Patent Publication Number: US-2002004072-A1

Title: &#34;composition providing a sustained release of l-histidine and methods of manufacture thereof&#34;

Description:
FIELD OF THE INVENTION  
       [0001] The present invention relates to compositions containing L-Histidine and which provide a sustained or controlled release of L-Histidine. More specifically, the present invention relates to coatings for L-Histidine which result in a sustained or controlled release of L-Histidine in the gastrointestinal tract.  
       BACKGROUND OF THE INVENTION  
       [0002] L-Histidine is an essential amino acid and is not manufactured in the human body. Therefore, L-Histidine must be obtained from dietary sources. In addition to L-Histidine&#39;s important role in protein assembly and metabolism, L-Histidine is also an effective antioxidant. Accordingly, L-Histidine may be useful in a variety of radical-based disorders. For example, L-Histidine has been demonstrated to be effective in the treatment of infectious diarrhea, inflammatory bowel diseases such as ulcerative colitis and Crohn&#39;s disease. Further, L-Histidine has proven to be useful in the treatment of menstrual cramps, endometriosis as well as ischemia-reprefusion injury and microscopic gastric injuries. The effective dosage range of L-Histidine for a 70 kg adult is from 50 mg to 32 grams per day.  
       [0003] However, one problem associated with the administration of L-Histidine to the gastrointestinal tract is the “rate limiting” effect of the transport systems for L-Histidine and other amino acids. Specifically, active amino acid transport systems are characterized by a maximum rate for the transfer of molar quantity and amino acid classes into a cell. Increasing the concentration of the amino acid available for transport once the maximum transport rate has been reached will not result in an additional increase in transport. As a result, the transport systems are “rate limiting”.  
       [0004] Further, other mechanism that exist to maintain appropriate physiological concentration ranges such as renal clearance, metabolic degration will reduce the excess amino acid present. As a result, the excess amino acid that is not being transported due to the rate limiting effect of the transport system is no longer available for the intended transport or therapeutic process. Amino acid transport systems are discussed by Christensen, “Role of Amino Acid Transport and Counter Transport in Nutrition and Metabolism”, Physiological Reviews, Vol. 70, No. 1 (1990).  
       [0005] A computer-generated pharmacocinetics profile of L-Histidine administered in 2 gram doses orally every two hours is illustrated in FIG. 1. It can be clearly seen from FIG. 1 that the concentration of L-Histidine rises dramatically immediately after the dose but then quickly drops off over the subsequent hour. If it were desired to maintain a 10 mg/dl plasma concentration of L-Histidine, it can be seen from FIG. 1 that it is not possible even with dosing as frequently as every 2 hours.  
       [0006] Accordingly, there is a need for a method for providing a sustained-release or a controlled-release formulation of L-Histidine which will not overload the transport system for this amino acid, the L-system. An advantage of a sustained-release or controlled-release formulation of L-Histidine and other amino acids would be that the transport systems for those amino acids would act more efficiently over a long time period by reducing the rapid peak of plasma concentration illustrated in FIG. 1.  
       [0007] A sustained-release feature would also allow more amino acid to be transported into cells over time without requiring the excessive peak concentrations illustrated in FIG. 1. Such peak concentrations could contribute to toxicity. Further, a sustained-release or controlled-release formulation or system would allow other amino acids to be transported by the same transport system. As a result, by not triggering the rate limiting properties of an amino acid transport system, more than one amino acid can be transported at a time thereby lessening the possibility of adverse effects from amino acid imbalance.  
