet It makes a once-a-day-administration possible. The conventional hard gelatine capsule lS has to be taken2 to 3 times a day.
Comparative test No. 3 .
In a further human study with 8 healthy male subjects, the normal uncoated capsule, described in comparative test No. 1, was compared in a cross-over design with three additional formu-lations, including the enteric coated retarded tablet of example 6 containing 50 mg of compound A in a 40% solid dispersion in polyethylene glycol 6000.
In this study all formulations were administPred to the fasted subjects with 150 ml of water. A standard breakfast was given 2,5 h later.
The mean curve 5 in fig. 3 shows the plasma levels of the enteric coated retarded tablet up to 72 hours.
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Concentrations between 3 and 5 nglml are obtained from 7 to 36 hours after digestion, a duration of absorption lasting 29 hours. In comparison to the normal capsule the relative bio-availability 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, indicating no loss of bioavailability.
A remarkable feature of the pharmacokinetic behaviour of this retard tablet is the relatively low intra individual variability, seen in the individual kinetic profiles curves 6 to 13 in fig. 4.
In all cases the plasma levels are seen to fall within the 2 to 8 ng/ml range with no significant drug burst occuring in any subject. Furthermore, the presence of the gastro-ristant coating gave a highly reproduceable lag time prior to absorption (2.6 ~ 0.8 h) when the tablets were administered in the fasting state.
These results demonstrate, that an enteric coated tablet composed of a 40% solid dispersion perform an excellent form to permit a once-a-day application of 50 mg and potentially higher doses, e.g. 100 mg of drug.
Example 7: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-d hydro-5-methoxy-carbonyl-2 _-dimethyl-3-pyridinecarboxylic acid iso-prop~ r (compound ~) Preparati-on of the solid dispersion and of the dispersion 25 granulate:
' -~L2~4~
- 25 - 1~0-6373 6 parts by weighk of polyethylene glycol 6000 are mixed with 2 parts by weight of a co~mercial mixture comprising mono-, di~ and triesters of pa,mitic and stearic acid and glycerol (Precirol*) and with 2 parts by weight of compound B, then melted at a temperature of 75 to 85C and dissolved as much as possible whi1e ~ntensive stirring at a constant temperature of 70C. The mixture is then cooled rapidly to room temperature by pouring it onto a precooled metal sheet and kept at 4C for 3 hours. It solidifies as a layer of approximately 4 mm thickness.
The solidified layer is reduced to coarse par~icles, which are passed through a hammer mill (type Fitzpatrick, USA) thus producing a granulate usable for the preparation of a tabletting or capsu-lating mixture.
The characteristic grain size of the RRS-B-distribution =
X'= ca 320 micrometre.
n = ca. 3 (reciprocal measure for the distribution range) (H. Sucker, c.s. Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart 1978, page 110).
Example 8 Tablet Components: quantities in mg:
l. Compound B - polyethylene glycol 6000 - fatty acid glyceryl ester mixture-granulate (produced according to example 7) 50 0 2. Lactose, anhydrous 68.8 3. Magnesium stearate 1.2 120.0 *Trademark of Gattefosse :,,~
The components l.and 2. are briefly mixed (5 min.). The mixture is sieved (mesh: 800 micrometres)~ sieved again (10 min.), mixed with component 3. (5 min.) and tabletted in conventional manner on a rotary tabletting machine.
The tablets have a diameter of 7 min. and show a compression strength of 46 Newton.
Example ~-.
T_blet Components: quantities in mg:
1. Compound B - polyethylene glycol 6000-fatty acid glyceryl ester mixture -granulate (according to example 7) 50.00 2. Lactose, anhydrous 61.42 3. Silicon dioxide 0.23 4. Sodium carboxymethylcellulose 2.20 5. Magnesium stearate 1.15 115.00 The components 1. 2. and 4. are briefly mixed (5 min.), the mixture sieved (mesh: 800 micrometres) and mixed again (10 min.).
The components 3. and 5. are mixed together with a part of the mixture of 1.,2. and 4., sieved (800 micrometres) and mixed with the remainder of the mixture of 1.,2. and 4. (5 min.).
