SUSTAINED-RELEASE DIHYDROPYRIDINE FORMULATION

Abstract: A long acting sustained release pharmaceutical composition for dihydropyridine calcium channel blockers wherein the calcium channel blocker and a pH-dependent binder are intimately admixed in essentially spherically shaped non-rugose particles of up to 1.2 mm in diameter.

Description: This invention concerns long acting sustained release pharmaceutical compositions and dosage forms for dihydropyridine calcium channel blockers. Calcium channel blockers are a relatively recently discovered class of compounds which possess a wide spectrum of properties useful in the treatment of cardiovascular and cerebrovascular disorders. Among the clinical applications for which this class of compounds has shown some useful therapeutic properties are the treatment of classic exertional angina, vasospastic angina, angina pectoris, acute myocardial infarction, cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial hypertension, and cardiomyopathies. Several structural classes of compounds are known which exhibit calcium channel blocking utility. Compounds representative of some of these classes include nicardipine, verapamil, diltiazam, perhexiline and lidoflazine. The structural class of calcium channel blockers of interest in this invention, of which nicardipine is a member, are 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives of the general formula: in which X is hydrogen or one or more substituents such as nitro, halo and trifluoromethyl, and R₁ and R₂ are variously substituted alkyl, aryl or aralkyl groups or one of R₁ and R₂ is hydrogen. Many compounds within this general class are known and have been shown to have calcium channel blocking activity. It is known, for example, that 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester shows calcium channel blocking activity (US-A-3 644 627). Other compounds within this structural and pharmacologic class include those disclosed in US-A-3 511 837 (4-pyrimidyl-1,4-dihydropyridine derivatives), US-A-3 691 177 (cyanophenyl-1,4-dihydropyridine derivatives), DE-A-1 813 436 (N-alkyl-1,4-dihydropyridine derivatives), 1 963 185 (4-nitro and other group substituted phenyl-1,4-dihydropyridine derivatives), 1 963 186 (sulfur containing 4-aryl-1,4-dihydropyridine derivatives), 2 005 116 (1,4-dihydropyridine-3,5-dicarboxylic acid unsaturated alkyl esters), 2 003 146 (3-alkanoyl-1,4-dihydropyridine-5-carboxylic acid esters, and US-A-3 511 837 (1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-3,5-pyridine dicarboxylic acid diethyl ester). Other 1,4-dihydropyridine compounds with cardiovascular activity are disclosed in 3 644 627 and 3 485 847, in DE-A-1 670 827 and in DE-B 17 92 764. Calcium channel blockers of particular interest in this invention are compounds selected from the group represented by the formula: where; R₁ is -NO₂, -CF₃, or halo; R₂ is alkyl or -CH₂CH₂OCH₃; and R₆ is hydrogen or alkyl; and R₃ is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted naphthyl alkyl, or in which: A is alkylene; R₄ is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and R₅ is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof. Several compounds within this group are known to possess a high degree of calcium channel blocking activity. These include, for example, 4-(2′-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, generic name: nifedipine (US-A-3 644 627), 4-(3′-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid di-n-propyloxyethyl ester, generic name: niludipine, 4-(3′-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester, generic name: nitrendipine, 4-(3′-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(2-methoxyethyl) ester, generic name: nimodipine, 4-(2′-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-isobutyl ester, generic name: nisoldipine, 4-(2′,3′-dichloro)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester, generic name: felodipine, 4-(3′-nitro- phenyl)-2,6-dimethyl-1,4- dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-β-(N-benzyl-N-methylamino)-ethyl ester, generic name: nicardipine, and 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2[4-(2,3-dihydroxy-propoxy)phenyl]-ethoxycarbonyl)-1,4-dihydropyridine (US-A-4 595 690). Calcium channel blockers of the 1,4-dihydropyridine class share a number of pharmacological and pharmacokinetic properties in common which render them well suited to administration by the long acting sustained release methods of this invention. They are drugs which are extensively lipid-soluble and therefore are widely and extensively distributed within body tissues at steady state. They are also rapidly absorbed after oral administration, showing peak plasma levels within approximately about one hour (T max ). The half-life of elimination of these compounds is generally in the range of two to five hours, thus necessitating administration of standard oral dosage forms three to four times daily. Additionally, some of the compounds, in particular, nicardipine, undergo extensive first pass metabolism. The pharmaceutical compositions and dosage forms of this invention are particularly well suited for the administration of nicardipine and its pharmaceutically acceptable salts, such as nicardipine hydrochloride. The preparation and use of nicardipine and other closely related compounds and their pharmaceutically acceptable salts are described in US-A-3 985 758. At the present time, the preferred route of administration for most therapeutic applications of the dihydropyridine calcium channel blockers is via an oral dosage form. These are typically compressed tablets, hard gelatin capsules filled with a powder mix, or soft gelatin capsule filled with a solution, and are conventionally adminstered three or four times daily. However, conventional release oral dosage forms are poorly suited to dihydropyridine calcium channel blocker therapy. At the acid pH that occurs in the stomach, the solubility of the basic dihydropyridines is relatively high, resulting in rapid dissolution and absorption. As the pH increases along the gastrointestinal tract, dihydropyridine solubility, and hence the dissolution rate, decreases. As a result, conventional release oral dosage forms release calcium channel blocker more rapidly in the more acidic stomach region and less rapidly in the less acidic intestinal region. The release profiles of such dosage forms are inherently dependent upon the location of the calcium channel blocker within the gastrointestinal tract. There is a need, therefore, for a long acting dosage form with sustained release properties capable of providing therapeutic calcium channel blocker plasma concentrations when the dosage form is