Abstract:
Oral dosage forms for poorly soluble amine drugs are provided. Such dosage forms include an ionizable compound such as an organic acid, an amphiphilic polymer and a release rate-controlling membrane. Such dosage forms allow for the consistent release of the active agent in both gastric pH conditions and in the intestine. Methods of making such dosage forms are also provided.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to oral dosage forms for poorly soluble amine drugs. 
       BACKGROUND OF THE INVENTION 
       [0002]    It is well understood that solubility of therapeutic agents in physiological fluids is a prerequisite for absorption in the gastrointestinal tract and that weak bases are soluble in gastric pH. Poorly soluble basic active compounds tend to dissolve in the stomach but may precipitate at a higher pH, as in the intestine, or result in dangerously high C max  levels of the active compound. 
         [0003]    Several strategies have been adopted in an attempt to address such problems. These include (a) co-administration of an ionizable compound that promotes solubility in situ in the intestine and (b) use of a sustained release coat to protect the poorly soluble basic drug from rapid dissolution in the stomach. 
         [0004]    However, such attempts have not been entirely successful and have a tendency (a) for acid compounds to react with the drug substance or base resulting in the formation of salts; (b) for acid interaction to result in other types of incompatibility between the dosage form and the active agent; and (c) when released intact in the gastrointestinal tract to create hyperacidity which may cause gastric upset, or after long term use, ulceration. 
       SUMMARY OF THE INVENTION 
       [0005]    The present invention provides oral dosage forms for poorly soluble amine drugs that overcome the problems characterizing previous dosage forms. Such dosage forms may include an ionizable core, an amphiphilic polymer, a poorly soluble amine active pharmaceutical ingredient (“API”) and a rate-controlling membrane coating. 
         [0006]    Embodiments of the present invention provide a solid dosage form for oral administration that comprises an ionizable compound used as a core which is coated with the following: (a) a barrier layer with or without release rate-controlling properties; (b) a mantle which includes a matrix of API and amphiphilic polymers, wherein such matrix may be prepared by dispersing the API and a solubilizer in a solvent in appropriate proportions; and (c) a release rate-controlling layer wherein the substrate comprises a permeable membrane which includes hydrophobic and hydrophilic polymers, and a plasticizer. 
         [0007]    The present invention also includes methods of making dosage forms for poorly soluble amine drugs. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0008]      FIG. 1  is a schematic of a representative dosage form according to the present invention. 
           [0009]      FIG. 2  is a schematic of a second representative dosage form according to the present invention. 
           [0010]      FIG. 3  provides a representative flow chart for making oral dosage forms according to the present invention. 
           [0011]      FIG. 4  provides a representative flow chart for making oral dosage forms according to the present invention. 
           [0012]      FIG. 5  provides a representative flow chart for making oral dosage forms according to the present invention. 
           [0013]      FIG. 6  provides a representative flow chart for making oral dosage forms according to the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0014]    The present invention provides oral dosage forms for poorly soluble amine drugs and methods of making such dosage forms that unexpectedly overcome the problems characterizing previously described dosage forms. 
         [0015]    It has been unexpectedly discovered that the combination of an ionizable compound with an amphiphilic compound provides greatly enhanced solubility of a poorly soluble amine compound. It has also been unexpectedly discovered that the solubility of poorly soluble amine compounds may be further enhanced when the amphiphilic compound has a hydrophilic-lipophilic balance (“HLB”) greater than about 7.0. 
         [0016]    In certain embodiments the amphiphilic polymer may have an HLB above about 8.0 or 9.0 or 10.0. In additional embodiments the amphiphilic polymer may have an HLB above about 12.0, 14.0, 16.0, 18.0 or 20.0. 
         [0017]    As shown in  FIG. 1 , in a representative embodiment of the present invention, the oral dosage form may include (1) an ionizable compound, (2) an amphiphilic polymer, (3) an API and (4) a rate-controlling membrane. 
         [0018]    In certain embodiments the ionizable compound may include an organic acid. As shown in Table 1 below, such organic acids may include, for example, citric acid, tartaric acid, fumaric acid, maleic acid, succinic acid, carbomer (polyacrylic acid), phthalic acid, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate or combinations thereof. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Organic Acid 
                 pKa 
               