Comparative test No. 4 A conventional uncoated hard gelatine capsule containing a mixture of components 1 to 6 ,.,,~
4~L
- 27 - lC0-6373 quantities in mg 1. Compound B 10.0 2. Lactose (filler) 167.0 3. Sodium laurylsulphate (solubilizing agent) 5.5 4. Silicon dioxide (glidant) 1.5 5. Corn starch (desintegrant) 128.0 6. Polyethylene glycol 60Q0 (solubilizing 8 0 agent) 320.0 was compared with th.e retarded tablet of example 8.
In 8fasted healthy male volunteers in an age of 19 to 40 years, the retarded tablet of example 8 sh.owed practically constant plasma levels of drug between 2.3 and 1 ng/ml and, on an average, between 1.5 and 1 ng/ml from 2 to 24 hours after administration (see mean curve 23 in fig. 7). The non retarded conventional capsule showed in the same volunteers the conventional picture of mean curve 24 and a drug release within 6 hours.
The areas under both curves 23 and 24 are practically the same:
By comparison of the AUC28 of curves 23 and 24 a relative bio-availability of even 96.~ % for the retard tablet of example 8 could be established.
The retard tablet of example 8 produced~compared with the con-ventional uncoated hard gelatine capsule, a hardly detectable drug burst.
Whereas 2 to 3 conventional capsules must be administered a day, divided over regular periods of time, the retarded tablet makes a once-a-day administration possible.
-. .
: :.. , ,, . . .:
E_ample 10;
Preparation of the solid dispersi4n and of the dispersion granulate;
~2~
was compared with the enteric coated retarded capsule of example 3 and with the uncoated retarded capsule of example 2.
In 8 healthy fasted male volunteers of 19 to 40 years the enteric coated retarded capsules of example 3 produced almost constant plasma levels of compound A (about 5 nanogram/ml) from 3 hours till 28 hours after administration (mean curve 1 in fig. 1).
Conventional hard gelatin capsules caused in the same volunteers the conventional picture of mean curve 2 in fig. 1, the active agent for the most part being released within 6 hours. The areas under both curves 1 and 2 are almost the same: AUCoC~ * = 210 and 196.2 nanograms/ml/h respectively. This indicates that the capsule of the invention has no significant loss of bioavailability.
In a second test the uncoated retarded capsule of example 2 was administered to 8 healthy male volunteers. 4 of the volunteers were also participants in the first test with the enteric coated retarded capsule. In comparison to the conventional capsule (curve 2) a retard effect is obtained (mean curve 3, in fig. 1).
However, the uncoated retarded capsule of example 2 has a tendency to cause a drug burst (curve 3).
From both tests it can now be established, that the combination of the new solid dispersion granulate with the enteric coating has an excellent controlled release effect.
The retarded capsules of examples 2 and 3, particularly the enteric coated of example 3, make a once-a-day-administration possible;
of the conventional ~orm 2 to 3 capsules have to be taken a day in regular periods of time.
* = AUCG~ = Area under the curve (extrapolated to infinite) . ~
fl~L
Comparative test No. 2 The conventional uncoated hard gelati~ capsule of comparative test No. 1 was compared again, but instead with the enteric coated retarded tablet of example 5,and tested in another group of healthy male volunteers.
The enteric coated retarded tablet of example 5 produced plasma levels of the mean curve 4 in fig. 2 and the conventional capsule of comparative test No. 1 produced a mean result, comparable with curve 2. The enteric coated retarded tablet of example 5 produced practically ccnstant plasma levels of compound A (about 6 to 7 ng/ml), from 5 and till 32 hours after administration (curve 4).
Again, there ;s no significant loss in (relative) bioavailability, using the enteric coated retarded tablet It makes a once-a-day-administration possible. The conventional hard gelatine capsule lS has to be taken2 to 3 times a day.
Comparative test No. 3 .
In a further human study with 8 healthy male subjects, the normal uncoated capsule, described in comparative test No. 1, was compared in a cross-over design with three additional formu-lations, including the enteric coated retarded tablet of example 6 containing 50 mg of compound A in a 40% solid dispersion in polyethylene glycol 6000.
In this study all formulations were administPred to the fasted subjects with 150 ml of water. A standard breakfast was given 2,5 h later.
The mean curve 5 in fig. 3 shows the plasma levels of the enteric coated retarded tablet up to 72 hours.
:
.
,, ~ ' 4~
Concentrations between 3 and 5 nglml are obtained from 7 to 36 hours after digestion, a duration of absorption lasting 29 hours. In comparison to the normal capsule the relative bio-availability 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, indicating no loss of bioavailability.