administered less frequently, preferably once or twice daily. In addition to providing convenience for the patient, such a sustained release dosage form would minimize undesirable fluctuations in drug plasma concentration. In US-A-4 343 789, formulations and dosage forms for nicardipine and related compounds are described which provide some dissolution control, and hence sustained release of the drug. As described in the patent, a powder containing amorphous nicardipine, polyethylene oxide, and other excipients is formed which can then be formed into granules, tablets, pills or capsules by conventional means. The formulation requires that the nicardipine or salt thereof be in amorphous form, and be combined with polyethylene oxide in a fine particle powder or granules. The formulation may additionally contain a pH-dependent agent for dissolution control, such as a copolymer of methacrylic acid and a methacrylic acid ester. While the specific disclosure is primarily directed to tablet formulations, one capsule dosage form is disclosed which contains small coated pills, part of which are film coated, and part of which are coated with Eudragit® (methacrylic acid/methyacrylic acid ester copolymer). However, the preparation of the drug in amorphous form, the incorporation of polyoxyethylene, and the coating of pills or granules to obtain the necessary dissolution and release characteristics are time consuming and expensive manufacturing procedures. Other granular and particulate calcium channel blocker compositions formulated with a pH-dependent binding agent are known; see e.g. Journal of Pharmaceutical Sciences, Vol. 65, No. 1, pages 57-61. However, the manufacture of these compositions has required the use of an organic solvent, which must subsequently be removed by arduous and lengthy drying procedures. These compositions have additionally required the application of a sustained-release or enteric coating material to obtain adequate dissolution control. There is, therefore, a need for a pharmaceutical composition which provides therapeutically effective dihydropyridine calcium channel blocker plasma levels, when administered as infrequently as twice daily, avoids the phenomenon of dose dumping, and provides readily and economically manufacturable drug-containing particles of substantially uniform and regular size and shape suitable for incorporation in hard gelatin capsules and other oral and parenteral dosage forms. In one aspect, this invention provides a method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids. In a second aspect, the invention provides a long acting sustained release pharmaceutical composition for administration of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which comprises spherical, non-coated, non-rugose particles having diameters up to 1.2 millimeters, comprised of an effective amount of calcium channel blocker in intimate admixture with at least 3 weight percent of a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH. A further aspect of the invention provides a long acting sustained release pharmaceutical dosage form such as a capsule or injectable suspension, for administration of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which dosage form consists essentially of an inert pharmaceutical carrier in which is contained: (a) a long acting pharmaceutical composition as described above for prolonged administration of the calcium channel blocker; in combination with (b) a fast release pharmaceutical composition for administration of a loading dose of the calcium channel blocker, wherein the relative proportions of long acting pharmaceutical composition and fast release pharmaceutical composition are in the range of 50:50 to 100:0. Yet a further aspect of the invention is a method of preparing a long acting pharmaceutical composition of this invention suitable for treating cardiovascular disease in a mammal. In the drawings: FIG. 1 is a graphical illustration of the results of the test described in Example 5 and shows comparative plasma concentration profiles of nicardipine hydrochloride achieved after administration of a conventional fast acting dosage form (Dosage Form A) and two long acting dosage forms prepared according to the present invention (Dosage Forms B and C). FIG. 2 is a graphical illustration of the results of the test described in Example 7 and shows the comparative plasma concentration profiles of nicardipine hydrochloride achieved after administration of a conventional fast acting dosage form and a long acting dosage form prepared in accordance with this invention. FIG. 3 is a graphical illustration of the results of the test described in Example 9 and shows the comparative plasma concentration profiles of nicardipine hydrochloride achieved after administration of a conventional fast acting dosage form (Dosage Form A) and two long acting dosage forms prepared according to this invention (Dosage Forms B and C). Definitions As used herein, the following terms have the meaning described below unless otherwise indicated: The term "alkyl" refers to a straight or branched hydrocarbon chain having from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. The term "alkoxy" means a moiety of the formula -OR in which R is alkyl as defined above. The term "alkylenyl" means a straight or branched chain bivalent alkyl bridging group. The term "alkylenyloxyalkyl" means a moiety of the formula -R a OR in which R a is alkylenyl and R is alkyl as defined above. The term "halo" refers to chloro, bromo, iodo and fluoro. Chloro is a preferred halo substituent on the phenyl ring of the 1,4-dihydropyridine calcium channel blockers compounds of interest in this invention. Nitro is the preferred substituent on the phenyl ring of the 1,4-dihydropyridine calcium channel blocker compounds of interest in this invention. The term "aryl" refers to homocyclic and heterocyclic moieties which are substantially aromatic in character. Examples of aryl groups are phenyl, naphthyl, imidazolyl, pyrrolyl, pyridyl and thienyl. The term "aralkyl" refers to alkylaryl moieties. The terms "phenyl alkyl" and "naphthyl alkyl" mean radicals of the structure: respectively, in which R is alkyl as defined above. The terms "optional" and "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted phenyl" means that the phenyl moiety may or may not be substituted and that the description includes both substituted and unsubstituted phenyl. The phrase "optional pharmaceutical excipients" indicates that a composition or dosage form so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation or dosage form so described includes instances in which optional excipients are present and instances in which