               
                   
                   
               
             
             
               
                   
                 Citric Acid 
                 3.13, 4.76, 6.40 
               
               
                   
                 Tartaric Acid 
                  2.98 
               
               
                   
                 Fumaric acid 
                  3.03 
               
               
                   
                 Maleic acid 
                 1.92, 6.27 
               
               
                   
                 Succinic Acid 
                 4.16, 5.61 
               
               
                   
                 Carbomer 
                 6.0 
               
               
                   
                 Phthalic acid 
                 2.95, 5.41 
               
               
                   
                 Poly-(methacrylic acid, methyl 
                 6.0 
               
               
                   
                 methacrylate) 1:1 polymer [Eudragit L] 
               
               
                   
                 Poly-(methacrylic acid, methyl 
                 6.0 
               
               
                   
                 methacrylate) 1:2 polymer [Eudragit S] 
               
               
                   
                 Hydroxypropyl methylcellulose 
                 5.5 
               
               
                   
                 phthalate 
               
               
                   
                   
               
             
          
         
       
     
         [0019]    In certain embodiments the ionizable compound has a pKa less than or equal to about 6.0. 
         [0020]    In certain embodiments the ionizable core may be coated with a barrier membrane which serves as a physical barrier preventing the interaction of the core with the API. This barrier may be coated onto the core by fluid-bed coat or by other suitable means. The composition of the barrier coat may include an ionizable compound release rate-controlling agent such as ethyl cellulose and hydroxypropyl methylcelluose. Such barrier membranes may be used to regulate the availability of an organic acid for the API during the dissolution process, which, in certain embodiments of the present invention, may improve the bioavailability of the poorly soluble amine drug. Such barrier membranes also reduce the risk of dose dumping of the ionizable core and the side effects associated therewith, such as gastro-intestinal upset, or after chronic use, ulceration. Such barrier membranes also may lower the risk of dose dumping of the API and side effects associated therewith, such as high C max . 
         [0021]    Certain embodiments of the present invention also may include a mantle which may comprise an API in an amphiphilic polymer. Such mantle may be coated on the barrier layer described above. The mantle may be prepared by dispersing an API and an amphiphilic polymer in an appropriate solvent and spray-coating the dispersion onto the core. 
         [0022]    In certain embodiments the amphiphilic polymer may include polyethylene glycol 6000/vinylcaprolactam/vinyl acetate 13/57/30 (SoluPlus®), d-α-tocopheryl polyethyleneglycol 1000 succinate (Vitamin E-TPGS), poloxamer (Pluronic®) or combinations thereof. In certain embodiments the amphiphilic polymer may have a molecular weight greater than about 50,000 Da. The amphiphilic polymer also may have an HLB greater than or equal to about 7.0. 
         [0023]    According to certain embodiments of the present invention, the API may have a molecular weight less than about 550 Da, preferably less than about 500 Da. The nitrogen content of the API in certain embodiments may be from about 3% to about 23%, and in other embodiments from about 8% to about 15%. In certain embodiments the API may have a pKa from about 5 to about 11 and in other embodiments from about 8 to about 9. Table 2 provides a non-limiting list of representative poorly-soluble amine APIs. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                 Nitrogen Content 
                   
               
               
                 Amine Drug 
                 Molecular Weight 
                 (% of mol. Wt.) 
                 pKa 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Paliperidone 
                 426.484 
                 13.13 
                 8.2, 8.6 
               
               
                 Donepezil 
                 379.492 
                 3.7 
                 8.9 
               
               
                 Tamsulosin 
                 408.48 
                 6.85 
                  8.37, 10.23 
               
               
                 MethylPhenidate 
                 233.31 
                 6 
                 8.9 
               
               
                 Olanzapine 
                 312.439 
                 17.92 
                     5, 7.4 
               
               
                 Dipyridamole 
                 504.626 
                 22.1 
                 6.4 
               
               
                   
               
             
          
         
       
     
