MetyylilitiumProcess for the preparation of steroids having a dihydropyridine calcium channel steroidien valmistus used siumkanavan long-acting sustained release 1 88 5 The present invention relates to a method of steroids Steroidien valmistus ester, with a dihydropyridine calcium channel blocker used avlmistus a therapeutically effective amount of a long-acting steroidien valmistus release. Calcium channel blockers are a relatively asket louse found a class of compounds with a broad spectrum of characteristics which are valmistks in the treatment of cardiovascular and cerebrovascular diseases. Clinical applications in which this class of compounds has been found to be useful therapeutic properties are the treatment of classic angina 15 pectoris, due to spasm of blood vessels pectoris, prohormone trenbolone pectoris, acute myocardial infarction, cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial hypertension, and cardiomyopathies. Compounds which represent some of these classes steroidien valmistus nicardipine, verapamil, diltiazam, perhexiline and lidoflazine. It is known, for example, that 4- 2'-nitrophenyl -2,6-dimethyl-l, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in the skull siumkanavaa blocking activity US-A-3
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Process for the preparation of steroids having a dihydropyridine calcium channel blocker used siumkanavan long-acting sustained release 1 88 5 The present invention relates to a method of steroids Val ester, with a dihydropyridine calcium channel blocker used in a therapeutically effective amount of a long-acting sustained release. Calcium channel blockers are a relatively asket louse found a class of compounds with a broad spectrum of characteristics which are useful in the treatment of cardiovascular and cerebrovascular diseases.
Clinical applications in which this class of compounds has been found to be useful therapeutic properties are the treatment of classic angina 15 pectoris, due to spasm of blood vessels pectoris, angina pectoris, acute myocardial infarction, cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial hypertension, and cardiomyopathies.
Compounds which represent some of these classes include nicardipine, verapamil, diltiazam, perhexiline and lidoflazine. It is known, for example, that 4- 2'-nitrophenyl -2,6-dimethyl-l, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in the skull siumkanavaa blocking activity US-A-3 Further to this structural and pharmacologic class of compounds included is described in US-A-3 4-pyrimidyl-1,4-dihydropyridine derivatives , US-A-3 cyanophenyl-1,4-dihydropyridiinijohdannai set , German Patent Applications 1 n-a-alkyl-1,4-dihydropyridine derivatives , 1 4-nit ro and other groups, substituted phenyl-1,4-dihydropyridine derivatives , 1 sulfur containing 4-aryl-Li 1,4-dihydropyridine derivatives , 2 1,4-di hydropyridine-3,5-dicarboxylic acid unsaturated alkyl esters , 2 3-alkanoyl-l, 4-dihydropyrimidine-pyrimidinecarboxylic acid esters , and U.
Other 1,4-dihydropyridine compounds with cardiovascular activity, is described in U. Patents 3 and 3 , German Offenlegungsschrift 1 and DE-patent publication 17 92 Several compounds of this group is known to be potent calcium channel blocking activity. They are highly soluble in lipids, which is why they are widely distributed to tissues of the body at a constant speed. They are also rapidly absorbed after oral administration, peak plasma levels of about an hour TMX.
These yhdis hardware elimination half-life is usually a coffee Desta five hours, which is why conventional oral dosage forms have to be administered three or four times a day. In addition, some of the compounds, in particular nikardi-silicon, have an extensive first-order metabolism. The preparation and use of nicardipine and other related compounds, and their pharmaceutically acceptable salts of the compounds 35 are described in patent US-A-3 , shown here as a reference.
Today, most economical way to dispense dihydropyridine most therapeutic applications, the calcium channel blocker is an oral dosage form. These are typically compressed tablets, hard gelatin capsules, 5 of which are filled with powdered mixture, or as soft gelatin capsules which are filled with a solution and will generally be administered three or four times a day. However, conventional release oral dosage forms an-dihydropyridines are not well suited for carrying out 10, but the calcium channel blocking therapy.
Abdominal acidic pH, the solubility of the basic dihydropyridines is relatively high, and this leads to a rapid disintegration and absorption. Since the pH of the gastrointestinal tract increases when going forward, dihydropyridine solubility, and at the same time 15 the rate of degradation is reduced. Thus, conventional-release oral dosage forms release calcium channel blocker more rapidly the acid in the abdominal area and a slower rate less acidic intestinal region.
Such a dosage-dependent release profiles of organizations naturally calcium-channel blocker 20 location of the digestive area.
Thus, there is need for a sustained-release a dosage filtrate to be given the sustained release properties that provide therapeutic calcium channel blocker plasma concentrations when the dosage form is administered less frequently 25, preferably once or twice per day.
In addition, bringing convenience to the patient such a sustained dosage form would minimize undesirable fluctuations in plasma concentration of the drug. Patent 4 describes nicardipine 30 and the preparations and dosage forms that provide some form of regulation of the solubility of related compounds, and thus the delayed release of the drug. As described in the patent, forming a powder containing amorphous nicardipine, polyethylene oxide and other additive agents 35, and then this may be formed into granules, tablets, pills or capsules by conventional means.