       [0008] Accordingly, there is a need for a sustained-release and/or a controlled-release composition, method or system for L-Histidine and other amino acids.  
       SUMMARY OF THE INVENTION  
       [0009] The present invention satisfies the aforenoted need by providing a composition that provides a sustained release of L-Histidine. The composition comprises L-Histidine coated with a hydrophobic coating or an acid-resistant coating.  
       [0010] In an embodiment, the hydrophobic coating comprises resins, sugars, methylcellulose, magnesium styrate, lactose, and cocoa butter.  
       [0011] In an embodiment, the composition comprises a mixture of uncoated L-Histidine and sustained release or controlled release L-Histidine.  
       [0012] In an embodiment, the L-Histidine is coated with glyceride.  
       [0013] In an embodiment, the L-Histidine is hot-melt coated with glyceride.  
       [0014] In an embodiment, the coating is a glyceride derived from rapeseed.  
       [0015] In an embodiment, the coating is a glyceride sold under the trademark COMPRITOL®888.  
       [0016] In an embodiment, the weight percent of COMPRITOL®888 ranges from about 5% to about 20%.  
       [0017] In an embodiment, the L-Histidine has a particle size ranging from about 125 μm to about 500 μm.  
       [0018] In an embodiment, the composition is provided in a tablet form, gelcap form, a powdered form, a drink form such as a sports drink, an oral rehydration solution, eye drops or ophthalmic solutions, intravenous solutions.  
       [0019] In an embodiment, the present invention provides a method of manufacturing an L-Histidine containing composition that provides a sustained release of L-Histidine. The method comprises the steps of providing L-Histidine particles, fluidizing the L-Histidine particles in a gas flow, and introducing a hydrophobic or acid-resistant coating into the gas flow to coat the L-Histidine particles with the glyceride.  
       [0020] In an embodiment, the coating is a glyceride.  
       [0021] In an embodiment, the gas has a temperature ranging from about 100° C. to about 200° C.  
       [0022] In an embodiment, the glyceride is introduced into the gas flow with a nozzle.  
       [0023] In an embodiment, the gas flow has a pressure ranging from 2 bars to 4 bars.  
       [0024] In an embodiment, the glyceride is a glyceride derived from rapeseed.  
       [0025] In an embodiment, the glyceride is sold under the trademark COMPRITOL®888.  
       [0026] In an embodiment, the weight percent of the COMPRITOL®888 ranges from about 5% to about 20%.  
       [0027] In an embodiment, the L-Histidine particles have a particle size ranging from 125 μm to 500 μm.  
       [0028] In an embodiment, the present invention provides a composition for providing a sustained release of an amino acid for therapeutic purposes. The composition comprises said amino acid coated with a glyceride.  
       [0029] In an embodiment, the therapeutic amino acid is hot-melt coated with the glyceride and, in a further embodiment, the glyceride is sold under the trademark COMPRITOL®888.  
       [0030] It is an advantage of the present invention to provide an improved formulation for the controlled or sustained release of L-Histidine.  
       [0031] It is a further advantage of the present invention to provide an improved formulation for the controlled or sustained release of L-Histidine for the treatment or prevention of cardiac diseases and cardiac surgery, central nervous conditions and neurosurgery, infectious diseases, inflammatory conditions, neurodegenerative disorders, cancers, cancer treatments, digestive, metabolic and gastrointestinal disorders, gynecological conditions, joint, muscle and other pains, inflammation, aging and the sequelae of these conditions.  
       [0032] It is a further advantage of the present invention to provide an improved sustained or controlled release of L-Histidine for use as a drug, a medical food, a dietary supplement and/or a nutritional or nutriceutical product.  
       [0033] It is another advantage of the present invention that a lower overall dose of L-Histidine can be administered using the sustained-release and controlled-release formulations of the present invention. 
     