         [0024]    In certain embodiments the mantle may be coated with a drug release rate-controlling membrane. Such membranes include, but are not limited to, hydrophobic polymers such as ethylcellulose, methylcellulose, propylcellulose, ethylmethylcellulose, cellulose acetate, cellulose acetate propionate or ethyl acrylate and methyl methacrylate copolymer, and optionally include enteric polymers such as methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcelluose phthalate and hydroxypropyl methylcellulose acetate succinate, hydrophilic polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, copovidone, and plasticizers such as polyethylene glycol, triacetin, dibutyl sebacate, triethyl citrate, or combinations of any of the above. 
         [0025]    In another representative embodiment, a release controlling membrane may coat an admixture of an API, an ionizable compound and an amphiphilic polymer (See  FIG. 2 ). 
         [0026]    The present invention also includes methods of making oral dosage forms described above. A representative method is illustrated in  FIG. 3 . Such methods may include the use of an ionizable compound as a starting material or seed. In certain embodiments the coated seed may be coated by a hydrophilic substrate. In other embodiments the coated seed may be coated by a hydrophobic and hydrophilic substrate to control the release rate of the ionizable compound. 
         [0027]    In certain embodiments the seed (or coated seed) may be coated with a matrix comprising an API and an amphiphilic polymer. The next step may include the application of an SR coating to form an extended-release oral dosage form for poorly soluble amine drugs. As used herein “extended-release” refers to an oral dosage form that allows for the prolonged or delayed release of an active agent as compared to an immediate release dosage form. For example, an extended-release dosage form may be capable of being administered once or twice daily rather than more frequently. 
         [0028]    More detailed representative process flowcharts are shown in  FIGS. 4-6 . In a representative embodiment the dosage form may be a tablet comprising, for example, (a) tartaric acid as the core (b) tartaric acid release rate-controlling barrier coat (c) an API and an amphiphilic polymer, SoluPlus® coat as a layer, and (d) a sustained release/controlled release layer. 
         [0029]    The solid oral dosage form referred to in  FIG. 4  also may be manufactured using seeds/pellets of an ionizable compound. Such seeds/pellets may be prepared by extrusion-spheronization of the ionizable compound, microcrystalline cellulose and hydrophilic polymers such as hydroxypropyl methyl cellulose, or by layering the ionizable compound onto sugar or microcrystalline cellulose spheres in, for example, a fluid bed coater. Such seeds/pellets may be further coated with a rate-controlling or a non rate-controlling barrier coat comprising hydroxypropyl methyl cellulose, ethyl cellulose, or combinations thereof, in a fluid bed coater. Such coated seeds may be further coated with a mantle comprising a dispersion of API in an amphiphilic polymer, followed by a final coat of rate-controlling membrane. The rate controlling membrane may include ethyl cellulose, hydroxypropyl methyl cellulose, dibutyl sebacate, triethyl citrate, or combinations thereof. 
         [0030]      FIG. 5  shows another representative method for making representative dosage forms according to the present invention. As shown in  FIG. 5 , the solid oral dosage form may be a tablet which may be manufactured by compression of granules prepared by wet granulation. The granules may be prepared by granulating the API, ionizable compound, an amphiphilic polymer, and microcrystalline cellulose along with a binder such as Povidone K90. These granules may be dried, milled and compressed into a tablet. The tablet then may be coated with a drug release rate-controlling membrane which may include ethyl cellulose, hydroxypropyl methyl cellulose, dibutyl sebacate, triethyl citrate, and combinations thereof. 
         [0031]    The solid oral dosage form referred to in  FIG. 5  also may be prepared by wet granulation of an ionizable compound, an amphiphilic compound, and microcrystalline cellulose along with a binder such as Povidone K90. Such granules may be dried, milled and compressed into a tablet. The tablets then may be coated with a functional or non-functional barrier comprising hydrophilic and/or hydrophobic polymers such as hydroxypropyl methyl cellulose, ethyl cellulose, and combinations thereof. Coated tablets may be further coated with API dispersed in amphiphilic and hydrophilic polymers. Finally, the tablets may be coated with a drug release rate-controlling membrane which may include ethyl cellulose, hydroxypropyl methyl cellulose, dibutyl sebacate, triethyl citrate, and combinations thereof. 
         [0032]    The solid oral dosage form referred to in  FIG. 6  may include a drug release rate-controlling membrane coated matrix tablet. Such tablet may be manufactured by compression of granules prepared by wet granulation. The granules may be prepared by granulating the API, ionizable compound, amphiphilic polymer, and hydrophobic polymers such as ethylcellulose, using a binder such as Povidone K90. Such granules may be dried, milled and compressed into a drug release rate-controlling matrix tablet. The tablet then may be further coated with a drug release rate-controlling membrane such as ethyl cellulose, hydroxypropyl methyl cellulose, dibutyl sebacate, triethyl citrate, and combinations thereof. 
         [0033]    The solid oral dosage form referred to in  FIG. 6  also may include drug release rate-controlling membrane coated matrix tablet. Such tablets may be prepared by wet granulation of the ionizable compound, amphiphilic compound, and hydrophobic polymers such as ethylcellulose, using a binder such as Povidone K90. Such granules may be dried, milled and compressed into an ionizable compound release rate-controlling matrix tablet. The tablets then may be coated with a non-functional barrier which may include hydrophilic polymers such as hydroxypropyl methyl cellulose. The coated tablets may be further coated with the API dispersed in amphiphilic and hydrophilic polymers. Finally, the tablets may be coated with a drug release rate-controlling membrane which may include ethyl cellulose, hydroxypropyl methyl cellulose, dibutyl sebacate, triethyl citrate, and combinations thereof. 
       Example 1 
       [0034]    A representative oral dosage form according to the present invention is shown in Table 3 below. 
         [0000]    
       
