Abstract:
A solid composition is disclosed comprising an active ingredient that is not in amorphous form in association with polyethylene oxide and conventional additives, excluding basic compounds. Such compositions are suitable for use as pharmaceutical compositions. A method for their preparation is also disclosed.

Description:
This application is a continuation of PCT/FR96/00574, filed Apr. 15, 1996. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to novel solid compositions, notably pharmaceutical compositions, containing polyethylene oxide and an active ingredient, and to methods for their preparation. 
     BACKGROUND OF THE INVENTION 
     Certain medicaments need to be formulated in so-called delayed-release or sustained release form. 
     Polyethylene oxide referred to as PEO below is moreover known as a component of medicaments in tablet form designed to be administered by oral route. This compound is marketed by the Union Carbide Corporation under the commercial name Polyox®. The use of PEO for formulating medicaments has furthermore been the subject matter of many earlier patents. 
     EP-A-0 277 092, in the name of Ciba-Geigy relates to a composition comprising a casing in a material that is porous to water but not to the active ingredient, surrounding a central core consisting of a mixture of a substance that is weakly soluble in water, and a hydrophilic swelling material, said material consisting of a mixture of PEO and a vinyl pyrrolidone/vinyl acetate polymer. The composition in that patent is an example of current compositions in which a core which swells when exposed to water is surrounded by a water-porous material, release of the active ingredient being delayed or sustained as a result of the time necessary to expand the core, and for diffusion to take place through the casing following the penetration of water. 
     The abstract of the U.S. Pat. No. 4,404,183 and U.S. Pat. No. 4,343,789 discloses two embodiments of a sustained release composition. In the first embodiment, the composition contains PEO, the active ingredient in an amorphous form, and a basic component. In the second embodiment, the active ingredient is nicardipine in an amorphous state, it being possible to omit the basic component. 
     Actually, the compositions according to the prior art are complex, require specific active ingredients or are provided in a specific form. Moreover, the results achieved are not always very good. 
     SUMMARY OF THE INVENTION 
     The present invention provides a simple composition which is suitable for use with a multiplicity of active ingredients, and has a remarkable delaying or sustaining effect. 
     Thus, the present invention provides a solid composition comprising, by weight based on the total weight of the composition: 
     (a) from 1 to 70% of an active ingredient which is not in an amorphous form; 
     (b) from 10 to 95% of polyethylene oxide; 
     (c) the balance consisting of conventional additives, excluding basic components. 
     The expression &#34;solid composition&#34; means that the composition is in a tablet or mini-tablet form, these in their turn being able to be encapsulated using for example the conventional hard gelatin. 
     The expression &#34;active ingredient&#34; should be understood in its normal sense and, generally speaking, covers medicaments for treatment of the human or animal body as well as an association of one or several such medicaments. Active ingredients that are either hydrophilic or lipophilic are envisaged. 
     The expression &#34;not in amorphous form&#34; should be understood in its conventional meaning. Various sources give a definition of this term &#34;amorphous&#34; as meaning non-crystalline, lacking the lattice structure characterizing the crystalline state. The following references, which provide a definition of the term amorphous (or the opposite thereof) are, in a on-limiting manner: Hawley&#39;s, Condensed Chemical Dictionary, 12th Edition, p. 71; Handbook of Chemistry and Physics, 65th Edition, F-67; The Theory and Practice of Industrial Pharmacy, 1970, pp. 253-255; Remington&#39;s Pharmaceutical Sciences, 14th Edition, p. 182; General Chemistry 1992, pp. 314-315; Encyclopedia of Pharmaceutical Technology, vol I, pp. 12-13. 
     The expression &#34;excluding basic compounds&#34; should be understood as excluding the presence of a compound or a group of compounds that confer a basic nature on the composition, in other words a pH greater than 7, when the composition is diluted in water at a rate of 10 g per liter of water. In particular, this term should be taken as excluding the presence of one or several basic component(s) such as described in column 1, lines 38 to 62 of U.S. Pat .No. 4,404,183 if no acid compound is counteracting the effect of said basic compound, or if the basic compound is present in a relatively large amount. 
     According to one preferred embodiment, the composition according to the invention, comprises: 
     (a) from 5 to 45% of an active ingredient; 
     (b) from 25 to 70% polyethylene oxide 
     (c) the balance consisting of conventional additives, excluding basic components. 
     According to one preferred embodiment of the composition according to the invention, the active ingredient is a hydrophilic or lipophilic active ingredient, advantageously a hydrophilic ingredient. 
     According to one preferred embodiment of the composition according to the invention, the active ingredient is selected from the group comprising acyclovir, nifedipine, nicardipine, captopril, verapamil, diltiazem, oxybutynine, valacyclovir, glipizide, felodipine, isosorbide, carbidopa, levodopa, pentoxiphylline, and their pharmaceutically acceptable salts. 
     According to one alternative embodiment, in the composition according to the invention, the polyethylene oxide has a molecular weight which varies from 50,000 to 8,000,000, and preferably from 100,000 to 3,000,000. The required molecular weight for the PEO can be obtained by mixing PEO of differing molecular weights, that are available commercially. 
     According to a further embodiment, in the composition according to the invention, the balance consisting of conventional additives comprises microcrystalline cellulose, lacose, ascorbic acid, pigments, plastifying agents, lubricants and so on. Obviously, other conventional additives known to those skilled in the art can be employed. 
     According to one embodiment of the invention, in a composition, the balance consisting of conventional additives comprises magnesium stearate and/or glycerol behenate and/or sodium stearyl fumarate, which is employed as a lubricant ensuring better compression of the composition when provided in tablet form, for example. 
     According to one or alternative embodiment, the composition is additionally coated. Surface coating is employed for the purposes of improving appearance making the drug more readily acceptable to the patient, or for dimensionally stabilising the compressed tablet. The coating can be a conventional coating suitable for enteral use. It is obtained using any conventional technique employing conventional ingredients. A surface coating can for example be obtained using a quick-dissolving film. It should be noted that the coating according to this invention is fundamentally different from the coating used in EP-A-0,277,092 as one does not encounter, in the invention, the dichotomy (water-swellable core)/(water-porous coating), and moreover, the coating in the invention dissolves and/or disintegrates whereas the coating in EP-A-0,277,092 does not dissolve. 
     The present solid compositions are suitable for the administration of medicaments. Thus, the invention also relates to pharmaceutical compositions deriving therefrom as well as to compositions thereof for use as medicaments. 
     The present composition can be obtained by any conventional method known to those skilled in the art such as, for example direct compression after simply mixing the dry ingredients, moist or wet granulation involving the use of a granulation liquid, and dry granulation involving a densification phase for the dry mixture. 
     However, use is preferably made of a process comprising the steps of: 
     (i) mixing in the dry state and for a sufficient time, the active ingredient, polyethylene oxide and optionally, one or several additives; 
     (ii) optionally adding solvent when this is used, followed by mixing for a sufficient period of time; 
     (iii) granulation by passage through a suitable sieve; 
     (iv) drying the granules thus formed for a sufficient period of time; 
     (v) optionally adding one of more additives, with mixing in the dry state for a sufficient time and passage through a suitable sieve; 
     (vi) optionally adding one or several additives and mixing in the dry state for a sufficient period of time; 
     (vii) compressing the mixture obtained from the preceding steps to obtain the desired compressed tablet; and 
     (viii) optionally coating said compressed tablet. 
     The solvent employed, when use is made of a solvent, is preferably an alcohol. The solvent is eliminated by drying at one point or another in the process, and is substantially not encountered in the final composition. 
     The choice of mixing times, apparatus used, sieve mesh, and other operating conditions are within the province of the normal knowledge of those skilled in the art. 
    