they are not. "Optionally substituted" phenyl and naphthyl moieties may be substituted with one or two alkyl, alkoxy, or mono-or dihydroxyalkoxy (such as 2,3-dihydroxypropoxy) radicals, as those terms are defined herein. The term "pharmaceutically acceptable acid addition salts" refers to salts of the subject compounds which possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid and p-toluenesulfonic acid. "Nicardipine" identifies the compound 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-β-(N-benzyl-N-methylamino)-ethyl ester, or any of its pharmaceutically acceptable salts. This compound can also be named 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-[methyl(phenylmethyl)amino]ethyl ester or 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, methyl 2-[methyl-(phenylmethyl)amino]ethyl ester, monohydrochloride or (2)2-(benzylmethylamino)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride. The salt, nicardipine hydrochloride, is the preferred calcium channel blocker of this invention. The terms "treating" and "treatment" refer to any treatment of a disease in a mammal, particularly a human, and include: (i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. The terms "fast release" and "conventional release" refer to calcium channel blocker composition that are substantially completely dissolved and absorbed in the stomach or upper gastrointestinal tract. The terms "long acting" and "sustained release" refer to calcium channel blocker compositions that are slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of at least two hours. Preferred long acting compositions and dosage forms exhibit plasma concentration profiles suitable for twice daily administration of the dosage form. The pharmaceutical compositions, dosage forms and methods of the invention can be used to provide long acting sustained release administration of any of the 1,4-dihydropyridine derivatives having calcium channel blocking activity. The preferred dihydropyridine calcium channel blockers of this invention are selected from the group represented by the formula: where; R₁ is -NO₂, -CF₃, or halo; R₂ is alkyl or -CH₂CH₂OCH₃; and R₆ is hydrogen or alkyl; and R₃ is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted naphthyl alkyl, or in which: A is alkylene; R₄ is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and R₅ is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof. The long acting sustained release pharmaceutical compositions of the invention are spheroids, which are essentially spherical particles having substantially smooth, non-rugose surfaces. In contrast to conventional granules, which may be approximately spherical in their outermost surface dimensions, but are actually loose particulate aggregates with highly rugose surfaces and area radius to circumference radius ratios in the range of 0.6 to 0.8, the spheroids of this invention have area radius to circumference radius ratios in the range of 0.85 to 1.0, preferably in the range of 0.9 to 1.0. As used herein area radius is given by the formula: the square root of [the projected area divided by pi], and the circumference radius is given by the formula: the projected circumference divided by 2 pi. The projected area and projected circumference including indentations or projections are determined from a projected image of the particles in question. As used herein, "non-rugose" refers to an outer surface which is substantially lacking in wrinkles, craters and other surface irregularities. The terms "spheroids" and "spherical particles" are used interchangeably herein. Further in contrast to conventional granules, the spheroids of this invention are relatively dense. Whereas conventional granules have variable and significant degrees of porosity in the range of about 30-50% internal void volume (see for example, Chalmers A.A. and Elworthy P.H. (1976) J. Pharm. Pharmacol. , 28 , 239-243), the spheroids of this invention have substantially decreased porosities in the range of less than about 20 % internal void volume, preferably 15 % internal void volume or less. The smooth surface and low porosity of the spheroids provide substantially greater dissolution control than can be achieved with conventionally manufactured granules. The long acting sustained release pharmaceutical compositions of this invention are prepared from an essentially aqueous, wet mass containing the calcium channel blocker, pH-dependent binder, and any optional pharmaceutical excipients. The term "essentially aqueous, wet mass" refers to a powder mass which has been wetted with an essentially aqueous binding solution to a consistency suitable for extrusion. The powder mass is made by dry-blending the active ingredient(s) and any desired optional pharmaceutical excipients such as a diluent. The term "essentially aqueous" means that water is the predominant liquid in the binding solution, which may include, but preferably will not include, up to 25 % other water-miscible solvents. In the preferred embodiments of this invention, the pH-dependent binder is dissolved or dispersed in the aqueous binding solution which is used to wet the dry powder mass. However, depending on the choice of active ingredient, pH-dependent binder and other excipients, it may in some instances be preferable to include some or all of the pH-dependent binder in the dry powder mass prior to wetting with water or other essentially aqueous binding solution. Whether the pH-dependent binder is included in the dry powder mass or in the aqueous wetting solution, or both, the mixing of components which takes place to form and extrude the wet mass should be sufficient to place the active agent in intimate and substantially uniform admixture with the binder and any other excipients which may be incorporated. In addition to, and intimately admixed with the calcium channel blocker and the pH-dependent binder in the wet mass may be other optional pharmaceutically acceptable excipients. These may include diluents such as lactose, mannitol, dry starch and microcrystalline cellulose, additional binders such as starch, gelatin, sugars, carboxymethylcellulose and methylcellulose, lubricants such as talc and magnesium stearate, coloring agents and flavoring agents. The wet mass is then extruded to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters. As used herein, the term "extrusion" refers to a process whereby a cohesive rod-shaped, substantially cylindrical material of specific cross section is formed by forcing the wet mass, from a wide diameter reservoir, through an orifice of small diameter, such that the product substantially retains the cross section of the orifice. These rod-shaped segments can then be