Enzyme delivery systems and methods of preparation and use

Abstract

This invention relates to coated digestive enzyme preparations and enzyme delivery systems and pharmaceutical compositions comprising the preparations. This invention further relates to methods of preparation and use of the systems, pharmaceutical compositions and preparations to treat persons having ADD, ADHD, autism, cystic fibrosis and other behavioral and neurological disorders.

What is claimed is: 
     
         1 . An encapsulated digestive enzyme preparation comprising:
 (a) a core containing a digestive enzyme particle; and   (b) a coating comprising an emulsifiable lipid, wherein the coating continuously coats the core and the emulsifiable lipid emulsifies upon exposure to a solvent, wherein the enzyme is present in the preparation in an amount of from about 5% to 95% by weight of the particles.   
     
     
         2 . The preparation of  claim 1 , wherein the core further comprises an amount of pancreatic or digestive enzymes effective for treating a subject suffering from autism, ADD, ADHD, Parkinson's disease, cystic fibrosis, or other neurological conditions or behavioral disorders susceptible to treatment by the enzymes. 
     
     
         3 . The preparation of  claim 1 , wherein the core is of at least about 105 μm to at most about 425 μm. 
     
     
         4 . The preparation of  claim 1  wherein the core is sifted to be at most 40 mesh and at least 140 mesh. 
     
     
         5 . The preparation of  claim 1 , wherein the preparation is non-aerosolizable. 
     
     
         6 . The preparation of  claim 1 , wherein the lipid is selected from hydrogenated soy oil, hydrogenated castor wax, and carnauba wax. 
     
     
         7 . The preparation of  claim 1 , wherein at least about 80% of the enzyme is released by 30 minutes in a dissolution test performed at pH 6.0. 
     
     
         8 . The preparation of  claim 1 , wherein the coating consists essentially of one or more monoglycerides. 
     
     
         9 . The preparation of  claim 1 , wherein the coating comprises monoglycerides. 
     
     
         10 . A pharmaceutical composition comprising a therapeutically effective amount of an encapsulated enzyme preparation, comprising a core which comprises an amount of pancreatic or digestive enzymes effective for treating a subject suffering from autism, ADD, ADHD, Parkinson's disease, cystic fibrosis, or other neurological condition or behavioral disorder susceptible to treatment by the enzymes; and
 a coating comprising an emulsifiable lipid.   
     
     
         11 . The pharmaceutical composition of  claim 10 , in the form of a capsule, a tablet, an ovule, a suppository, a wafer, a chewable tablet, a buccal tablet, a sublingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a pellet, a bead, a pill, a sachet, a sprinkle, a film, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an implant, a powder, a triturate, a platelet, or a strip. 
     
     
         12 . An enzyme delivery system comprising encapsulated enzyme preparation having particles which comprise :
 a core comprising pancreatic or digestive enzymes present in an amount of from about 5% to 95% by weight of the particles; and   a generally uniform coating to provide for controlled release of the enzymes, said coating comprising an emulsifiable lipid;   wherein the particles are non-aerosolizable.   
     
     
         13 . The enzyme delivery system of  claim 12 , wherein the core further comprises an amount of pancreatic or digestive enzymes effective for treating a subject suffering from autism, ADD, ADHD, Parkinson's disease, Cystic fibrosis and/or other neurological condition, the enzymes present in an amount of from about 5% to 95% by weight of the particles. 
     
     
         14 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the emulsifiable lipid is present at about 5%, 30% or 50% by weight in the encapsulated enzyme preparation. 
     
     
         15 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the amount of pancreatic or digestive enzyme present in the encapsulated enzyme preparation is about 5 to 95% by weight of the encapsulated enzyme preparation. 
     
     
         16 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the amount of enzyme present in the encapsulated enzyme preparation is about 80% by weight of the encapsulated enzyme preparation. 
     
     
         17 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the amount of enzyme present in the encapsulated composite is about 70% by weight of the encapsulated enzyme preparation. 
     
     
         18 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the amount of enzyme present in the encapsulated composite is about 70% to 90% by weight of the encapsulated enzyme preparation, and the emulsifiable lipid is hydrogenated soy oil, hydrogenated castor wax, or carnauba wax. 
     
     
         19 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the encapsulated enzyme preparation contains particles, and further wherein at least about 90% of the encapsulated enzyme preparation particles in the encapsulated enzyme preparation are between about #40 and #140 mesh in size, or between about 105 to 425 μm, or where at least about 75% of the particles are between about #40 and #80 mesh, or about 180 to 425 μm. 
     