    
     BRIEF DESCRIPTION OF THE DRAWING 
     FIG. 1 is a graphical illustration of percentage in vitro release of an active ingredient as a function of time for the solid compositions of Examples 1 and 2. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The invention will now be described in more detail, with reference to FIG. 1 which shows percentage in-vitro release of an active ingredient as a function of time for the solid compositions of examples 1 and 2. 
     Without wishing to be bound by any theory, the applicant believes that the PEO, in the formulation, forms a hydrogel from contact with water. This hydrogel dissolves more or less rapidly as a function of the molecular weight of the PEO employed. Choosing the molecular weight of the PEO, in combination with the suitable choice of the weight concentrations of the active ingredient, of PEO, and of additives enables release of the active ingredient to be controlled. 
     Moreover, the present composition exhibits particularly surprising results. In a hydrophilic matrix, when the concentration of the hydrophilic active ingredient increases, one would expect that the rate of release of the active ingredient would increase. The present composition exhibits the opposite effect, in the case, for example, of acyclovir as active ingredient. This is clearly shown in FIG. 1, which gives in-vitro dissolution of the compositions of examples 1 and 2. The composition of example 1 has a lower concentration of the active ingredient (200 mg medicament in a 905 mg tablet) and shows a faster in-vitro release of the drug as compared to the formulation of example 2 which has a higher concentration of the active ingredient (400 mg of medicament in a 905 mg tablet). This result is particularly surprising. 
     The examples below are provided as examples illustrating the invention and should not be considered as limiting its scope. In the examples, the amount of solvent employed is given in brackets, it being understood that the solvent is substantially absent in the final composition. 
     EXAMPLE 1 
     