         
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                 Formula A 
                 Formula B 
               
               
                 Ingredient 
                 mg per Dose 
                 mg per Dose 
               
               
                   
               
             
             
               
                 IONIZABLE COMPOUND SEEDS 
                 Starting seeds: Sugar or 
                 Starting seeds: 
               
               
                   
                 MCC spheres 
                 Extrusion/spherization 
               
               
                   
                   
                 pellets 
               
               
                 Sugar or Macrocrystalline Cellulose 
                 100 
                 N/A 
               
               
                 Spheres 
               
               
                 Macrocrystalline Cellulose (Avicel PH 
                 N/A 
                 100 
               
               
                 101) 
               
               
                 Tartaric Acid, Powder 
                 20 
                 20 
               
               
                 Hydroxypropyl Methylcellulose 
                 5 
                 5 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Isopropyl Alcohol, USP* 
                 q.s. 
                 q.s. 
               
               
                 Purified Water, USP* 
                 q.s. 
                 q.s. 
               
               
                 BARRIER COAT 
                 Ionizable compound 
                 Non rate-controlling 
               
               
                   
                 release rate-controlling 
                 barrier coat 
               
               
                   
                 barrier coat 
               
               
                 Ethylcellulose (Ethocel Standard 10 
                 10 
                 N/A 
               
               
                 Premium) 
               
               
                 Hydroxypropyl Methylcellulose 
                 10 
                 20 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Polyethylene Glycol (Polyglykol 3350) 
                 5 
                 5 
               
               
                 Isopropyl Alcohol, USP* 
                 q.s. 
                 q.s. 
               
               
                 Purified Water, USP* 
                 q.s. 
                 q.s. 
               
             
          
           
               
                 API/AMPHIPHILIC POLYMER MATRIX COAT 
               
             
          
           
               
                 Paliperidone 
                 9 
                 9 
               
               
                 PEG 6000/vinylcaprolactam/vinylacetate 
                 20 
                 20 
               
               
                 (SoluPlus ®) 
               
               
                 Polyethylene Glycol (Polyglykol 3350) 
                 6 
                 6 
               
               
                 Isopropyl Alcohol, USP* 
                 q.s. 
                 q.s. 
               
               
                 Purified Water, USP* 
                 q.s. 
                 q.s. 
               
             
          
           
               
                 DRUG RELEASE RATE-CONTROLLING MEMBRANE COAT 
               
             
          
           
               
                 Ethylcellulose (Ethocel Standard 10 
                 8 
                 8 
               
               
                 Premium) 
               
               
                 Hydroxypropyl Methylcellulose 
                 4 
                 4 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Dibutyl Sebacate 
                 1.5 
                 1.5 
               
               
                 Triethyl Citrate 
                 1.5 
                 1.5 
               
               
                 Isopropanol Alcohol* 
                 q.s. 
                 q.s. 
               