     
         20 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the encapsulated enzyme preparation contains particles, and further wherein less than about 20% or less than about 15% of the encapsulated enzyme preparation particles can be sieved through #100 mesh, or about 150 gm. 
     
     
         21 . The enzyme delivery system of  claim 12 , further comprising a sachet or pouch. 
     
     
         22 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the emulsifiable lipid comprises at least one hydrophilic group and at least one hydrophobic group. 
     
     
         23 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 22 , wherein the lipid is capable of forming a hydrophilic and hydrophobic interface. 
     
     
         24 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 23 , wherein the interface is a micelle interface. 
     
     
         25 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 24 , wherein the interface is a bilayer interface. 
     
     
         26 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 22 , wherein the emulsifiable lipid is derived from animal or vegetable origins. 
     
     
         27 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 26 , wherein the lipid is selected from the group consisting of palm kernel oil, soybean oil, cottonseed oil, canola oil, and poultry fat, hydrogenated soy oil, hydrogenated castor wax, and carnauba wax. 
     
     
         28 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the emulsifiable lipid is hydrogenated, saturated or partially saturated. 
     
     
         29 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the emulsifiable lipid consists essentially of hydrogenated soy oil. 
     
     
         30 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the emulsifiable lipid is selected from the group consisting of monoglycerides, diglycerides, fatty acids, esters of fatty acids, phospholipids, salts thereof, and combinations thereof 
     
     
         31 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the emulsifiable lipid is a food grade emulsifiable lipid. 
     
     
         32 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 31  wherein the food grade emulsifiable lipid comprises from sorbitan monostearates, sorbitan tristearates, or calcium stearoyl lactylates. 
     
     
         33 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 22  wherein the fatty acid esters are selected from the group consisting of acetic acid esters of mono- and diglycerides, citric acid esters of mono- and di-glycerides, lactic acid esters of mono- and di-glycerides, polyglycerol esters of fatty acids, propylene glycol esters of fatty acids, and diacetyl tartaric acid esters of mono- and diglycerides. 
     
     
         34 . The pharmaceutical composition or enzyme delivery system delivery system of  claim 10  or  12 , wherein at least about 80% of the enzyme is released by 30 minutes in a dissolution test performed at pH 6.0. 
     
     
         35 . The enzyme preparation, pharmaceutical composition or enzyme delivery system of  claim 1 ,  10 , or  12 , wherein the cores are processed by a technique selected from the group consisting of encapsulation, compression, extrusion or molding. 
     
     
         36 . A method for controlling rate of release of a digestive enzyme from an encapsulated digestive enzyme preparation upon exposure to a solvent, the method comprising:
 (a) providing digestive enzyme particles,   (b) coating the digestive enzyme particles with an emulsifiable lipid to form an encapsulated digestive enzyme preparation; wherein about 80% of the enzyme is released by 30 minutes in a dissolution test performed at pH 6.0.   
     
     
         37 . A method for controlling rate of release of a digestive enzyme from an encapsulated composite upon exposure to a solvent, the method comprising:
 (a) providing digestive enzyme particles,   (b) blending an emulsifiable lipid with an amount of one or more additives to obtain a lipid blend; and   (c) coating the digestive enzyme particles with the lipid blend to form an encapsulated digestive enzyme preparation; wherein the emulsifiable lipid and additive are not the same, and wherein the rate of release of the digestive enzyme from the encapsulated composite is decreased as the amount of additive is increased.   
     
     
         38 . A method for controlling rate of release of a digestive enzyme from an encapsulated composite upon exposure to a solvent, the method comprising:
 (a) providing digestive enzyme particles;   (b) blending an emulsifiable lipid with an amount of one or more additives to obtain a lipid blend; and   (c) coating the digestive enzyme particles with the lipid blend to form an encapsulated digestive enzyme preparation; wherein the emulsifiable lipid and additive are not the same, and wherein the rate of release of the digestive enzyme from the encapsulated composite is increased as the amount of additive is decreased.   
     
     
         39 . The method of any one of  claims 36 - 38 , wherein the emulsifiable lipid is hydrogenated soy oil. 
     
     
         40 . The method of any one of  claims 36 - 38 , wherein the particles are of at least about 105 μm to at most about 425 μm 
     
     
         41 . A method for controlling rate of release of a digestive enzyme from an encapsulated digestive enzyme preparation upon exposure to a solvent, the method comprising:
 (a) providing digestive enzyme particles,   (b) coating the digestive enzyme particles with an emulsifiable lipid to form an encapsulated digestive enzyme preparation; wherein the encapsulated digestive enzyme preparation consists essentially of particles of less than about 150 um.   
     