         ______________________________________The following composition was prepared:______________________________________Acyclovir             200.0   mgPEO (MW = 100 000)    700.0   mgMagnesium stearate    5.0     mgIndustrial alcohol    (260.0  mg)______________________________________ 
    
     The acyclovir and PEO are weighed and added to a mixer kneader. Mixing in the dry state is performed for 5 minutes. Alcohol is added to the mixture and followed by mixing by 5 minutes. Granulation is achieved by passing through a sieve of 1.6 mm mesh. The granules are dried and are passed through a 0.8 mm mesh sieve. After weighing, the magnesium stearate is added and mixing in the dry state is performed during 2 minutes. Tablets are obtained by compression using a Frogerais MR 15 machine. 
     EXAMPLE 2 
     
         ______________________________________The following composition is prepared:______________________________________Acyclovir             400.0   mgPEO (MW = 100 000)    500.0   mgMagnesium stearate    5.0     mgIndustrial alcohol    (260.0  mg)______________________________________ 
    
     The acyclovir and PEO are weighed and added in a mixer kneader. Mixing in the dry state is performed for 5 minutes. Alcohol is added to the mixture and followed by mixing by 5 minutes. Granulation is achieved by passing through a sieve of 1.6 mm mesh. The granules are dried and are passed through a 0.8 mm mesh sieve. After weighing, the magnesium stearate is added and mixing in the dry state is performed during 2 minutes. Tablets are obtained by compression using a rotary Frogerais MR 15 type machine. 
     EXAMPLE 3 
     
         ______________________________________The following composition was prepared:______________________________________Nifedipine            60.0    mgMicrocristalline cellulose                 100.0   mgPEO (MW = 3 000 000)  336.0   mgColloidal silicon dioxide                 2.5     mgMagnesium stearate    2.5     mgIndustrial alcohol    (150.0  mg)______________________________________ 
    
     The nifedipine, microcrystalline cellulose (available from the company FMC under the commercial name Avicel PH 101) and the PEO are weighed and added to a mixer kneader. They are mixed in the dry state for 5 minutes and the alcohol is added to the mixture with further mixing for 5 minutes. Granulation is performed by passage through a 1.8 mm mesh sieve. The granules are dried. The colloidal silicon dioxide (available from Degussa under the commercial name Aerosil 200) is weighed and added and mixing is carried out in the dry state for 5 minutes followed by passage through a 0.6 mm mesh sieve. The magnesium stearate is weighed and added with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     EXAMPLE 4 
     
         ______________________________________CoreNifedipine            60.0    mgMicrocristalline cellulose                 100.0   mgPEO (MW = 3 000 000)  336.0   mgColloidal silicon dioxide                 2.5     mgMagnesium stearate    2.5     mgIndustrial alcohol    (150.0  mg)Coating:Iron oxide            2.0     mgTitanium dioxide      1.0     mgMethylcellulose       12.0    mgIndustrial alcohol    (150.0  mg)______________________________________ 
    
     The nifedipine, microcrystalline cellulose (available from the company FMC under the commercial name Avicel PH 101) and the PEO are weighed and added to a mixer kneader. They are mixed in the dry state for 5 minutes and the alcohol is added to the mixture with further mixing for 5 minutes. Granulation is performed by passage through a 1.6 mm mesh sieve. The granules are dried. The colloidal silicon dioxide (available from Degussa under the commercial name Aerosil 200) is weighed and added and mixing is carried out in the dry state for 10 minutes followed by passage through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     Following this, the methylcellulose (available from Colorcon under the commercial name Methocel) is dissolved in the alcohol. The iron oxide and titanium dioxide are added to the solution, followed by homogenization in an Ultra Turrax apparatus for 10 minutes. The tablets are coated by spraying this suspension in a perforated pan coating apparatus of the &#34;Glatt coater&#34; type. 
     EXAMPLE 5 
     