A remarkable feature of the pharmacokinetic behaviour of this retard tablet is the relatively low intra individual variability, seen in the individual kinetic profiles curves 6 to 13 in fig. 4.
In all cases the plasma levels are seen to fall within the 2 to 8 ng/ml range with no significant drug burst occuring in any subject. Furthermore, the presence of the gastro-ristant coating gave a highly reproduceable lag time prior to absorption (2.6 ~ 0.8 h) when the tablets were administered in the fasting state.
These results demonstrate, that an enteric coated tablet composed of a 40% solid dispersion perform an excellent form to permit a once-a-day application of 50 mg and potentially higher doses, e.g. 100 mg of drug.
Example 7: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-d hydro-5-methoxy-carbonyl-2 _-dimethyl-3-pyridinecarboxylic acid iso-prop~ r (compound ~) Preparati-on of the solid dispersion and of the dispersion 25 granulate:
' -~L2~4~
- 25 - 1~0-6373 6 parts by weighk of polyethylene glycol 6000 are mixed with 2 parts by weight of a co~mercial mixture comprising mono-, di~ and triesters of pa,mitic and stearic acid and glycerol (Precirol*) and with 2 parts by weight of compound B, then melted at a temperature of 75 to 85C and dissolved as much as possible whi1e ~ntensive stirring at a constant temperature of 70C. The mixture is then cooled rapidly to room temperature by pouring it onto a precooled metal sheet and kept at 4C for 3 hours. It solidifies as a layer of approximately 4 mm thickness.
The solidified layer is reduced to coarse par~icles, which are passed through a hammer mill (type Fitzpatrick, USA) thus producing a granulate usable for the preparation of a tabletting or capsu-lating mixture.
The characteristic grain size of the RRS-B-distribution =
X'= ca 320 micrometre.
n = ca. 3 (reciprocal measure for the distribution range) (H. Sucker, c.s. Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart 1978, page 110).
Example 8 Tablet Components: quantities in mg:
l. Compound B - polyethylene glycol 6000 - fatty acid glyceryl ester mixture-granulate (produced according to example 7) 50 0 2. Lactose, anhydrous 68.8 3. Magnesium stearate 1.2 120.0 *Trademark of Gattefosse :,,~
The components l.and 2. are briefly mixed (5 min.). The mixture is sieved (mesh: 800 micrometres)~ sieved again (10 min.), mixed with component 3. (5 min.) and tabletted in conventional manner on a rotary tabletting machine.
The tablets have a diameter of 7 min. and show a compression strength of 46 Newton.
Example ~-.
T_blet Components: quantities in mg:
1. Compound B - polyethylene glycol 6000-fatty acid glyceryl ester mixture -granulate (according to example 7) 50.00 2. Lactose, anhydrous 61.42 3. Silicon dioxide 0.23 4. Sodium carboxymethylcellulose 2.20 5. Magnesium stearate 1.15 115.00 The components 1. 2. and 4. are briefly mixed (5 min.), the mixture sieved (mesh: 800 micrometres) and mixed again (10 min.).
The components 3. and 5. are mixed together with a part of the mixture of 1.,2. and 4., sieved (800 micrometres) and mixed with the remainder of the mixture of 1.,2. and 4. (5 min.).
Comparative test No. 4 A conventional uncoated hard gelatine capsule containing a mixture of components 1 to 6 ,.,,~
4~L
- 27 - lC0-6373 quantities in mg 1. Compound B 10.0 2. Lactose (filler) 167.0 3. Sodium laurylsulphate (solubilizing agent) 5.5 4. Silicon dioxide (glidant) 1.5 5. Corn starch (desintegrant) 128.0 6. Polyethylene glycol 60Q0 (solubilizing 8 0 agent) 320.0 was compared with th.e retarded tablet of example 8.
In 8fasted healthy male volunteers in an age of 19 to 40 years, the retarded tablet of example 8 sh.owed practically constant plasma levels of drug between 2.3 and 1 ng/ml and, on an average, between 1.5 and 1 ng/ml from 2 to 24 hours after administration (see mean curve 23 in fig. 7). The non retarded conventional capsule showed in the same volunteers the conventional picture of mean curve 24 and a drug release within 6 hours.
The areas under both curves 23 and 24 are practically the same:
By comparison of the AUC28 of curves 23 and 24 a relative bio-availability of even 96.~ % for the retard tablet of example 8 could be established.