The product should be nicardipine or salt thereof be in amorphous form, in combination with a polyethylene oxide powder composed of dust or granules. The preparation may further contain a pH-dependent solubility of the substance 5 in the regulation, such as methacrylic acid and methacrylic acid ester copolymer.
However, the manufacture of the drug in the amorphous form, the addition of polyoxyethylene, and the coating of pills or granules of the necessary solubility and vapautumisominai 15 to provide the properties are time-consuming and expensive to manufacture. Muitakin rakeisia ja erityisesti kalsiumkanavaa salpaavia valmisteita, jotka on valmistettu pH-riippuvaisen sitojan kanssa, tunnetaan. Other granular and especially the calcium channel-blocking products, which are prepared with the pH-dependent binder, is known.
However, the manufacture of these products has required the use of an organic solvent 20, and this must then be removed by complex and long drying methods.
In these products, it is necessary to use a sustained-vapaututuvaa or I-bacterial coating material in order to achieve a suitable control of solubility.
Consequently, a pharmaceutical Val preparation is to provide a therapeutically effective dihydropyridine used in blocking calcium channels in the plasma concentration when administered as infrequently as twice daily, to avoid dose dumpausvaikutus, and which can be easily and economically fabricated, no particles containing the drug via, which are practically composition even and regular in shape with a shape suitable for hard gelatin capsules and other oral and parenteral dosage form-an.
These are prepared by using organic solvents, they are cylindrical in shape and, A is the exception, they have a viscosity-enhancing agent. The closest prior art 5 represents the composition A. The composition is not at all characterized as cited above.
Compositions B and C therefore operate diffuusioit mechanism, and thus do not represent very closely technology. According to the publication the formulation E, plasma levels were less variable, the peak plasma level was lower and the duration of action was longer than both the commercially available SA fine particle preparation and formulation B are concerned. Edullisena pidetty formulaatti E on pH: The preferred formulation E is a pH-independent formulation, so the publication teachings, no one had started a pH dependent on the compositions of the present invention.
According to the publication the pH-dependent particles are applied to the cellulose-le-mikrokiteisel using evaporative. According to the teachings of the publication can not be prepared from the compositions described herein, as it means that the formulation is coated with microcrystalline cellulose and the water is used in the formulation as a solvent. In the compositions disclosed is not a result of organic solvent residues 30 contained therein can be administered to a human without the permission of the health authorities.
This is obviously a contributing factor to the fact that all tests have been carried in rabbits. According to this invention no organic solvents; 35 required.
Organic solvents such as acetone, residue is very difficult to remove a product and can have good 8 88 long-term eg. The toxic on the tip humans. For this reason, it is important to prepare such compositions that do not contain traces of organic solvents, when it is desired to provide a composition for humans. The compositions do not contain viscosity-increasing substances. The particle size, density porosity , and the individual poimullisuus is described in detail.
According to the publication, the pH of the composition riippuvainene 15 passed mesh sieve to form the compacted material into a cylindrical shape. The material removed from sieve spatula, and a granulafraktio with a specific mesh size. The invention provides a sustained release of hiinhibited-release pharmaceutical preparation which can be administered in a therapeutically effective amount of a dihydropyridine calcium channel blocker, which comprises essentially spherical, uncoated, non-convoluted particles having diameters of not more than 1.
In preparation can be treated with cardiovascular verisuonisai rauksia mammal. Figure 1 is a graphical representation of the results of the test described in Example 5, and the image of nicardipine hydrochloride comparative plasma concentration profiles obtained from the administration of conventional immediate-release dose-. Figure 2 is a graphical representation of the results of the test described in Example 7, and illustrates nicardipine hydrochloride 5 comparative plasma concentration profiles obtained from the administration of conventional rapid acting dosage form and a long acting dosage form, prepared in accordance with the present invention.
Figure 3 is a graphic representation of the results of 10 test described in Example 9, and it describes a nicardipine hydrochloride comparative plasma concentration profiles obtained from the administration of conventional rapid acting dosage form Dosage Form A and two long acting dosage forms prepared according to this invention an dosage forms B and C.
In this disclosure, the following terms have the meanings described below unless otherwise indicated: Termi "alkyyli" viittaa suoraketjuiseen tai haarautuneeseen hiilivetyketjuun, jossa on hiiliatomia. The term "alkyl" refers to a straight or branched hydrocarbon chain having carbon atoms.
Pre alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. The term "alkoxy" refers to a group of the formula -OR wherein R is alkyl as defined above. The term "alkylenyylioksialkyyli" tarkittaa -Ra0R group of the formula wherein Ra is alkylenyl and R is alkyl as defined above. Chlorine is the most preferred halogen substituent in accordance with the present invention to be used as a blocking agent for calcium channel-1,4-dihydropyridine phenyl ring.
The nitro substituent is most preferred in accordance with this invention 35 to be used as a blocking agent for calcium channel-1,4-dihydropyridine phenyl ring. U U The term "aryl" refers to a cyclic gay and pilasters heterocyclyl group, which is substantially aromatic in nature. Examples of aryl groups include phenyl, naphthyl style, imidazolyl, pyrrolyl, pyridyl, thienyl, and the 5 like.