formed into spheres, as described below, and it is therefore important that they be substantially cylindrical and of relatively uniform cross section. The extrusion step should also impart additional density (low porosity) to the material, which may be further densified during the spheronization step. There are a wide variety of such extrusion methods known and available in the pharmaceutical industry. In general, these methods rely on generation of a continuous pressure of sufficient magnitude to induce the material to flow and retain the shape of the die on exit. The degree of wetness, flow and cohesive properties of the wet mass also affect the quality and uniformity of the extruded material. Well known, standard types of extrusion equipment suitable for use in this invention include screw extruders, cylinder extruders, gear extruders, ram extruders and radial screen rotating head type extruders. The extruded rod-shaped segments are then shaped into spherical particles, which when dry, are long acting sustained release spheroids suitable for use in a variety of oral and parenteral dosage forms. As discussed above, in order to provide the desired prolonged dissolution and release profiles, the outer surface of the spheroids must be substantially smooth, non-rugose and essentially spherical. Spheronization equipment capable of forming spheroids having the desired properties from cylindrical extrudate is commercially available. For example, the Marumerizer® machine (Conine J.W. and Hadley H.R., (1970) Drug Cosmet. Ind., 106 , 38-41) can be used to provide spherical particles of suitable surface smoothness and regularity of size and shape. In the Marumerizer®, the rod-shaped segments of extrudate are shaped into spheroids by centrifugal and frictional forces on a rotating disc or pan. This method of spheronization offers the opportunity to regulate the size of the spherical particles. The spheroids may be varied in size up to about 1.2 mm, and the size of the spheroids can be adjusted to control the rate of spheroid dissolution and drug release. Smaller spheroids have higher surface to volume ratios, and hence faster dissolution rates, than larger spheroids. The preferred size for spheroids is between 0.5 mm and 1.2 mm, most preferably between 0.7 mm and 1.0 mm. It is also preferred that the size distribution of the spheroids be as narrow as possible; spheroids within a narrow size distribution range provide a plasma concentration profile which is more flat and constant than that achieved with particles of widely differing sizes. In the preferred embodiments of this invention at least 70 weight percent of the spheroids will have diameters which are within upper and lower limits differing by not more than a factor of the square root of two from each other. In order to provide sustained release of the dihydropyridine calcium channel blocker, the binder materials suitable for use in this invention must control the dissolution profile of the drug-containing spheroids so that they dissolve slowly and continuously throughout their passage within the stomach and along the gastrointestinal tract. The dissolution control capacity of the binding agent is particularly important in a long-acting dosage form; a sustained release dosage form which contains sufficient drug for once or twice daily administration may cause untoward side effects if it dissolves too rapidly and dumps all of the drug into the stomach and upper gastrointestinal tract in a short period of time. Accordingly, binders suitable for use in this invention are materials which prevent rapid dissolution of the spheroids during their residence in the very acidic environment of the stomach (where the pH is generally less than about 4.5) and prolong the dissolution of the spheroids in the intestinal tract (where the pH is generally greater than about 5.5). Any material which is pharmaceutically acceptable for oral ingestion and which can impart such dissolution control to the calcium channel blocker spheroids can be used in this invention. Generally these materials are substantially insoluble at a pH of less than 4.5 and are soluble at a pH of greater than 5.5. Many materials known in the pharmaceutical art as "enteric" binders and coating agents have the desired properties. These include a large number of phthalic acid derivatives such as the phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates, and the partial esters thereof; and polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and the partial esters thereof. Examples of specific pH-dependent binder materials which may be used include hydroxypropyl cellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, polyvinylpyrrolidone phthalate, hydroxypropylmethyl cellulose phthalate and copolymers of methacrylic acid and methacrylic or acrylic acid esters. Particularly preferred binders for use in this invention are the commercially available copolymers of methacrylic acid and a methacrylic or acrylic acid ester, for example the Eudragit® polymers, particularly the Eudragit® L series such as Eudragit® L30D and Eudragit® L100/55, sold by the Rohm and Haas Company. Eudragit® L30D is a dispersion of 30% Eudragit® L powder in water, and is the preferred pH dependent binder for use in this invention. It is to be noted that viscosity enhancing agents such as hydroxypropylmethylcellulose, methylcellulose and polyvinylpyrrolidone which dissolve at a rate independent of pH, do not provide the required dissolution control. The spheroids may contain the calcium channel blocker in any proportion from as little as 1 weight percent or less up to 95 weight percent. The pH-dependent binder may be present in any proportion from as little as 3 weight percent up to 95 weight percent. While the proportion of active agent present will depend largely on its potency, the proportion of pH-dependent binder will depend on the degree of release rate control which is needed for the particular active agent. Generally, the pH-dependent binder will constitute 5 to 50 weight percent, preferably 5 to 20 weight percent of each spherical particle. A preferred spheroid composition for the administrationof nicardipine hydrochloride will contain 10 to 20 weight percent nicardipine and 5 to 20 weight percent pH-dependent binder, with the remainder being non-essential fillers, binders and other optional excipients. Because the spheroids are not coated, and do not contain central seeds or cores, if an error has been made in the preparation of the wet mass, extrudate, or spheroids, the incorrectly formed material can readily be reworked and reformed. Utility and Administration Depending on the particular calcium channel blocker which is