The retard tablet of example 8 produced~compared with the con-ventional uncoated hard gelatine capsule, a hardly detectable drug burst.
Whereas 2 to 3 conventional capsules must be administered a day, divided over regular periods of time, the retarded tablet makes a once-a-day administration possible.
-. .
: :.. , ,, . . .:
E_ample 10;
Preparation of the solid dispersi4n and of the dispersion granulate;
10 parts by weight of compound B are dissolved at a temperature of 125C in liquified polyethylene glycol 6000.
The mixture is quickly cooled to room temperature by pouring it onto a precooled metal sheet and is kept over night.
The solidified layer is reduced to coarse particles and passed through a hammer mill (typ Fitzpatrick, USA) to obtain a granulate, usa~le for the preparation of a tabletting or capsulating mixture.
Example 11:
Tablet Components: quantities in mg 1. Compound B - polyethylen glycol 6000 -granulate (20%, prepared according to example 10) 50-00 2. Lactose, anhydrous 63.85 3. ~agnesium stearate 1.15 115.00 The tablet is produced in an analogous manner as described in example 8 (the sieve had a mesh of 1250 micrometre).
Tablets: diameter 7 mm compression strength: 40 Newton ' `,' ~'` .:
.~ ;
'~ ' . .
.. : : . :
~L2 ~ L4~L
- 2~ - 100-6373 Example 12:
The tablet of example 11 is enteric coated in a conventional manner in a Wurster column with a mlxture of quantities in mg hydroxypropylmethylcellulosephthalate 13.8 Iron oxide pigment, red. 0.6 Titanium oxide 0.6 15.0 Comparative test No. 5 Two conventional not retarded capsules each containing a mixture of components 1 to 6 quantities in mg 1. Compound B 5.0 2. Lactose 172.0 3. Sodium laurylsulphate 5.5 4. Silicon dioxide 1.5 5. Corn starch 128.0 6. Polyethyleneglycol 6000 (solubilizing agent) 8.0 320.0 were compared with the enteric coated retard tablet of example 12.
The test was carried out as described in comparative test ~o. 4, with the difference that the number of volunteers was raised to 11.
The conventional not retarded capsules both together showed the conventional picture of the mean curve 25 in fig. 8, the drug was released within 10 hours.
~L2G444~
The enteric coated retarded tablet of example 12 produced a mean plasma level between 2.5 and 0.8 ng/ml of compound B (mean cur~e 26) from 3 to 28 hours after admintstration and had an undiminished relative bioavailability, is compared with the conventional capsules.
The enteric coated retard tablet of example 12 makes a once-a-day admin~stration possible, whereas the conventional capsule has to be ta~en regularly 2 to 3 times a day.
Example 13~ (5~-4-(2,1,3-benzoxadiazol-4-yl)-1,4~dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyr~dine-carboxylic-acid isopropylester (compound C) In an analogous manner as is described in the examples 1 and 7, a 20, 30, 40 and 50% dispersion of compound C in polyethylene glycol 6000 was prepared.
Of the obtained dispersion granulates which contained 50 mg of compound C, the dissolution rate was determined in an aqueous medium according to the Rotating-Paddle-~ethod (USP XX).
Dispersion granulate -Time in hours 20% 30% 40% 50%
O O O O O
2 lOG 86 54 27 6 90 72 4i3 ~ ~gjf~4~L
Nifedipine -Example 14 In an analcgous manner as is descri~ed in examples 1 and 7 a 20%
and a 40% dispersion of Nifedipine in polyethylene glycol 6000 was prepared.
Of the obtained dispersion granulates containing 50 mg Nifedipine the dissolution rates were determined in an aqueous medium according to the Rotating-Paddle-Method (USP XX).
Dispersi:on granulate Time in hours 20% 40%
-O ~) O
6 90 ~1 8 ~7 51 ~ 72 101 7g . ~
..
.
. ~
:: .. .. .... .
The mixture is quickly cooled to room temperature by pouring it onto a precooled metal sheet and is kept over night.
The solidified layer is reduced to coarse particles and passed through a hammer mill (typ Fitzpatrick, USA) to obtain a granulate, usa~le for the preparation of a tabletting or capsulating mixture.