         ______________________________________The following composition is prepared:______________________________________Core:Nicardipine.HCl       60.0    mgMicrocrystalline cellulose                 77.0    mgPEO (MW = 2 000 000)  270.0   mgMagnesium stearate    3.0     mgIndustrial alcohol    (150.0  mg)Coating:Iron oxide            2.0     mgTitanium dioxide      1.0     mgMethylcellulose       12.0    mgIndustrial alcohol    (150.0  mg)______________________________________ 
    
     The nicardipine.HCl, microcrystalline cellulose (Avicel PH 101) and PEO are weighed and added to a kneader. Mixing in the dry state is carried out for 5 minutes. The alcohol is added to the mixture with further kneading for 5 minutes. Granulation is carried out by passage through a 1.6 mm mesh sieve. The granules are dried and passed through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added followed by dry mixing for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     Following this, the methylcellulose (Methocel) is dissolved in the alcohol. The iron oxide and titanium oxide are added to the solution followed by homogenization in an Ultra Turrax apparatus for 10 minutes. The tablets are coated by spraying this suspension in a Glatt coater type coating apparatus. 
     EXAMPLE 6 
     
         ______________________________________The following composition is prepared:______________________________________Core:Captopril             50.0    mgMicrocrystalline cellulose                 100.0   mgPEO (MW = 2 500 000)  300.0   mgAscorbic acid (powder)                 100.0   mgMagnesium stearate    3.0     mgCoating:Titanium dioxide      1.0     mgMethylcellulose       10.0    mgIndustrial alcohol    (150.0  mg)______________________________________ 
    
     The captopril, microcristalline cellulose (Avicel 200), ascorbic acid and PEO are weighed and added to a mixer kneader. Dry mixing is carried out during 5 minutes, followed by a passage through 1.6 mm mesh sieve. The magnesium stearate is weighed and added with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     Next, the methylcellulose (Methocel) is dissolved in the alcohol. The titanium dioxide is added to the solution followed by homogenization in an Ultra Turrax apparatus for 10 minutes. The tablets are spray coated with this suspension in a Glatt coater type coating apparatus. 
     EXAMPLE 7 
     
         ______________________________________The following composition is prepared:______________________________________Verapamil.HCl         240.0   mgLactose               100.0   mgPEO (MW = 1 000 000)  200.0   mgMagnesium stearate    5.0     mgIndustrial alcohol    (200.0  mg)______________________________________ 
    
     The Verapamil.HCl, lactose (available from the company HMS under reference 80 mesh) and the PEO are weighed and added to a mixer kneader followed by mixing in the dry state for 5 minutes. The alcohol is added to the mixture with further kneading for 5 minutes. Granulation is achieved by passage through a 1.6 mm mesh sieve. The granules are dried and passed through a 0.8 mm sieve. The magnesium stearate is weighed and added, with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     EXAMPLE 8 
     
         ______________________________________The following composition is prepared:______________________________________Diltiazem HCl         180.0   mgLactose               100.0   mgPEO (MW = 1 500 000)  160.0   mgMagnesium stearate    3.0     mgIndustrial alcohol    (150.0  mg)______________________________________ 
    
     The diltiazem.HCl, lactose (HMS, 80 mesh) and PEO are weighed and added to a mixer kneader. Mixing is carried out in the dry state for 5 minutes. The alcohol is added to the mixture with mixing for 5 minutes. Granulation is achieved by passage through a 1.6 mm mesh sieve. The granules are dried and passed through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added, followed by mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     EXAMPLE 9 
     
         ______________________________________The following composition is prepared:______________________________________Oxybutynine.HCl       15.0    mgMicrocrystalline cellulose                 75.0    mgPEO (MW - 1 000 000)  120.0   mgColloidal silicon dioxide                 1.5     mgMagnesium stearate    1.5     mgIndustrial alcohol    (110.0  mg)______________________________________ 
    
     The oxybutynine.HCl, microcrystalline cellulose (Avicel PH101) and PEO are weighed and added to a mixer kneader. Mixing in the dry state is performed for 5 minutes. The alcohol is added to the mixture with further mixing for 5 minutes. Granulation is achieved by passage through a 1.6 mm mesh sieve. The granules are dried. The colloidal silicon dioxide (Aerosil 200) is weighed and added followed by mixing in the dry state for 10 minutes and passage through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added, with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine. 
     EXAMPLE 10 
     