incorporated, the pharmaceutical compositions and dosage forms of the invention may be used for treating a wide variety of disease states which involve one or more forms of cardiovascular and cerebrovascular disfunction. The calcium channel blockers of interest in the invention generally possess a broad spectrum of cardiovascular and cerebrovascular activities including anti-anginal and antihypertensive properties. Nicardipine also possesses anit-ischemic properties. The invention compositions can therefore be beneficially used in treating cardiovascular and cerebrovascular disorders in patients who are susceptible to calcium ion entry blockade. The preferred method of administration of these compositions is oral, except in those cases where the patient is unable to ingest, by himself, medication. In such instances it may be necessary or desirable to administer the composition parenterally. The preferred oral dosage forms of the invention are capsules, preferably hard gelatin capsules, which contain the long acting spheroids in amounts suitable for the desired dosage period. Other dosage forms for oral administration include powders or spherical particulates for ingestion with foods or beverages. Because the spherical particles of the invention exhibit a prolonged release profile in physiological environments of pH 4 to 7, they can also be formulated in parenteral suspensions or slow release depot formulations for subcutaneous or intramuscular injection. The parenteral dosage forms can be prepared by suspending the spheroids and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline solutions, aqueous dextrose and glycerol. The dosage form may also contain minor but effective amounts of non-toxic auxiliary substances such as wetting and emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate and triethanolamine oleate. Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in this art; for example, see Remington's Pharmaceutical Sciences , Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. Depending on the intended therapeutic application of the calcium channel blocker, it may be desirable to administer a loading dose of a fast-release calcium channel blocker composition (i.e. a composition that is substantially completely dissolved and absorbed in the stomach and upper gastrointestinal tract) in conjunction with a long acting sustained release composition. The long-acting spheroids of this invention can be readily formulated in a pharmaceutical dosage form, such as a hard gelatin capsule, which also contains a fast release composition for administration of a loading dose of the calcium channel blocker. Where a fast release loading dose is desired, the relative proportions of long acting pharmaceutical compostion and fast release pharmaceutical composition should preferably be in the range of 50:50 to 100:0, most preferably in the range of 60:40 to 80:20. The fast release composition may simply be additional quantities of the dry powder mass used to form the spheroids, and may contain optional pharmaceutical excipients. Alternatively, it can be a granulated or spherical particulate, or any other physical form which incorporates the drug in an inert non-sustained release pharmaceutical carrier material. In a long acting capsule dosage form, the void spaces between the essentially spherical particles may be filled with a fast release calcium channel blocker powder composition. The long acting capsule dosage form would then possess the combined release properties of the fast release and long acting compositions. The overall release rate profile of the dosage form can be controlled by varying the ratios of the fast release portion and the long acting portions of the final preparation. When the capsule is ingested, the fast release portion provides a loading dose while the contents of the capsule are in the stomach. As the contents of the capsule move into the intestine, the long acting spheroids continue to dissolve, providing release of calcium channel blocker over at least two hours, preferrably over at least four to eight hours. The blood plasma levels approach therapeutic levels rapidly and remain at therapeutic levels for an extended period of time. In addition to providing ease and economy of manufacture, the compositions and dosage forms of the present invention provide several therapeutic advantages. Because of the long-acting properties of the spheroids, the pharmaceutical compositions and dosage forms of the invention can be designed to provide therapeutic calcium channel blocker plasma concentration profiles suitable for twice daily administration. In measurements of drug plasma concentration versus time, the long acting compositions of the invention provide therapeutic plasma concentrations for a period at least about twice that which is provided by a conventional fast release formulation. Embodiments of the invention which combine a fast release composition with a long acting composition also exhibit greatly enhanced drug plasma profiles suitable for twice daily administration. EXAMPLES The following examples are exemplary of the invention described in the specification and claims. They are not to be construed as limiting the scope of the claims. Example 1 Preparation of Long Acting Spheroids A. 1.0 Kg nicardipine hydrochloride, 1.2 Kg lactose monohydrate, 1.0 Kg Avicel® PH 102, and 1.0 Kg maize starch were blended for 20 minutes in a Hobart® mixer. A mixture of 2.4 Kg of Eudragit® L30D (brand copolymer of methacrylic acid and acrylic acid ethyl ester, a 30% dispersion of Eudragit® L in water), and 1.4 Kg of distilled water were added to the dry mixture and the wet mass mixed for 5 minutes in a Hobart® mixer. The wet mass was then extruded through an Elanco® extruder having a screen size of 1 mm, giving substantially cylindrical rod-shaped segments approximately 1 mm in diameter. The rod-shaped segments were placed into a GB Caleva® Model 15 spheronizer having a plate that rotated at about 800 revolutions per minute for 5 minutes. The spheronized particles were then dried in an oven at 50°C for 180 minutes. (The residence time in the spheronizer is variable for any batch of particles, and varies from 3 to 10 minutes). B. In like manner, long acting sustained release spheroids may be prepared from other dihydropyridine calcium channel blocker including nifedipine, niludipine, nitrendipine, nisoldipine, nimodipine, and felodipine. Example 2 Preparation of Fast Release Powder A. 1.0 Kg nicardipine hydrochloride and 3.975 Kg pregelatinized starch were blended for 20 minutes in a Hobart® mixer. 