     
         42 . A method of treatment comprising administering to a subject with autism, ADD, ADHD, Parkinson's′ disease, cystic fibrosis, or other behavioral or neurological condition susceptible to treatment with digestive enzymes, at least two doses of a composition comprising a therapeutically effective amount of an encapsulated digestive enzyme preparation comprising:
 (a) a core comprising a digestive enzyme; and 
 (b) a coating comprising an emulsifiable lipid. 
 
     
     
         43 . A method of administering digestive enzymes to a subject with autism, ADD, ADHD, Parkinson‘s’ disease, cystic fibrosis, or other behavioral or neurological condition susceptible to treatment with digestive enzymes, at least two doses of an encapsulated enzyme preparation wherein about 80% of the enzyme is released by 30 minutes in a dissolution test performed at pH 6.0. 
     
     
         44 . A method of administering a sachet or pouch comprising an encapsulated digestive enzyme preparation to a patient in need thereof, the method comprising providing a powered preparation, housed in a sachet or pouch wherein the preparation is administered by addition to food or drink, through direct administration into the oral cavity, or by direct administration into the GI system through an NG-tube, G-tube or other GI entrances or deliveries. 
     
     
         45 . The method of any one of  claims 42 - 44 , wherein the encapsulated digestive enzyme preparation contains only one excipient, whereby the safety of administration is increased. 
     
     
         46 . The method of  claim 45 , wherein the excipient is hydrogenated soy oil. 
     
     
         47 . The method of  claim 45 , wherein the encapsulated digestive enzyme preparation is hypoallergenic. 
     
     
         48 . The method of  claim 44 , wherein the individual is susceptible to treatment with digestive enzymes has an enzyme deficiency. 
     
     
         49 . The method of  claim 48 , where the determination of whether the individual has an enzyme deficiency is made using a biochemical marker. 
     
     
         50 . The method of  claim 49 , where the biochemical marker is FCT level. 
     
     
         51 . The method of  claim 49 , where the biochemical marker is a MET gene mutation. 
     
     
         52 . The method of  claim 48 , wherein the individual has a pathogenic marker of gastrointestinal dysfunction. 
     
     
         53 . A method of preparing an encapsulated controlled release digestive enzyme preparation with enhanced flow properties useful in the treatment of individuals with autism, ADD, ADHD, Parkinson's disease, cystic fibrosis and other neurological conditions, the method comprising:
 (a) screening uncoated digestive enzyme particles to obtain particles of a suitable size for encapsulation; and   (b) coating the screened digestive enzyme particles with an emulsifiable lipid to form an encapsulated digestive enzyme containing a core which contains the digestive enzyme and a coating which contains the emulsifiable lipid.   
     
     
         54 . A method of preparing an encapsulated controlled release digestive enzyme preparation useful in the treatment of individuals with autism, ADD, ADHD, Parkinson's disease, cystic fibrosis and other neurological conditions, the method comprising:
 (a) obtaining digestive enzyme particles ranging from about 105 to 450 microns; and   (b) coating the pancreatic/digestive enzyme with an emulsifiable lipid to form an encapsulated pancreatic/digestive enzyme containing a core which contains the pancreatic/digestive enzyme and a coating which contains the blend of emulsifiable lipid.   
     
     
         55 . The method of  claim 53 , wherein the screened enzyme particles are obtained by sieving digestive enzyme particles using a 40 mesh and a 140 mesh. 
     
     
         56 . The method of  claim 54 , wherein the enzyme particles are obtained by sieving digestive enzyme particles using a 40 mesh and a 140 mesh. 
     
     
         57 . The method of  claim 53  or  54 , wherein the emulsifiable lipid is hydrogenated soy oil. 
     
     
         58 . A method of preparing an encapsulated controlled release digestive enzyme preparation useful in the treatment of individuals with autism, ADD, ADHD, Parkinson's disease, cystic fibrosis and other neurological conditions, the method comprising:
 (a) blending an emulsifiable lipid with one or more additives to obtain a blend;   (b) obtaining screened digestive enzyme particles;   (c) coating the pancreatic/digestive enzyme with a lipid blend to form an encapsulated pancreatic/digestive enzyme containing a core which contains the pancreatic/digestive enzyme and a coating which contains the blend of emulsifiable lipid; and   (d) adjusting batch and oil temperatures during the spray process at periodic time intervals whereby optimal spray conditions are maintained during said process.   
     
     
         59 . The method of  claim 58  wherein the screened enzyme particles range from about 105 to 450 microns.