         ______________________________________The following composition was prepared:______________________________________Core:Nifedipine              66.0    mgMicrocristalline cellulose                   100.0   mgPEO (MW = 3 000 000)    336.0   mgColloidal silicon dioxide                   2.5     mgMagnesium stearate      2.5     mgIndustrial alcohol      (150.0  mg)Coating 1:Ammonio methacrylate copolymer type A                   160.0   mgHydroxy propyl methyl cellulose                   20.0    mgWater                   30.0    gIndustrial alcohol      (150.0  mg)Coating 2:Iron oxide              2.0     mgTitanium dioxide        1.0     mgMethylcellulose         12.0    mgIndustrial alcohol      (150.0  mg)______________________________________ 
    
     The method of preparing the core is identical to that described in Example 4. 
     Coating 1 is prepared as follows. 
     The hydroxyl propyl methyl cellulose is weighed and dissolved in the water/alcohol mixture. The amminio methacrylate copolymer (USP XXIII, 12.5% solid available from Rohm Pharma, German under the commercial name Eudragit RL) is weighed and added followed by mixing. Coating is done in a Glatt coater type apparatus. 
     The method for preparing coating 2 and the application of the coating to the tablet obtained from the previous step are identical to those described in Example 4. 
     EXAMPLE 11 
     
         ______________________________________The following composition is prepared:______________________________________Valacyclovir         200.0   mgPEO (MW = 300 000)   700.0   mgMagnesium stearate   5.0     mgIndustrial alcohol   (260.0  mg)______________________________________ 
    
     The valacyclovir and PEO are weighed and added in a mixer kneader. Mixing in the dry state is performed for 5 minutes. Alcohol is added to the mixture, followed by mixing by 5 minutes. Granulation is achieved by passing through a sieve of 1.6 mm mesh. The granules are dried and are passed through a 0.8 mm mesh sieve. After weighing, magnesium stearate is added and mixing in the dry state is performed during 2 minutes. Tablets are obtained by compression using a Frogerais MR 15 type machine. 
     According to the general process disclosed in the previous examples, the following compositions are prepared, where the active ingredient is a crystalline powder. 
     EXAMPLE 12 
     
         ______________________________________The following composition was prepared:______________________________________Core:Glipizide               10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgLactose                 50.0   mgSodium stearyl fumarate 1.7    mgCoating:Methacrylic acid copolymer                   10.0   mgPolyethylene glycol     2.0    mgTalc                    2.5    mgSilicon dioxide         4.5    mg______________________________________ 
    
     EXAMPLE 13 
     
         ______________________________________The following composition was prepared:______________________________________Core:Glipizide               10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgLactose                 50.0   mgSodium stearyl fumarate 1.7    mgCoating:Ammonio methacrylate copolymer                   10.0   mgTriethyl citrate        3.0    mgPolyethylene glycol     1.0    mgHydroxypropylmethylcellulose                   7.0    mg______________________________________ 
    
     EXAMPLE 14 
     
         ______________________________________The following composition was prepared:______________________________________Core:Glipizide               10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgLactose                 50.0   mgSodium stearyl fumarate 1.7    mgCoating:Ammonio methacrylate copolymer                   10.0   mgLactose                 10.0   mgSilicon dioxide         4.0    mg______________________________________ 
    
     EXAMPLE 15 
     
         ______________________________________The following composition was prepared:______________________________________Core:Glipizide               10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgLactose                 50.0   mgSodium stearyl fumarate 1.7    mgCoating:30% polyacrylate dispersion                   15.0   mgSilicon dioxide         6.0    mgTalc                    2.0    mgHydroxypropylmethylcellulose                   6.0    mg______________________________________ 
    
     EXAMPLE 16 
     
         ______________________________________The following composition was prepared:______________________________________Core:Felodipine              10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgSodium stearyl fumarate 1.5    mgCoating:Methacrylic acid copolymer                   10.0   mgPolyethylene glycol     2.0    mgTalc                    2.5    mgSilicon dioxide         4.5    mg______________________________________ 
    
     EXAMPLE 17 
     
         ______________________________________The following composition was prepared:______________________________________Core:Felodipine              10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgSodium stearyl fumarate 1.5    mgCoating:Ammonio methacrylate copolymer                   10.0   mgTriethyl citrate        3.0    mgPolyethylene glycol     1.0    mgHydroxypropylmethylcellulose                   7.0    mg______________________________________ 
    