0.025 Kg of magnesium stearate was then added and blended for 3 minutes. This powder was then used as a fast release composition in the capsules described in Example 3. B. In like manner, fast release powder compositions may be prepared from other dihydropyridine calcium channel blocker including nifedipine, niludipine, nitrendipine, nisoldipine, nimodipine, and felodipine. Example 3 Preparation of Long Acting Dosage Form Containing Fast Release Loading Dose Hard gelatin capsules were filled with a mixture of the dried and sized nicardipine spheroids of Example 1.A. and the fast release nicardipine powder of Example 2.A., in the relative proportions of 50 weight percent and 50 weight percent, respectively. Example 4 This example shows the dissolution rates in a standard USP paddle test of a fast release nicardipine composition prepared as described in Example 2, two long acting spheroid compositions prepared accordingly to the procedure described in Example I, and two compositions combining long acting spheroids with fast release powder. A standard USP paddle dissolution test was run at 50 RPM in 1000 ml of pH 4.5 citrate buffer solution containing samples of the formulations to be tested. The two long acting spheroid compositions were made by varying the amounts of Eudragit® L (expressed in % dry weight of the spheroid components). The fast release composition and the long acting composition were combined as in Example 3 to give 30 mg nicardipine hydrochloride in the fast release composition and 30 mg nicardipine hydrochloride in the long acting spheroids. Dissolution rate results for each composition and combination tested are given in Table 1. The results show that the fast release component is completely dissolved in about 30 minutes. The two long acting compositions exhibit much slower and more prolonged dissolution profiles. Example 5 In this example the post administration drug plasma concentrations of three dosage forms, one a conventional fast release capsule, and the two others long acting dosage forms prepared according to this invention, are compared. The fast acting dosage form (Dosage Form A) was a fast release powder prepared as described in Example 2 and placed in single dose capsules, each containing 30 mg of nicardipine hydrochloride. The long acting dosage forms were also capsules, each containing 30 mg nicardipine hydrochloride in the fast release powder composition and 30 mg nicardipine hydrochloride in long acting spheroid compositions having either 14.4% (Dosage Form B) or 7.2% Eudragit® L (Dosage Form C). The testing was conducted in five human volunteers in a three-way balanced crossover test, comparing the two long acting formulations with the fast release formulation. Plasma samples were removed and tested by gas chromatography for nicardipine at intervals. The results are tabulated in Table 2 as plasma levels observed at a given time after dosage administration. A comparison of the pharmacokinetic parameters of the formulations of Table 2 are shown in Table 3. Figure 1 graphically depicts the data set forth in Table 2 and shows the profiles of the mean plasma nicardipine level versus time achieved with each of Dosage Forms A, B and C. For each of the three dosage forms, Table 3 shows the maximum nicardipine plasma concentration (C max ) in ng/ml and the total area under the plasma concentration/time curve (Total AUC) in ng.hr/ml. The data recorded in Tables 2 and 3 show that the long acting compositions do not dump the calcium channel blocker dose, nor release it as quickly as the conventional fast release formulation. Substantially higher Total AUC values were exhibited by the long acting compositions, indicating the prolonged maintenance of plasma levels. Three to five fold higher plasma concentrations after four hours were also exhibited by the two long acting compositions. EXAMPLE 6 Preparation of Long Acting Dosage Form Hard gelatin capsules were filled with nicardipine spheroids prepared according to the method described in Example 1 with sufficient Eudragit® L30D to give a final composition containing 11 weight% Eudragit® L. Each capsule contained 60 mg of nicardipine hydrochloride in the long acting spheroid composition only. EXAMPLE 7 In this example the post administration drug plasma concentrations of two dosage forms, one a conventional fast release capsule and the other a long acting dosage form, prepared according to this invention are compared. The fast acting dosage form was a fast release powder prepared as described in Example 2 and placed in a single dose capsule containing 30 mg of nicardipine hydrochloride. The long acting dosage form was also a capsule, containing 60 mg of nicardipine hydrochloride in the long acting spheroid compositions described in Example 6. The testing was carried out in five human volunteers in a two-way balanced crossover study. Plasma samples were removed and tested by gas chromatography for nicardipine at intervals. The results are tabulated in Table 4 as plasma levels observed at a given time after dosage administration. A comparison of the pharmacokinetic parameters are shown in Table 5. Figure 2 graphically depicts the data set forth in Table 4, and shows the profiles of mean plasma nicardipine concentration level versus time achieved with the fast acting and long acting dosage forms. For both dosage forms, Table 5 shows the time after administration at which maximum nicardipine plasma concentration occurred (T max ) in hours, the maximum nicardipine plasma concentration (C max ) in ng/ml and the total area under the plasma concentration/time curve (Total AUC) in ng.hr/ml. The data recorded in Tables 4 and 5 show that the long acting composition does not dump the calcium channel blocker dose, nor release it as quickly as the conventional fast release formulation. Substantially higher T max and Total AUC values were exhibited by the long acting composition, indicating the prolonged maintenance of plasma levels. Five to ten fold higher plasma concentrations were exhibited by the long acting composition at sampling times of 4 hours and longer after dosage administration. EXAMPLE 8 Preparation of Long Acting Dosage Form Containing a Fast Release Loading Dose Hard gelatin capsules were filled with a combination of nicardipine spheroids prepared according to to the method set forth in Example 1 containing 11% Eudragit® L, and the fast release nicardipine powder of Example 2, in the relative proportions of 75 weight percent and 25 weight percent respectively. The capsules contained 45 mg or 60 mg of nicardipine hydrochloride, distributed in the fast release and long acting compositions in the amounts shown in Table 6. EXAMPLE 9 In this example the post administration drug plasma concentration profiles achieved with three dosage forms, one a