Abstract:
A method for the manufacture of oral controlled release dosage units containing hydroxypropyl methylcellulose wherein the aqueous granulation is performed in the presence of one or more solutes, which inhibit gel formation during the granulation but allows the formation of a gel when administered orally. Also the new dosage units prepared according to the invention are included.

Description:
This application is a continuation of application Ser. No. 07/803,474, filed Dec. 4, 1991, and now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a method of manufacture of a controlled release solid unit dosage form based on the hydrophilic gel matrix principle for administration of medicaments. Also the solid unit dosage forms are included. Specifically, this invention relates to the use of a waterbased granulating solution containing an additive which inhibits gel formation of hydroxypropyl methylcellulose (HPMC) during granulation but not of the gelling of the final dosage form in vivo, which is necessary for its function. 
     2. Background and Prior Art 
     Granulation of hydrophilic gel matrix dosage forms containing HPMC as main gelling agent, has usually been performed with ethanol and methanol (U.S. Pat. No. 4,871,548), isopropanol and aqueous mixtures thereof (EP-A-157695). According to the product information brochure from a manufacturer of this polymer, (DOW 1987, `Formulating for controlled release with METHOCEL cellulose ethers`, page 24-5) aqueous granulation of very finely sized particles can be applied, but it is also pointed out that in doing so, a situation may occur, where the granules obtained are very hard and difficult to grind. This is connected with a high polymer content of the granulate. The proposed way in the brochure to minimize these problems is to granulate with a hydroalcoholic solution and thereby reduce the water content in the system. 
     Production of such dosage forms has also been performed by water granulation of parts of the composition, exluding the gelling agent. This is described in the above cited EP-A-157695. In other cases direct compression have been used (U.S. Pat No. 4,369,172). 
     SUMMARY OF THE INVENTION 
     The object of the present invention is to provide a method of manufacture, which includes a water-based granulation process for controlled release dosage forms containing HPMC as gel forming agent. 
     The method provides homogenous granulates with desired flow properties and enables production of controlled release tablets without the use of volatile organic solvents. 
     It has been found that this waterbased granulation procedure for HPMC based dosage forms can be successfully performed by the use of a granulating solution containing an additive of a polyhydric alcohol or other substances which inhibit the rapid hydration of the gelling substance or substances during granulation. 
     DETAILED DESCRIPTION OF THE INVENTION 
     According to the present invention, advantages and improvements over prior art describing water-based granulation of HPMC based dosage forms can be obtained by adding one or more substances, dissolved in the granulating solution. The solutes inhibit the rapid hydration of HPMC during the said process step. Examples of such substances are polyhydric alcohols or other substances defined below. Without the addition of the above-mentioned substances very hard or flaky granules with poor flowability are produced. 
     The polyhydric alcohols, effective in the water-based granulation of this invention, include, but are not limited to, polyethylene glycols (PEG), polypropylene glycols (PPG), poloxyethylene-polyoxypropylene glycols (Pluronics®) sugar alcohols such as sorbitol, mannitol, xylitol etc and sugars, for instance such as sucrose, galactose, glucose, fructose. Another substance found to achieve the same effect is polyvinyl pyrrolidone (PVP). The said additive substances, usually in the concentration range between 20-50% w/w, preferably between 25-45%, have been found to be effective on, but are not limited to, viscosity grades of hydroxypropyl methylcelluloses including 50 cps and high viscosity grades of 4,000, 10,000 and 15,000 cps. 
     In the following examples the term &#34;active substance&#34; is any compound suitable as the active component in a pharmaceutical dosage form. 
    
    
     EXAMPLES 
     Example 1 
     Controlled release tablets were prepared by granulating 19.0 parts active substance, 100 parts lactose, 78.0 parts HPMC 50 cps, 60 parts HPMC 10,000 cps, 25 parts hydroxypropyl cellulose (HPC), with a solution of 30 parts PEG 6,000 dissolved in 70 parts of water. The dried granulate was lubricated with 3.2 parts sodium stearyl fumarate. 
     As reference preparation (Ref.ex. I) the same ingredients were granulated with pure water, that is without the addition of the polyhydric alcohol. 
     
         ______________________________________                Example 1 Ref. ex. IIngredient           mg/tablet mg/tablet______________________________________1.  Active substance     19.0      19.02.  Lactose pwd          100.0     100.03.  HPMC (Metolose ® 60SH50)                    78.0      78.04.  HPMC (Methocel ® E10MCR)                    60.0      60.05.  HPC (Klucel ® LF)                    25.0      25.06.  PEG (Carbowax ® 6000)                    35        --7.  Water, purified      81.7      1178.  Sodium stearyl fumarate (Pruv ®)                    3.2       3.2______________________________________ 
    
     Ingredients 1 to 5 were mixed. The mixture was granulated with a solution made of ingedients 6 and 7. After drying, the granulate was mixed with the lubricant, 8. The granulate obtained in ref.ex. I, was hard and flaky, and the milling was almost impossible to perform. Some of it had to be ground with pestle and mortar. No difficulties were experienced with the granulate in example 1. 
     Compression to tablets were performed on a Korsch Pharmapress 100 with 10 mm circular punches. The tablet machine was equipped with compression force registration. 
     