     EXAMPLE 18 
     
         ______________________________________The following composition was prepared:______________________________________Core:Felodipine              10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgSodium stearyl fumarate 1.5    mgCoating:Ammonio methacrylate copolymer                   10.0   mgLactose                 10.0   mgSilicon dioxide         4.0    mg______________________________________ 
    
     EXAMPLE 19 
     
         ______________________________________The following composition was prepared:______________________________________Core:Felodipine              10.0   mgPEO                     220.0  mgMicrocristalline cellulose                   55.0   mgHydroxy propyl methyl cellulose                   20.0   mgSodium stearyl fumarate 1.5    mgCoating:30% polyacrylate dispersion                   15.0   mgSilicon dioxide         6.0    mgTalc                    2.0    mgHydroxypropylmethylcellulose                   6.0    mg______________________________________ 
    
     EXAMPLE 20 
     
         ______________________________________The following composition was prepared:______________________________________Core:Isosorbide mononitrate   60.0   mgPEO                      100.0  mgMicrocristalline cellulose                    25.0   mglow substituted Hydroxypropylcellulose                    5.0    mgGlycerol behenate        1.9    mgCoating:Methacrylic acid copolymer                    10.0   mgPolyethylene glycol      2.0    mgTalc                     2.5    mgSilicon dioxide          4.5    mg______________________________________ 
    
     EXAMPLE 21 
     
         ______________________________________The following composition was prepared:______________________________________Core:Isosorbide mononitrate   60.0   mgPEO                      100.0  mgMicrocristalline cellulose                    25.0   mglow substituted Hydroxypropylcellulose                    5.0    mgGlycerol behenate        1.9    mgCoating:Ammonio methacrylate copolymer                    5.0    mgTriethyl citrate         1.5    mgPolyethylene glycol      0.5    mgHydroxypropylmethylcellulose                    3.5    mg______________________________________ 
    
     EXAMPLE 22 
     
         ______________________________________The following composition was prepared:______________________________________Core:Isosorbide mononitrate   60.0   mgPEO                      100.0  mgMicrocristalline cellulose                    25.0   mglow substituted Hydroxypropylcellulose                    5.0    mgGlycerol behenate        1.9    mgCoating:Ammonio methacrylate copolymer                    5.0    mgLactose                  5.0    mgSilicon dioxide          2.0    mg______________________________________ 
    
     EXAMPLE 23 
     
         ______________________________________The following composition was prepared:______________________________________Core:Isosorbide mononitrate   60.0   mgPEO                      100.0  mgMicrocristalline cellulose                    25.0   mglow substituted Hydroxypropylcellulose                    5.0    mgGlycerol behenate        1.9    mgCoating:30% polyacrylate dispersion                    7.5    mgSilicon dioxide          3.0    mgTalc                     3.0    mgHydroxypropylmethylcellulose                    3.0    mg______________________________________ 
    
     EXAMPLE 24 
     
         ______________________________________The following composition was prepared:______________________________________Core:Carbidopa                25.0   mgLevodopa                 100.0  mgMicrocristalline cellulose                    20.0   mgPovidone                 4.0    mgLow substituted Hydroxypropylcellulose                    8.0    mgPEO                      20.0   mgSodium stearyl fumarate  1.7    mgCoating:Methacrylic acid copolymer                    50.0   mgPolyethylene glycol      1.0    mgTalc                     1.25   mgSilicon dioxide          2.25   mg______________________________________ 
    
     EXAMPLE 25 
     
         ______________________________________The following composition was prepared:______________________________________Core:Carbidopa                25.0   mgLevodopa                 100.0  mgMicrocristalline cellulose                    20.0   mgPovidone                 4.0    mgLow substituted Hydroxypropylcellulose                    8.0    mgPEO                      20.0   mgSodium stearyl fumarate  1.7    mgCoating:Ammonio methacrylate copolymer                    5.0    mgTriethyl citrate         1.5    mgPolyethylene glycol      0.5    mgHydroxypropylmethylcellulose                    3.5    mg______________________________________ 
    