               
                 Purified Water* 
                 q.s 
                 q.s 
               
             
          
           
               
                 FINAL BLENDING 
               
             
          
           
               
                 Talc 
                 1 
                 1 
               
               
                 Colloidal Silicon Dioxide, NF 
                 1 
                 1 
               
               
                 TOTAL 
                 202 
                 202 
               
             
          
           
               
                 Encapsulated into size #2 hard gelatin capsule shell 
               
               
                   
               
               
                 *Removed during the manufacturing process. 
               
             
          
         
       
     
       Example 2 
       [0035]    A representative oral dosage form according to the present invention is shown in Table 4 below. 
         [0000]    
       
         
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                   
                 Formula A 
                 Formula B 
                 Formula C 
               
               
                 Ingredient 
                 mg per Dose 
                 mg per Dose 
                 mg per Dose 
               
               
                   
               
             
             
               
                 IONIZABLE 
                 API Containing 
                 Placebo Core 
                 Placebo Core 
               
               
                 COMPOUND/AMPHIPHILIC 
                 Core 
               
               
                 POLYMER CORE 
               
               
                 Donepezil HCl 
                 23 
                 N/A 
                 N/A 
               
               
                 Tartaric Acid, Powder 
                 50 
                 50 
                 50 
               
               
                 PEG 
                 50 
                 50 
                 50 
               
               
                 6000/vinylcaprolactam/vinylacetate 
               
               
                 (SoluPlus ®) 
               
               
                 Microcrystalline Cellulose Avicel 
                 71 
                 34 
                 34 
               
               
                 PH 101 
               
               
                 Povidone K90 
                 5 
                 5 
                 5 
               
               
                 Purified Water, USP* 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                 Magnesium Stearate 
                 1 
                 1 
                 1 
               
               
                 Core Tablet Total 
                 200 
                 140 
                 140 
               
               
                 BARRIER COAT 
                 N/A 
                 Ionizable 
                 Non rate- 
               
               
                   
                   
                 compound release 
                 controlling barrier 
               
               
                   
                   
                 rate-controlling 
                 coat 
               
               
                   
                   
                 barrier coat 
               
               
                 Hydroxypropyl Methylcellulose 
                 N/A 
                 10 
                 20 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Ethylcellulose (Ethocel Standard 10 
                 N/A 
                 10 
                 N/A 
               
               
                 Premium) 
               
               
                 Polyethylene Glycol (Polyglykol 
                 N/A 
                 5 
                 5 
               
               
                 3350) 
               
               
                 Isopropyl Alcohol, USP* 
                 N/A 
                 q.s. 
                 q.s. 
               
               
                 Purified Water, USP* 
                 N/A 
                 q.s. 
                 q.s. 
               
               
                 API/AMPHIPHILIC POLYMER 
               
               
                 MATRIX COAT 
               
               
                 Paliperidone 
                 N/A 
                 9 
                 9 
               
               
                 PEG 
                 N/A 
                 20 
                 20 
               
               
                 6000/vinylcaprolactam/vinylacetate 
               
               
                 (SoluPlus ®) 
               
               
                 Polyethylene Glycol (Polyglykol 
                 N/A 
                 6 
                 6 
               
               
                 3350) 
               
               
                 Isopropyl Alcohol, USP* 
                 N/A 
                 q.s. 
                 q.s. 
               
               
                 Purified Water, USP* 
                 N/A 
                 q.s. 
                 q.s. 
               
             
          
           
               
                 DRUG RELEASE RATE-CONTROLLING MEMBRANE COAT 
               
             
          
           
               
                 Ethylcellulose (Ethocel Standard 10 
                 16 
                 16 
                 16 
               
               
                 Premium) 
               
               
                 Hydroxypropyl Methylcellulose 
                 16 
                 16 
                 16 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Dibutyl Sebacate 
                 4 
                 4 
                 4 
               
               
                 Triethyl Citrate 
                 4 
                 4 
                 4 
               
               
                 Isopropanol Alcohol* 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                 Purified Water* 
                 q.s 
                 q.s 
                 q.s 
               
               
                 TOTAL 
                 240 
                 240 
                 240 
               
               
                   
               
               
                 *Removed during the manufacturing process. 
               