         ______________________________________             Ex. 1 Ref. ex. I______________________________________Tablet weight:      320 mg  319 mgTablet compression force (kN):               13.20   11.2Tablet hardness (kP):               5.5      5.6______________________________________ 
    
     Example 2. 
     Controlled release tablets were prepared by granulating 95.0 parts active substance, 40.0 parts HPMC 50 cps, 160 parts HPMC 10,000 cps, 50 parts HPC with a solution of 30 parts PEG 6,000 dissolved in 70 parts of water. The dried granulate was lubricated with 3.6 parts of sodium stearyl fumarate. 
     As a reference preparation (Ref.ex. II) the ingredients were granulated with 99.5% ethanol and then lubricated in the same manner. 
     
         ______________________________________                Example 2 Ref. ex. IIIngredient           mg/tablet mg/tablet______________________________________1.  Active substance     95.0      95.02.  HPMC (Metolose ® 60SH50)                    40.0      40.03.  HPMC (Methocel ® E10MCR)                    160.0     160.04.  HPC (Klucel ® LF)                    50.0      50.05.  PEG (Carbowax ® 6000)                    30        --6.  Water, purified      70        --    Ethanol 99.5%        --        2617.  Sodium stearyl fumarate                    3.6       3.3    (Pruv ®)______________________________________ 
    
     Ingredients 1 to 4 were mixed. The mixture was granulated with a solution made of ingredients 5 and 6. After drying the granulate was mixed with the lubricant, 7. 
     Compression to tablets were performed on a Korsch Pharmapress 100 with 11 mm circular punches. The tablet machine was equipped with compression force registration. 
     
         ______________________________________            Example 2.                    Ref. ex. II______________________________________Tablet weight:     379 mg    348 mgTablet compression force (kN):              14.0      8.6Tablet hardness (kP):               5.3      5.5______________________________________ 
    
     The release rate was determined from 6 individual tablets in USP dissolution apparatus 2 with the paddle rotating at 
     100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37° C. was used as dissolution medium. 
     
         ______________________________________    Ex. 2         Ref. ex. II    cumulative    cumulative    % released    % releasedhours    average (min-max)                  average (min-max)______________________________________2        14 (14-15)    15 (14-15)4        25 (24-25)    24 (23-25)6        36 (35-37)    34 (33-35)10       52 (51-54)    51 (48-52)24        98 (96-101)  91 (87-93)______________________________________ 
    
     In vitro data obtained show no difference in the release rates of the two formulations. 
     Examples 3-4 
     Controlled release tablets were prepared by granulating 38.0 parts active substance, 19.5 parts lactose, 37.2 parts HPMC 50 cps, 82.8 parts HPMC 10,000 cps, 37.5 parts HPC with a solution of 30 parts PEG 6,000 (Ex. 3) or PVP K-25 (Ex. 4) dissolved in 70 parts of water. The dried granulate was lubricated with 1.2 parts of sodium stearyl fumarate. 
     
         ______________________________________                Example 3 Example 4Ingredient           mg/tablet mg/tablet______________________________________1.  Active substance     38        382.  Lactose pwd          19.5      19.53.  HPMC (Metolose ® 60SH50)                    37.2      37.24.  HPMC (Methocel ® E10MCR)                    82.8      82.85.  HPC (Klucel ® LF)                    37.5      37.56.  PEG (Carbowax ® 6000)                    30        --    PVP (Povidone ® K-25)                    --        307.  Water, purified      70        708.  Sodium stearyl fumarate                    1.2       1.2    (Pruv ®)______________________________________ 
    
     Ingredients 1 to 5 were mixed. The mixture was granulated with a solution made of 6 and 7. After drying the granulate was mixed with 8. 
     Compression to tablets were performed on a Korsch Pharmapress 100 with 9 mm circular punches. The tablet machine was equipped with compression force registration. 
     
         ______________________________________          Example 3                  Example 4______________________________________Tablet weight:   246 mg    246 mgcompression force (kN):            10.4      10.9tablett hardness (kP):             4.9       7.0______________________________________ 
    
     The release rate was determined in USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37° C. was used as dissolution medium. 
     