Example 11:
Tablet Components: quantities in mg 1. Compound B - polyethylen glycol 6000 -granulate (20%, prepared according to example 10) 50-00 2. Lactose, anhydrous 63.85 3. ~agnesium stearate 1.15 115.00 The tablet is produced in an analogous manner as described in example 8 (the sieve had a mesh of 1250 micrometre).
Tablets: diameter 7 mm compression strength: 40 Newton ' `,' ~'` .:
.~ ;
'~ ' . .
.. : : . :
~L2 ~ L4~L
- 2~ - 100-6373 Example 12:
The tablet of example 11 is enteric coated in a conventional manner in a Wurster column with a mlxture of quantities in mg hydroxypropylmethylcellulosephthalate 13.8 Iron oxide pigment, red. 0.6 Titanium oxide 0.6 15.0 Comparative test No. 5 Two conventional not retarded capsules each containing a mixture of components 1 to 6 quantities in mg 1. Compound B 5.0 2. Lactose 172.0 3. Sodium laurylsulphate 5.5 4. Silicon dioxide 1.5 5. Corn starch 128.0 6. Polyethyleneglycol 6000 (solubilizing agent) 8.0 320.0 were compared with the enteric coated retard tablet of example 12.
The test was carried out as described in comparative test ~o. 4, with the difference that the number of volunteers was raised to 11.
The conventional not retarded capsules both together showed the conventional picture of the mean curve 25 in fig. 8, the drug was released within 10 hours.
~L2G444~
The enteric coated retarded tablet of example 12 produced a mean plasma level between 2.5 and 0.8 ng/ml of compound B (mean cur~e 26) from 3 to 28 hours after admintstration and had an undiminished relative bioavailability, is compared with the conventional capsules.
The enteric coated retard tablet of example 12 makes a once-a-day admin~stration possible, whereas the conventional capsule has to be ta~en regularly 2 to 3 times a day.
Example 13~ (5~-4-(2,1,3-benzoxadiazol-4-yl)-1,4~dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyr~dine-carboxylic-acid isopropylester (compound C) In an analogous manner as is described in the examples 1 and 7, a 20, 30, 40 and 50% dispersion of compound C in polyethylene glycol 6000 was prepared.
Of the obtained dispersion granulates which contained 50 mg of compound C, the dissolution rate was determined in an aqueous medium according to the Rotating-Paddle-~ethod (USP XX).
Dispersion granulate -Time in hours 20% 30% 40% 50%
O O O O O
2 lOG 86 54 27 6 90 72 4i3 ~ ~gjf~4~L
Nifedipine -Example 14 In an analcgous manner as is descri~ed in examples 1 and 7 a 20%
and a 40% dispersion of Nifedipine in polyethylene glycol 6000 was prepared.
Of the obtained dispersion granulates containing 50 mg Nifedipine the dissolution rates were determined in an aqueous medium according to the Rotating-Paddle-Method (USP XX).
Dispersi:on granulate Time in hours 20% 40%
-O ~) O
6 90 ~1 8 ~7 51 ~ 72 101 7g . ~
..
.
. ~
:: .. .. .... .
Claims (35)
1. A solid dispersion of a pharmacologically active agent in a crystalline matrix as a 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 concentration of above 5 percent by weight, and c. is present in the matrix at a concentration of above 5 percent by weight in a coherent crystalline form.
2. A dispersion according to claim 1 wherein the active agent is a dihydropyridine.
3. A dispersion according to claim 2 wherein the active agent is a 1,4-dihydro-3,5-dicarboxylic acid diester-2,6-dimethyl-pyridine.
4. A dispersion according to claim 1 wherein the active agent has an optionally substituted 4-phenyl- or a 4-phenyl derivative group.
5. A dispersion according to claim 4 wherein the active agent has a 2,1,3-benzoxadiazol-4-yl group.
6. A dispersion according to claim 5, containing the 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-ethoxy-2,6-dimethyl-3-pyridinecarboxylic acid ethylester as active agent.
7. A dispersion according to claim 5, containing the 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropylester as active agent.
8. A dispersion according to claim 1, wherein the matrix is a polyalkyleneglycol.
9. A dispersion containing 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine-carboxylic acid ethylester as active agent in a polyalkylene glycol matrix.
10. A dispersion containing 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester as active agent in a polyalkylene glycol matrix.