     EXAMPLE 26 
     
         ______________________________________The following composition was prepared:______________________________________Core:Carbidopa                25.0   mgLevodopa                 100.0  mgMicrocristalline cellulose                    20.0   mgPovidone                 4.0    mgLow substituted Hydroxypropylcellulose                    8.0    mgPEO                      20.0   mgSodium stearyl fumarate  1.7    mgCoating:Ammonio methacrylate copolymer                    5.0    mgLactose                  5.0    mgSilicon dioxide          2.0    mg______________________________________ 
    
     EXAMPLE 27 
     
         ______________________________________The following composition was prepared:______________________________________Core:Carbidopa                25.0   mgLevodopa                 100.0  mgMicrocristalline cellulose                    20.0   mgPovidone                 4.0    mgLow substituted Hydroxypropylcellulose                    8.0    mgPEO                      20.0   mgSodium stearyl fumarate  1.7    mgCoating:30% polyacrylate dispersion                    7.5    mgSilicon dioxide          3.0    mgTalc                     1.0    mgHydroxypropylmethylcellulose                    3.0    mg______________________________________ 
    
     EXAMPLE 28 
     
         ______________________________________The following composition was prepared:______________________________________Core:Pentoxiphylline        400.0  mgPEO                    150.0  mgPovidone               30.0   mgGlycerol behenate      6.0    mgCoating:Methacrylic acid copolymer                  20.0   mgPolyethylene glycol    4.0    mgTalc                   5.0    mgSilicon dioxide        9.0    mg______________________________________ 
    
     EXAMPLE 29 
     
         ______________________________________The following composition was prepared:______________________________________Core:Pentoxiphylline         400.0  mgPEO                     150.0  mgPovidone                30.0   mgGlycerol behenate       6.0    mgCoating:Ammonio methacrylate copolymer                   20.0   mgTriethyl citrate        6.0    mgPolyethylene glycol     2.0    mgHydroxypropylmethylcellulose                   14.0   mg______________________________________ 
    
     EXAMPLE 30 
     
         ______________________________________The following composition was prepared:______________________________________Core:Pentoxiphylline         400.0  mgPEO                     150.0  mgPovidone                30.0   mgGlycerol behenate       6.0    mgCoating:Ammonio methacrylate copolymer                   20.0   mgLactose                 20.0   mgSilicon dioxide         8.0    mg______________________________________ 
    
     EXAMPLE 31 
     
         ______________________________________The following composition was prepared:______________________________________Core:Pentoxiphylline         400.0  mgPEO                     150.0  mgPovidone                30.0   mgGlycerol behenate       6.0    mgCoating:30% polyacrylate dispersion                   30.0   mgSilicon dioxide         12.0   mgTalc                    4.0    mgHydroxypropylmethylcellulose                   12.0   mg______________________________________ 
    
     EXAMPLE 32 
     
         ______________________________________The following composition was prepared:______________________________________Core:Nicardipine            30.0   mgPEO                    150.0  mgMicrocristalline cellulose                  30.0   mgPovidone               5.0    mgMagnesium stearate     2.0    mgCoating:Methacrylic acid copolymer                  6.0    mgPolyethylene glycol    1.2    mgTalc                   1.5    mgSilicon dioxide        2.7    mg______________________________________ 
    
     EXAMPLE 33 
     
         ______________________________________The following composition was prepared:______________________________________Core:Nicardipine              30.0   mgPEO                      150.0  mgMicrocristalline cellulose                    30.0   mgPovidone                 5.0    mgMagnesium stearate       2.0    mgCoating:Ammonio methacrylate copolymer                    6.0    mgTriethyl citrate         1.8    mgPolyethylene glycol      0.6    mgHydroxypropylmethylcellulose                    4.2    mg______________________________________ 
    
     EXAMPLE 34 
     
         ______________________________________The following composition was prepared:______________________________________Core:Nicardipine             30.0   mgPEO                     150.0  mgMicrocristalline cellulose                   30.0   mgPovidone                5.0    mgMagnesium stearate      2.0    mgCoating:Ammonio methacrylate copolymer                   6.0    mgLactose                 6.0    mgSilicon dioxide         2.4    mg______________________________________ 
    
     EXAMPLE 35 
     
         ______________________________________The following composition was prepared:______________________________________Core:Nicardipine             30.0   mgPEO                     150.0  mgMicrocristalline cellulose                   30.0   mgPovidone                5.0    mgMagnesium stearate      2.0    mgCoating:30% polyacrylate dispersion                   9.0    mgSilicon dioxide         3.6    mgTalc                    1.2    mgHydroxypropylmethylcellulose                   3.6    mg______________________________________