    
    
     [0034] Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred embodiments and upon reference to the accompanying figures.  
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0035]FIG. 1 illustrates, graphically, a pharmacokinetics profile of an uncoated oral dose of L-Histidine at 2 hour intervals; and  
     [0036]FIG. 2 illustrates, graphically, the dissolution profiles of L-Histidine preparations coated in accordance with the present invention and uncoated L-Histidine preparations. 
    
    
     DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS  
     [0037] In a preferred embodiment, L-Histidine powder is formulated into a drinkable suspension, solution or emulsion, an eatable powder and in tablet form by first coating the L-Histidine powder with a glyceride material, more specifically, a glyceride material derived from rapeseed and, still more specifically, a glyceride material sold under the trademark COMPRITOL®888 utilizing a hot melt coating process available from Gattefosse Corporation of Lyon, France. The specific process utilized is known as the “Gattecoat Hot Melt Coating Process”. L-Histidine particles, in a size ranging from 125 μm to 500 μm are provided and fluidized in a gas, such as air, at a temperature ranging from 100 ° C. to 200° C., more preferably, about 140° C. The pressure of the fluidizing air can range from 2 to 4 bars, preferably, 3 bars. The temperature of the COMPRITOL®888 coating is preferably about the same temperature as the fluidizing air. The ratio of the L-Histidine powder to the COMPRITOL®888 can range from 80:20 to 95:5. The COMPRITOL®888 is introduced into the fluidizing air flow by way of a spray nozzle.  
     [0038] Table 1 below summarizes the results of the coating levels achieved for two runs. In Run No. 1, the ratio of L-Histidine to COMPRITOL®888 was 93.3:6.7. The temperature of the fluidizing air was 140° C., the pressure of the fluidizing air was 3 bars. The particle sizes were less than 1 mm in diameter. In Run No. 2, the ratio of L-Histidine to Al 2 O 3  to COMPRITOL®888 was 89.6:2.8:7.6. Al 2 O 3  was introduced to reduce the electrostatic interaction between the particles. Al 2 O 3  is a standard tablet excipient. The temperature of the fluidizing air was 140° C.; the pressure of the fluidizing air was 3 bars. The results for Run Nos. 1 and 2 are provided in Table 1.  
               TABLE 1                          Determination of Coating Level Through Histidine       Quantification                                     Recorded   Estimated           Theoretical Value   Value   Value                                         L-His-   Compritol ®       L-His-   Compritol ®           tidine   888   Al 2 O 3     tidine   888                                                 L-Histidine   100.0%   0.0%       99.4%    0.0%       (n = 2)       Run No. 1   74.6%    25.4%       85.2%   14.2%       Run No. 2   89.6%    7.6%   2.8%   90.1%    6.3%                  
 
     [0039] The results of Table 1 are based upon a histidine quantification. The results illustrated in Table 2 are based upon a COMPRITOL®888 quantification and, as shown, are in agreement with those of Table 1.  
               TABLE 2                          Determination of Coating Level Though       Compritol ® 888 Determination                                     % Compritol ® 888                   estimated by           % Compritol ®   gravimetric difference   % Compritol ®           888   from L-His-   888           sprayed   dine determination   measured                                         Run No. 1   25.4   14.2   13.1        Run No. 2    7.6    6.3   6.54                  
 
     [0040] The particle size distribution of Run Nos. 1 and 2 are shown in Table 3.  
               TABLE 3                          Particle Size Classification                             Modal size of L-Histidine   Modal size of           powder 80 μm   coated material 125 μm                                     Run No. 1   75.8%   125 μm           15.5%   315 μm           19.7%    80 μm       Run No. 2   60.4%   125 μm            5.2%   315 μm           22.6%    80 μm                  
 
     [0041] Density measurements were carried out using standard pharmaceutical methods for the measurement of bulk and tapped density. A comparison of the apparent density of the freshly dispensed or bulk powder to that of powder after settling is shown in Table 4.  
               TABLE 4                          Apparent Bulk and Tapped Densities of Coated and       Uncoated L-Histidine                             Bulk Density   Tapped Density                                             L-Histidine   0.55   0.79           Run No. 1   0.53   0.66           Run No. 2   0.51   0.66                      
 