         ______________________________________      Cumulative % released      Average (min-max)      Example 3.              Example 4.______________________________________2 h          24 (23-24)                  23 (23-24)4 h          40 (38-43)                  40 (29-41)6 h          56 (54-60)                  57 (55-58)10 h         85 (81-91)                  85 (82-87)______________________________________ 
    
     The examples show that PEG 6000 and PVP K-25 both function in the process. 
     Examples 5-8 
     Controlled release tablets were prepared by granulating 38.0 parts active substance, 19.5 parts lactose, 51.4 parts HPMC 50 cps, 68.6 parts HPMC 10,000 cps, 37.5 parts HPC with a solution of 30 parts substances according to the table below, dissolved in 70 parts of water. The dried granulate was lubricated with 2.5 parts of sodium stearyl 30 fumarate. 
     
         ______________________________________             Example             5    6      7       8Ingredient          mg/tablet______________________________________1.  Active substance    38     38   38    382.  Lactose pwd         19.5   19.5 19.5  19.53.  HPMC (Metolose ® 60SH50)                   51.4   51.4 51.4  51.44.  HPMC (Methocel ® E10MCR)                   68.6   68.6 68.6  68.65.  HPC (Klucel ® LF)                   37.5   37.5 37.5  37.56.  PEG (Carbowax ® 6000)                   30     --   --    --    PEG (Carbowax ® 20M)                   --     30   --    20    PEG (Polyox ® WSRN 10)                   --     --   --    10    Sorbitol            --     --   30    --7.  Water, purified     70     70   70    708.  Sodium stearyl fumarate                   2.5    2.5  2.5   2.5    (Pruv ®)______________________________________ 
    
     Ingredients 1 to 5 were mixed. The mixture was granulated with a solution made of 6 and 7. After drying the granulate was mixed with 8. 
     Compression to tablets was performed on a Korsch Pharmapress 100 with 9 mm circular punches. The tablet machine was equipped with compression force registration. 
     
         ______________________________________          Ex. 5               Ex. 6    Ex. 7  Ex. 8______________________________________Tablet weight (mg):            247    247      247  247compression force (kN):            11.9   10.6     10.9 11.0tablet hardness (kP):             5.1    6.1      8.7  5.5______________________________________ 
    
     The release rates were determined in USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8, kept at 37° C., was used as dissolution medium. 
     
         ______________________________________Cumulative % releasedAverage (min-max)Ex. 5       Ex. 6      Ex. 7      Ex. 8______________________________________2 h  26 (25-27) 24 (23-25) 25 (24-26)                               26 (24-27)4 h  46 (44-46) 43 (41-44) 45 (43-46)                               44 (42-46)6 h  64 (63-66) 62 (60-64) 64 (62-67)                               62 (59-64)10 h  99 (96-108)            99 (97-102)                      96 (93-99)                                98 (91-103)______________________________________ 
    
     Examples 9-10 
     Controlled release tablets were prepared by granulating 54.3 parts active substance, 30.0 parts mannitol, 154 parts HPMC 50 cps, 221 parts HPMC 10,000 cps, 37.5 parts HPC, 0.3 parts propyl gallate with a solution of 45 parts PEG 20,000 (Ex. 9) or PVP K-25 (Ex. 10) dissolved in 105 parts of water. The dried granulate was lubricated with 2.7 parts of sodium stearyl fumarate. 
     
         ______________________________________                Example 9Ingredient           mg/tablet Example 10______________________________________1.  Active substance     54.3      54.32.  Mannitol pwd         30.0      30.03.  HPMC (Metolose ® 60SH50)                    154.0     154.04.  HPMC (Methocel ® E10MCR)                    221.0     221.05.  HPC (Klucel ® LF)                    37.5      37.56.  Propyl gallate       0.3       0.37.  PEG (Carbowax ® 20M)                    45.0      --    PVP (Povidone ® K-25)                    --        45.08.  Water                105.0     105.09.  Sodium stearyl fumarate (Pruv ®)                    2.7       2.7______________________________________ 
    
     Ingredients 1 to 6 were mixed. The mixture was granulated with a solution made of 7 and 8. After drying the granulate was mixed with 9. 
     Compression to tablets were performed on a Korsch Pharmapress 100 with 11 mm circular punches. The tablet machine was equipped with compression force registration. 
     
         ______________________________________          Example 9                  Example 10______________________________________Tablet weight:   545 mg    545 mgcompression force (kN):            20        19tablet hardness (kP):            7.7       12.2______________________________________ 
    
     The release rate was determined in USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37° C. was used as dissolution medium. 
     
         ______________________________________      Cumulative % released      Average (min-max)      Example 9              Example 10______________________________________2 h          17 (17-18)                  18 (17-18)4 h          28 (28-29)                  28 (28-29)6 h          38 (38-39)                  38 (37-39)10 h         55 (54-56)                  54 (53-56)16 h         74 (73-76)                  73 (71-74)______________________________________ 
    
     The examples show that PEG 20000 and PVP K-25 both function in the process. 
     The best mode known at present is to prepare dosage forms according to examples 9 or 10.