Termi "aralkyyli" viittaa alkyyliaryyliryhmiin. The term "aralkyl" refers to an aryl group. The terms "phenyl alkyl" and "naphthylalkyl" refers to radicals having the structure of, respectively, 10 15 wherein R is alkyl as defined above. The terms "optional" and "optionally" means that the after described event or circumstance may or may not occur, and the description includes instances where said event or circumstance 20 occurs and instances in which it does not.
For example, "optionally substituted phenyl" means that the phenyl can be substituted or unsubstituted and that the description includes both substituted and unsubstituted phenyl. The phrase "optional pharmaceutical additives" 25 means that the composition or dosage form as described above may or may not contain other pharmaceutical additives as those which have been specifically described to be present, and that the composition or dosage form so described includes those in which the possible additives are to be included and, '30 where they are not.
The term "pharmaceutically acceptable acid addition salts" refers to salts of the present compound having the desired pharmacological activity and which are not biologically or otherwise undesirable. This compound can also be used in the name of 1,4-dihydro-2,6-dimethyl 3-nitrophenyl ,5-pyridinedicarboxylic acid methyl 2- [methyl phenyl-methyl amino] ethyl ester or 3; 5-pyridiinikarboksyyli acid 1,4-dihydro-2,6-dimethyl 3-nitrophenyl -, methyl 2- [methyl phenylmethyl amino] ethyl ester, mono-hydrochloride, or 2 2- Benzyl Jetyylimetyy yl-1,4-dihydro-2,6-dimethyl m-nitrophenyl -3,5-pyridine diinikarboksylaatin monohydrochloride.
The terms "fast release" and "conventional release" refer to calcium channel salpaajavalmisteeseen, 5 that practically completely dissolved and absorbed in the stomach or upper gastrointestinal tract. The terms "long acting" and "sustained release" refer to calcium channel salpaajavalmisteisiin, 10 are slowly and uniformly dissolved and absorbed in the stomach and gastrointestinal tract for at least two hours.
Preferred sustained-release preparation and an-dosage form is the plasma concentration profiles suitable for twice daily administrable dosage forms. The pharmaceutical preparations 15 described herein, dosage forms and methods can be used to prepare a long-acting sustained-release preparation of any 1,4-dihydropyridine derivative which has the effect of calcium channel antagonist.
According to the invention obtained from long-term sustained-release pharmaceutical preparations are spheroids, which are essentially spherical with a particle particles, which is flat, not wrinkled surface. In contrast to conventional granules, which may be substantially spherical uloimmilta surface dimensions, but are actually loose particulate aggregates with highly wrinkled surface and the surface area ratio of the ring 20 radially precipitation range of 0.
As used herein, surface-alasadi calculated according to the following formula: The projected area and projected onto the circumferential uurteineen or projections are determined by the projected image of the article. As used herein, "wavy" 35 refers to the outermost surface, which virtually absent grooves, craters and other surface irregularities 15 88 heap. The terms "spheroids" and "spherical particles" are used interchangeably herein.
Further, in contrast to conventional granules, the spheroids of this invention are relatively tihei-5 s. Steroid flat surface and low porosity allows a substantially better control of the solubility than can be achieved with conventionally manufactured granules.
The term "essentially aqueous wet mass" refers to a powder mass which has been wetted with a substantially aqueous binder solution to a consistency suitable for extrusion. The powder mass is made by dry mixed-active agent s and any possibility set, the pharmaceutical additives such as a diluent. In a preferred embodiment 30 of this invention, the pH dependent binder is dissolved or dispersed in an aqueous sitojailuokseen used to wet the dry powder mass.
Pin 35 may in some cases be advantageous to include part of the pH-dependent binder or all of the IE 88 dry powdery mass prior to wetting with water or other essentially aqueous binder solution. Regardless Mixing of the pH-dependent binder in its dry powdered or aqueous-5 kostutusliuok to, or both, for shaping and compressing must be sufficient to allow the active material is thoroughly uniform mixture with a binding agent and possible other additives to the wet stock mixing of the components.
These can be diluents such as lactose, mannitol, dry starch, microcrystalline cellulose cellulose, and the like, additional binders such as starch, gelatin, sugars, carboxymethylcellulose, methylcellulose, carboxymethylcellulose, and the like, lubricants, such as talc and magnesium stearate, coloring agents, and flavors.
The wet mass is then extruded through a die 20 to give a rod-like, substantially cylinder-like pieces having diameters of not more than 1. As used herein, the term "extrusion" refers to the process of forming a cohesive rod-shaped, substantially cylindrical material 25 having a certain cross-section by forcing the wet mass is a container having a large diameter, through a nozzle having a small diameter, so that the product substantially retains the nozzle through surgery.
These rod-like pieces can then be formed into spheres, as described below 30, and for this reason, it is important that they are substantially cylindrical and of relatively uniform cross section. The compression step may also have more material density low porosity , and further condensation takes place in the ball forming step. In general, these methods are based on the development of a sufficiently high continuous pressure with which the material is caused to flow and to maintain the shape when it exits the die.