11. A dispersion according to claim 8 in a poly-(C2-3)alkylene glycol matrix.
12. A dispersion according to claim 11 in a polyethy-lene glycol.
13. A dispersion according to claim 12 in a polyethy-lene glycol having a molecular weight from 100 to 20,000.
14. A dispersion according to claim 1 having above 5 percent by weight of crystalline active agent particles of a diameter of up to 5 micrometres.
15. A dispersion according to claim 14, contain-ing additionally entrapped active agent particles of a diameter of up to 100 micrometres.
16. A dispersion according to claim 1, containing up to 80 percent of weight of active agent.
17. A dispersion according to claim 1 in a granulate form.
18. A dispersion according to claim 17, having a diameter of up to 2000 micrometres per granulate particle.
19. A secondary structure of an active agent, ob-tained from the solid dispersion according to claim 1, by selective removal of the matrix material.
20. A secondary active agent structure, obtainable from the solid dispersion according to claim 19 after removal of the matrix material with an aqueous medium.
21. A secondary active agent structure according to claim 20, irregularly penetrated by fissure like channels and containing small pores having a diameter of below 5 micrometres.
22. A secondary active agent structure according to claim 19 having a surface of 1 to 15 m2/g thereof, measured according to the BET-method and having a pore volume of 20 to 95%, measured by mercury-porosimetry.
23. A pharmaceutical composition comprising a dispersion according to claim 1 together with a pharmaceutically acceptable diluent or carrier.
24. A pharmaceutical composition comprising a secondary structure according to claim 19 together with a pharmaceutically acceptable diluent or carrier.
25. A pharmaceutical composition according to claim 23, in the form of a tablet.
26. A pharmaceutical composition according to claim 23 or 24, in the form of a capsule.
27. A pharmaceutical composition according to claim 23 or 24, in enteric coated form.
28. A pharmaceutical composition according to claim 6, 7 or 25, containing a solid dispersion and a fatty acid glycerol ester therein.
29. A pharmaceutical composition according to claim 6 or 7 for oral administration once a day, in unit dosage form containing up to 250 mg of active agent.
30. A pharmaceutical composition for oral administra-tion once a day, containing 4-(2,1,3-benzoxadiazol-4-yl)-1, 4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid ethylester as an active agent, together with a pharmaceutically acceptable carrier or diluent, said composition being capable of producing on administra-tion orally a plasma level of 2 to 8 ng of active agent/ml for at least 22 hours, in the event that it contains one dose of 50 Mg of 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid ethylester as active agent.
31. A pharmaceutical composition for oral administra-tion once a day containing 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester as an active agent together with a pharmaceutically acceptable carrier or diluent, said composition being capable of producing on administration orally a plasma level of 1 to 2.5 ng of active agent/ml for at least 22 hours, in the event that it contains one dose of 10 mg of 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester as active agent.
32. A process for the preparation of a solid disper-sion of a pharmacologically active agent in a crystalline matrix as a carrier, characterized in that an active agent having a maximum solubility of 0.01% in waler at 37°C, is dissolved at a concentration of above 5 percent by weight in a liquified matrix and the obtained mixture is transformed to a solid form and the active agent is crystallized.
33. A process for the preparation of a pharmaceuti-cal composition, characterized in that the product of the process according to claim 32 is reduced to granulate particle form and is formulated into tablets or capsules as unit dosage forms.
34. A process for the preparation of a secondary structure of an active agent, characterized in that the product of the process according to claim 32 is reduced to granulate particle form and the matrix material is selectively removed.