             
          
         
       
     
       Example 3 
       [0036]    A representative compound according to the present invention is shown in Table 5 below. 
         [0000]    
       
         
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                   
                 Formula A 
                 Formula B 
               
               
                 Ingredient 
                 mg per Dose 
                 mg per Dose 
               
               
                   
               
             
             
               
                 IONIZABLE 
                 API 
                 Placebo 
               
               
                 COMPOUND/AMPHIPHILIC 
                 Containing 
                 Core 
               
               
                 POLYMER EXTENDED RELEASE 
                 Core 
               
               
                 MATRIX CORE 
               
               
                 Donepezil HCl 
                 23 
                 N/A 
               
               
                 Tartaric Acid, Powder 
                 50 
                 50 
               
               
                 PEG 6000/vinylcaprolactam/vinylacetate 
                 50 
                 50 
               
               
                 (SoluPlus ®) 
               
               
                 Ethylcellulose (Ethocel Standard 10FP 
                 121 
                 84 
               
               
                 Premium) 
               
               
                 Povidone K90 
                 5 
                 5 
               
               
                 Purified Water, USP* 
                 q.s. 
                 q.s. 
               
               
                 Magnesium Stearate 
                 1 
                 1 
               
               
                 CORE TABLET TOTAL 
                 250 
                 190 
               
               
                 BARRIER COAT 
               
               
                 Hydroxypropyl Methylcellulose 
                 N/A 
                 20 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Polyethylene Glycol (Polyglykol 3350) 
                 N/A 
                 5 
               
               
                 Isopropyl Alcohol, USP* 
                 N/A 
                 q.s. 
               
               
                 Purified Water, USP* 
                 N/A 
                 q.s. 
               
             
          
           
               
                 API/AMPHIPHILIC POLYMER MATRIX COAT 
               
             
          
           
               
                 Paliperidone 
                 N/A 
                 9 
               
               
                 PEG 6000/vinylcaprolactam/vinylacetate 
                 N/A 
                 20 
               
               
                 (SoluPlus ®) 
               
               
                 Polyethylene Glycol (Polyglykol 3350) 
                 N/A 
                 6 
               
               
                 Isopropyl Alcohol, USP* 
                 N/A 
                 q.s. 
               
               
                 Purified Water, USP* 
                 N/A 
                 q.s. 
               
             
          
           
               
                 DRUG RELEASE RATE-CONTROLLING MEMBRANE COAT 
               
             
          
           
               
                 Ethylcellulose (Ethocel Standard 10 
                 20 
                 20 
               
               
                 Premium) 
               
               
                 Hydroxypropyl Methylcellulose 
                 20 
                 20 
               
               
                 (Methocel E5 Premium LV) 
               
               
                 Dibutyl Sebacate 
                 5 
                 5 
               
               
                 Triethyl Citrate 
                 5 
                 5 
               
               
                 Isopropanol Alcohol* 
                 q.s. 
                 q.s. 
               
               
                 Purified Water* 
                 q.s 
                 q.s 
               
               
                 TOTAL 
                 300 
                 300 
               
               
                   
               
               
                 *Removed during the manufacturing process. 
               
             
          
         
       
     
       Example 4 
       [0037]    A solubility test was performed to quantify the synergistic effects provided by the combination of an ionizable polymer and an amphiphilic compound. In this Example the ionizable compound was citric acid and the amphiphilic compound was SoluPlus®. 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 Paliperidone Solubility at Room 
               
               
                   
                 Temperature (mg/ml) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Paliperidone in Water 
                 0.0 
               
               
                 Paliperione in 10% Soluplus 
                 0.6 
               
               
                 Aqueous Solution 
               
               
                 Paliperione in 10% Citric Acid 
                 241.1 
               
               
                 Aqueous Solution 
               
               
                 Paliperione in 10% Soluplus 
                 323.8 
               
               
                 and 10% Citric Acid Aqueous 
               
               
                 Solution 
               
               
                   
               
             
          
         
       
     
         [0038]    As shown above the solubility of the active compound, the solubility of paliperidone was 34.3% higher in a solution containing an ionizable compound and an amphiphilic polymer compared to a solution containing an ionizable compound without an amphiphilic polymer.