     [0042] As shown in Table 4, the reduction in density is a result of the coating of the powder with the less dense COMPRITOL®888. The large reduction in tapped density, however, reflects the fact that the particles are lubricated by the COMPRITOL®888 coating and are easily able to slide over one another, allowing them to be packed more densely into a smaller volume. The coated L-Histidine is more hydrophobic than uncoated L-Histidine.  
     [0043] The dissolution of uncoated L-Histidine is illustrated in FIG. 1. Obviously, doses every 2 hours of 2 grams orally do not provide a consistent plasma histidine concentration. The ability of the COMPRITOL®888 coating to slow the dissolution of L-Histidine was carried out using standard pharmacopcal tablet dissolution equipment. Approximately 600 milligrams of coated material were filled into standard gelatin capsules. The capsules were placed in a “sinker”and lowered into a 1 liter chamber of an Erweka DT6 dissolution apparatus. The sample chambers each contained 1 liter of distilled water maintained at 37° C. The chambers were paddle-stirred at 100 rpm. Samples were taken at various time intervals and analyzed for L-Histidine concentration at various time intervals. A further run was carried out in which the capsules were filled with L-Histidine only; in this case, full dissolution of the capsule and contents were observed in under 5 minutes. The run was not analyzed for L-Histidine content since immediate full solubilisation was obvious.  
     [0044] The above parameters, together with the observations of the capsule behavior, are provided in Table 5. The parameters used to calculate the L-Histidine release from the Run Nos. 1 and 2 preparation, are provided in Tables 6 and 7 respectively. The L-Histidine release rate for Nos. 1 and 2 is compared, graphically, in FIG. 2.  
               TABLE 5                          Dissolution Parameters and Description of Experiment                                                 delta T       Chamber   Chamber   Chamber   Chamber   Chamber   Chamber           hours   Time   1   2   3   4   5   6   Observations                                                     Product Weight in   0.5393   0.5285   0.5495   0.5244   0.5407   0.5717           Capsule       Calculated Weight   0.4627   0.4932   0.4715   0.4914   0.4639   0.5357       of L-Histidine                                                     10 h 05                                     0.5   10 h 30       1   11 h 06   1       1       1       1   11 h 09       1       1       1           11 h 43                           Capsules in Chambers 2, 4 and 6                                       dissolving The remaining                                       chambers show no evidence of                                       dissolution       2   12 h 04   2       2       2       Capsules in Chamber 1, 3 and 5                                       dissolving       2   12 h 08       2       2       2       3   13 h 05       3       3       3   Dissolution in Chambers 1, 3 and                                       5 slow           14 h 05       5   15 h 05       4       4       4       6   16 h 05   3       3       3       6   16 h 08       5       5       5   Capsules in Chambers 2, 4 and 6                                       completely dissolved Particles                                       dispersed       7   17 h 05   4       4       4       In Chambers 1, 3 and 5 the                                       powder has remained in the form                                       of a capsule Particles have not                                       dispersed       7   17 h 08       6       6       6           18 h 30                           All material in Chambers 2, 4 and                                       6 dispersed In Chambers 1, 3                                       and 5 the powder has retained the                                       shape of the capsule and is not                                       dispersed       22, 33    8 h 20   5   7   5   7   5   7       24 h 00   10 h 00   6   8   6   8   6   8   Some particulate matter still                                       present in Chambers 1, 3 and 5                                  
 
     [0045]               TABLE 6                          Calculation of L-Histidine Release with Time for Run No. 1       Run No. 1, theoretical weight of L-Histidine present in       the chamber: 0.4627 g                                             Time                                   (h)   μmol % ml   Ci (g/L)   Vi (ml)   Vp (ml)   D   Cf (g/L)   %                                                     0   0.0   0.000   1000   1000    1.00   0.000   0.0       1   70.4   0.109   1000   1000    1.00   0.109   23.6       2   107.1   0.166   1000   990   1.01   0.165   35.6       6   245.6   0.381   1000   980   1.02   0.373   80.7       7   284.7   0.442   1000   970   1.03   0.429   92.6       24    321.8   0.499   1000   950   1.05   0.474   102.5                    
     [0046]               TABLE 7                          Calculation of L-Histidine Release with Time for Run No. 2       Run No. 2, theoretical weight of L-Histidine present in       the chamber 0.4952 g                                             Time                                   (h)   μmol % ml   Ci (g/L)   Vi (ml)   Vp (ml)   D   Cf (g/L)   %                                                     0   0.0   0.0   1000   1000    1.00   0.0   0.0       1   142.2   0.2   1000   1000    1.00   0.2   44.6       2   209.7   0.3   1000   990   1.01   0.3   65.1       3   272.8   0.4   1000   980   1.02   0.4   83.8       5   355.7   0.6   1000   970   1.03   0.5   108.1       6   321.1   0.5   1000   960   1.04   0.5   96.6       22.5   311.7   0.5   1000   940   1.06   0.5   91.8                    
     [0047] Obviously, the release curves shown in FIG. 2 indicate that coating the L-Histidine has a significant on slowing its dissolution. Furthermore, increasing the level of coating of the L-Histidine increases the degree to which the dissolution of the L-Histidine is retarded.  
     [0048] It is anticipated that an ideal particle size range will fall between 300 and 500 μm.  
     [0049] It is further anticipated that other hydrophobic and/or acid-resistant coatings will be useful as well. Hydrophobic coatings will delay the dissolution of the L-Histidine in the stomach and the gastrointestinal tract. Acid-resistant coatings will similarly delay the dissolution of the L-Histidine in the stomach and gastrointestinal tract.  
     [0050] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is, therefore, intended that such changes and modifications be covered by the appended claims.