conventional fast release capsule and the two others long acting dosage forms prepared according to this invention, are compared. The fast acting dosage form (Dosage Form A) was a fast release powder prepared as described in Example 2, and placed in single dose capsules each containing 30 mg of nicardipine hydrochloride. The long acting dosage forms (Dosage forms B and C) were also capsules each containing fast release powder and long acting spheroid nicardipine hydrochloride compositions in the relative porportions of 25 weight percent and 75 weight percent respectively. Two different nicardipine hydrochloride doses were evaluated in the long acting dosage forms. Dosage Form B contained a total of 45 mg of nicardipine hydrochloride, and Dosage Form C a total of 60 mg of nicardipine hydrochloride, each in the relative amounts set forth in Example 8. The testing was conducted in six human volunteers in a three-way balanced crossover study, comparing the two long acting dosage forms with the fast release dosage form. Plasma samples were removed and tested by gas chromatography for nicardipine at intervals. The results are tabulated in Table 7 as plasma levels observed at a given time after dosage administration. A comparison of the pharmacokinetic parameters are shown in Table 8. Figure 3 graphically depicts the data set forth in Table 7, and shows the profiles of mean plasma nicardipine concentration versus time achieved with each of Dosage Forms A, B and C. For each of the three dosage forms, Table 8, shows the time after administration at which maximum nicardipine plasma concentration occurred (T max ) in hours, the maximum nicardipine plasma concentration (C max ) in ng/ml and the total area under the plasma concentration/time curve (Total AUC) in ng.hr/ml. The data recorded in Tables 7 and 8 show that the long acting compositions do not dump the calcium channel blocker dose, nor release it as quickly as the conventional fast release formulation. Substantially higher T max and increased Total AUC values were exhibited by the long acting formulations indicating prolonged maintenance of plasma levels. The 45 mg nicardipine hydrochloride long acting dosage form exhibited two to five fold higher plasma levels after four hours post dosage administration than the conventional fast release dosage form. Three to six fold higher plasma levels after four hours post dosage administration were exhibited by the 60 mg nicardipine hydrochloride long acting formulation. Both long acting formulations showed similarily enhanced and extended overall plasma concentration/time profiles, evidence by extended T max values with elevated plasma levels at longer sampling times. The plasma levels and Total AUC values obtained were greater for the 60 mg long acting dosage form than for the 45 mg long acting dosage form. EXAMPLE 10 Determination of Particle Surface Characteristics The degree of rugosity of the surfaces of long acting spheroids and conventional granules were determined and compared as follows. Long acting nicardipine hydrochloride spheroids were prepared as described in Example 1 with enough Eudragit® L30D to give a final product containing 11 % Eudragit® L. Some of the spheroids were rotated in the spheronizer (spheronized) for one minute and some were rotated for three minutes. Conventional granules containing nicardipine hydrochloride were prepared as follows: 1.0 Kg nicardipine hydrochloride, 1.45 Kg lactose, 1 Kg Avicel® PH 102, and 1 Kg maize starch were blended for 20 minutes in a Hobart® Mixer. A mixture of 1.833 Kg Eudragit® L30D and 0.5 Kg of distilled water were added to the dry mixture. The wet mass was then screened through an oscillating granulator having a screen size of 1 mm. The granules were then dried in an oven at 50°C, resulting in dry granules containing approximately 11% Eudragit® L. Samples of the spheroids and granules were viewed and and their outline traced on paper under a microscope at x50 magnification. The "circumference", or distance around the periphery of each spheroid or granule, was determined using a map measuring pen (Jakar, Sime and Malloch Ltd., Edinburgh, Scotland). The area within the circumference was determined by carefully cutting out the traced circumferential shape, accurately weighing the cut-out using a Cahn Microbalance®, and calculating the actual area by reference to a sample of known area. The rugosity parameter (degree of rugosity) was determined as a function of the area radius and the circumference radius from the following radius estimations: The ratio R A /R C is thus a measure and function of the shape (1.0 for perfect sphere) and of the surface roughness. The mean values determined for the spheroids and granules are shown below.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids. The method of claim 1 in which the spheroids are formed on a rotating disc or pan. The method of claim 1 or 2 in which the pH dependent binder is a single material, or a mixture of materials selected from either of the groups a and b: (a) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates and the partial esters thereof; and (b) polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates and the partial esters thereof. The method of claim 3 in which the pH-dependent binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester. The method of any one of claims 1-4 in which the dihydropyridine calcium channel blocker is a compound chosen from the group represented by the formula: where; R₁ is -NO₂, -CF₃, or halo; R₂ is alkyl or -CH₂CH₂OCH₃; and R₆ is hydrogen or alkyl; and R₃ is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted naphthyl alkyl, or in which: A is alkylene; R₄ is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and R₅ is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof. The method of claim 5 in which the dihydropyridine calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof. A long acting sustained release pharmaceutical composition for administration of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which comprises spherical, non-coated, non-rugose particles having diameters up to 1.2 millimeters, comprised of an effective amount of calcium channel blocker in intimate admixture with at least 3 weight percent of a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH. A pharmaceutical composition according to claim 7 in which the spherical particles have 15% or less internal void volume. A pharmaceutical composition according to claim 7 or 8 in which at least 70 weight percent of the spherical particles have diameters which are within upper and lower limits which differ by not more than a factor of the square root of two from each other. A