35. A process for the preparation of a pharmaceuti-cal composition, characterized in that the product of the process according to claim 34 is encapsulated in capsules.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3422083.6 | 1984-06-14 | ||
| DE3422083 | 1984-06-14 | ||
| DEP3442566.7 | 1984-11-22 | ||
| DE3442566 | 1984-11-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1264441A true CA1264441A (en) | 1990-01-16 |
Family
ID=25822108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000483768A Expired CA1264441A (en) | 1984-06-14 | 1985-06-12 | Galenical retard form |
Country Status (21)
| Country | Link |
|---|---|
| AT (1) | AT391806B (en) |
| AU (2) | AU587190B2 (en) |
| BE (1) | BE902626A (en) |
| CA (1) | CA1264441A (en) |
| CY (1) | CY1635A (en) |
| DE (1) | DE3520184C2 (en) |
| DK (1) | DK167649B1 (en) |
| ES (1) | ES8702141A1 (en) |
| FR (1) | FR2565822B1 (en) |
| GB (3) | GB2160100B (en) |
| GR (1) | GR851430B (en) |
| HK (1) | HK25192A (en) |
| HU (1) | HU198844B (en) |
| IE (1) | IE58834B1 (en) |
| IL (1) | IL75490A0 (en) |
| IT (1) | IT1200080B (en) |
| LU (1) | LU85946A1 (en) |
| NL (1) | NL194389C (en) |
| NZ (1) | NZ212390A (en) |
| PT (1) | PT80635B (en) |
| SE (1) | SE504583C2 (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1187751B (en) * | 1985-10-15 | 1987-12-23 | Eurand Spa | PROCEDURE FOR THE PREPARATION OF SOLID FORMULATIONS OF NIFEDIPINE WITH HIGH BIO AVAILABILITY AND WITH PROLONGED EFFECT AND FORMULATIONS SO OBTAINED |
| US4816263A (en) * | 1987-10-02 | 1989-03-28 | Alza Corporation | Dosage form for treating cardiovascular diseases comprising isradipine |
| EP0406315B1 (en) * | 1988-03-24 | 1992-11-11 | Bukh Meditec A/S | Controlled release composition |
| GR1000270B (en) * | 1988-09-30 | 1992-05-12 | Alza Corp | Dose for cardiovascular troubles therapy |
| DK469989D0 (en) * | 1989-09-22 | 1989-09-22 | Bukh Meditec | PHARMACEUTICAL PREPARATION |
| MX9300110A (en) * | 1992-01-13 | 1994-07-29 | Gerhard Gergely | PHARMACEUTICAL PREPARATION IN THE FORM OF AN EFFERVESCENCE OR DISINTEGRATION TABLET OR OF AN INSTANT-TYPE GRANULATE AND PROCEDURE FOR ITS PREPARATION. |
| DE4201179A1 (en) * | 1992-01-17 | 1993-07-22 | Alfatec Pharma Gmbh | Granulates or pellets comprising dispersion of active agent in hydrophilic macromolecules - are e.g. for treatment of depression, hypertension, rheumatism, etc. |
| US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US6726930B1 (en) | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5773025A (en) | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
| GB2281697A (en) * | 1993-09-14 | 1995-03-15 | Euro Celtique Sa | Laxative compositions in capsules |
| WO1998001117A1 (en) | 1996-07-08 | 1998-01-15 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
| DE19710009A1 (en) * | 1997-03-12 | 1998-09-24 | Knoll Ag | Multi-phase preparation forms containing active ingredients |
| US6056977A (en) * | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| US6787157B1 (en) | 1998-03-10 | 2004-09-07 | Abbott Laboratories | Multiphase active ingredient-containing formulations |
| EP1189599A2 (en) * | 1999-06-11 | 2002-03-27 | Eli Lilly And Company | Pharmaceutical materials and methods for their preparation and use |
| US7001892B1 (en) | 1999-06-11 | 2006-02-21 | Purdue Research Foundation | Pharmaceutical materials and methods for their preparation and use |
| JP3462490B2 (en) * | 1999-08-04 | 2003-11-05 | 山之内製薬株式会社 | Stable oral pharmaceutical composition |
| IL143375A0 (en) | 1999-09-30 | 2002-04-21 | Penwest Pharmaceuticals Co | Sustained release matrix systems for highly soluble drugs |
| CA2434835A1 (en) * | 2001-02-13 | 2002-08-22 | Astrazeneca Ab | Novel modified released formulation |
| US7135436B2 (en) | 2003-05-05 | 2006-11-14 | J.F. Daley International, Ltd. | Solid algicide, preparation and usage in recirculating water |
| EP1690528A1 (en) | 2005-02-11 | 2006-08-16 | Abbott GmbH & Co. KG | Process for the preparation of dosage forms comprising a solid dispersion of a microcrystalline active agent |
| WO2008070118A1 (en) | 2006-12-05 | 2008-06-12 | Landec Corporation | Drug delivery |
| US8399007B2 (en) | 2006-12-05 | 2013-03-19 | Landec Corporation | Method for formulating a controlled-release pharmaceutical formulation |
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| MX2011001864A (en) * | 2008-08-20 | 2011-06-20 | Univ Texas | Hot-melt extrusion of modified release multi-particulates. |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1617362A1 (en) * | 1967-11-17 | 1971-03-25 | Beiersdorf Ag | Process for the production of medicaments with delayed release of active substances in the form of capsules |
| DE2400819C2 (en) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Process for the production of solid preparations of poorly soluble active pharmaceutical ingredients in extremely fine distribution |
| DE2546577B2 (en) * | 1975-10-17 | 1981-04-02 | Sandoz-Patent-GmbH, 7850 Lörrach | Solid substances made from polyvinylpyrrolidone and ergot alkaloids |
| GB1504553A (en) * | 1975-11-17 | 1978-03-22 | Sandoz Ltd | Tablet formulations |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| CH639659A5 (en) * | 1978-12-18 | 1983-11-30 | Sandoz Ag | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| FI64938C (en) * | 1977-06-20 | 1984-02-10 | Sandoz Ag | PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC THERAPEUTIC BENSOX A- AND OX BENZOTIADIAZOLYL-1,4-DIHYDROPYRID DERIVATIVES |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
| DK154607C (en) * | 1978-12-21 | 1989-06-05 | Sandoz Ag | PROCEDURE FOR PREPARING A PHARMACEUTICAL FORM FOR ORAL ADMINISTRATION OF ERGOTAL KALOIDS |
| DE2904310A1 (en) * | 1979-02-05 | 1980-08-07 | Boehringer Mannheim Gmbh | MOLDINGS WITH RETARDED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
| JPS56115726A (en) * | 1980-02-20 | 1981-09-11 | Kaken Pharmaceut Co Ltd | Pharmaceutical containing nifedipine |
| DE3033919A1 (en) * | 1980-09-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
| US4442112A (en) * | 1981-09-02 | 1984-04-10 | Sandoz Ltd. | Dihydropyridine derivatives useful in treating vascular headaches |
| DE3270785D1 (en) * | 1981-10-29 | 1986-05-28 | Bayer Ag | Process for preparing solid fast-releasing drug formulations of dihydropyridines |
| CA1208558A (en) * | 1982-10-07 | 1986-07-29 | Kazuo Kigasawa | Soft buccal |
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
-
1985
- 1985-05-31 NL NL8501578A patent/NL194389C/en not_active IP Right Cessation
- 1985-05-31 HU HU852126A patent/HU198844B/en unknown
- 1985-06-05 DE DE3520184A patent/DE3520184C2/en not_active Expired - Lifetime
- 1985-06-10 FR FR858508850A patent/FR2565822B1/en not_active Expired
- 1985-06-10 BE BE1/011271A patent/BE902626A/en not_active IP Right Cessation
- 1985-06-12 PT PT80635A patent/PT80635B/en unknown
- 1985-06-12 IE IE146085A patent/IE58834B1/en not_active IP Right Cessation
- 1985-06-12 ES ES544075A patent/ES8702141A1/en not_active Expired
- 1985-06-12 DK DK264785A patent/DK167649B1/en not_active IP Right Cessation
- 1985-06-12 NZ NZ212390A patent/NZ212390A/en unknown
- 1985-06-12 CA CA000483768A patent/CA1264441A/en not_active Expired
- 1985-06-12 IL IL75490A patent/IL75490A0/en not_active IP Right Cessation
- 1985-06-12 AT AT0174885A patent/AT391806B/en not_active IP Right Cessation
- 1985-06-12 AU AU43486/85A patent/AU587190B2/en not_active Ceased
- 1985-06-12 GR GR851430A patent/GR851430B/el unknown
- 1985-06-12 GB GB8514855A patent/GB2160100B/en not_active Expired
- 1985-06-13 LU LU85946A patent/LU85946A1/en unknown
- 1985-06-13 SE SE8502950A patent/SE504583C2/en not_active IP Right Cessation
- 1985-06-13 IT IT8548210A patent/IT1200080B/en active
-
1987
- 1987-11-19 GB GB8727055A patent/GB2196851B/en not_active Expired
- 1987-11-19 GB GB8727056A patent/GB2196852B/en not_active Expired
-
1989
- 1989-11-09 AU AU44543/89A patent/AU4454389A/en not_active Abandoned
-
1992
- 1992-04-02 HK HK251/92A patent/HK25192A/en not_active IP Right Cessation
- 1992-11-06 CY CY1635A patent/CY1635A/en unknown
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