pharmaceutical composition according to any one of claims 7 to 9 in which the binder is substantially insoluble at a pH of less than 4.5 and is soluble at a pH of greater than 5.5. A pharmaceutical composition according to any one of claims 7 to 10 which provides therapeutic plasma concentrations suitable for twice daily administration of the pharmaceutical composition. A pharmaceutical composition according to any one of claims 7 to 11 in which the spherical particles comprise: from 5 to 50 weight percent calcium channel blocker; and from 3 to 95 weight percent binder. A pharmaceutical composition according to any one of claims 7 to 12 in which the calcium channel blocker is a compound selected from the group represented by the formula: where; R₁ is -NO₂, -CF₃, or halo; R₂ is alkyl or -CH₂CH₂OCH₃; and R₆ is hydrogen or alkyl; and R₃ is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted naphthyl lower alkyl-, or in which: A is alkylene; R₄ is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and R₅ is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof. A pharmaceutical composition according to claim 13 in which the calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to any one of claims 7 to 14 in which the pH-dependent binder is a single material, or a mixture of materials selected from either of the groups a and b consisting of: (a) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates, and the partial esters thereof; and (b) polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and the partial esters thereof. A pharmaceutical composition according to claim 15 in which the binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester. A long acting sustained release pharmaceutical dosage form for administration of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which dosage form consists essentially of an inert pharmaceutical carrier in which is contained: (a) a long acting pharmaceutical composition according to claim 7 for prolonged administration of the calcium channel blocker; in combination with (b) a fast release pharmaceutical composition for administration of a loading dose of the calcium channel blocker, wherein the relative proportions of long acting pharmaceutical composition and fast release pharmaceutical composition are in the range of 50:50 to 100:0. The pharmaceutical dosage form of claim 17 in which the inert pharmaceutical carrier is a hard gelatin capsule. The pharmaceutical dosage form of claim 17 or 18 in which the calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof. The pharmaceutical dosage form of any one of claims 17 to 19 in which the pH-dependent binder is a copolymer of methacrylic acid and methacrylic or acrylic acid ethyl ester. A method according to any one of claims 1 to 6 for preparing a pharmaceutical composition suitable for treating cardiovascular disease in a mammal. Claims for the following Contracting States : AT, ES, GR A method of preparing spheroids which provide long-acting sustained release of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which method consists essentially of: (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes at least 3 weight percent of the dry components of the mass; (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters; (c) shaping the rod-shaped segments into spheroids; and (d) drying the spheroids. The method of claim 1 in which the spheroids are formed on a rotating disc or pan. The method-of claim 1 or 2 in which the pH dependent binder is a single material, or a mixture of materials selected from either of the groups a and b (a) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates and the partial esters thereof; and (b) polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates and the partial esters thereof. The method of claim 3 in which the pH-dependent binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester. The method of any one of claims 1-4 in which the dihydropyridine calcium channel blocker is a compound chosen from the group represented by the formula: where; R₁ is -NO₂, -CF₃, or halo; R₂ is alkyl or -CH₂CH₂OCH₃; and R₆ is hydrogen or alkyl; and R₃ is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted naphthyl alkyl, or in which: A is alkylene; R₄ is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and R₅ is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof. The method of claim 5 in which the dihydropyridine calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof. The method of any one of claims 1-6 in which the spherical particles are non-coated, non-rugose particles having diameters up to 1.2 millimeters. The method of claim 7 in which the spherical particles have 15% or less internal void volume. The method of claim 7 or 8 in which at least 70 weight percent of the spherical particles have diameters which are within upper and lower limits which differ by not more than a factor of the square root of two from each other. The method of any one of claims 7 to 9 in which the binder is substantially insoluble at a pH of less than 4.5 and is soluble at a pH of greater than 5.5. The method of any one of claims 1 to 10 in which the spherical particles comprise: from 5 to 50 weight percent calcium channel blocker; and from 3 to 95 weight percent binder. A method for preparing a long acting sustained release pharmaceutical dosage form for administration of a therapeutically effective amount of a dihydropyridine calcium channel blocker, which method comprises combining an inert pharmaceutical carrier with (a) a long acting pharmaceutical composition for prolonged administration of the calcium channel blocker comprising spheroids prepared according to the method of any one of claims 1-11; and (b) a fast release pharmaceutical composition for administration of a loading dose of the calcium channel blocker, wherein the relative proportions of long acting pharmaceutical composition and fast release pharmaceutical composition are in the range of 50:50 to 100:0. The method of claim 12 in which the inert pharmaceutical carrier is a hard gelatin capsule. The method of claim 12 or 13 in which the calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof. The method of any one of claims 12 to 14 in which the pH-dependent binder is a copolymer of methacrylic acid and methacrylic or acrylic acid ethyl ester. A method according to any one of claims 1 to 15 for preparing a pharmaceutical composition suitable for treating cardiovascular disease in a mammal.

Inventors: DEY, MICHAEL JOHN, MACFARLANE, CALUM BRECHIN, SELKIRK, ALASTAIR BRERETON
Applicants: SYNTEX (U.S.A.) INC.
Application year: 1987
Main classification: A61K31
IPC codes: A61K9, A61K45, A61P3, A61K47, A61K31, C07D211