Pharmaceutical Composition

Abstract

The present invention provides oral pharmaceutical compositions that enable the successful delivery of drugs in a pharmaceutically effective amount, particularly poly (amino acids) such as peptides, peptidomimetics and proteins, e.g. hormones to a subject via oral administration to accomplish the desired therapeutic effect. The oral pharmaceutical composition comprising a poly (amino acid) as the active ingredient, e.g. a peptide or protein, shows a rapid disintegration and/or dissolution such that the active ingredient is able to attain a therapeutic effect.

1 . An oral pharmaceutical composition in the solid phase comprising:
 iv. a poly(amino acid);   v. a delivery agent; and, optionally,   vi. a diluent;   wherein the composition has a disintegration time of no more than 10 minutes and a dissolution of >80% at 20 minutes.   
     
     
         2 . An oral pharmaceutical composition in the solid phase comprising:
 vii. a poly(amino acid);   viii. a delivery agent; and, optionally,   ix. a diluent;   wherein the composition has a disintegration time of no more than 6 minutes and a dissolution of >90% at 20 minutes.   
     
     
         3 . The composition of  claim 1  which has a disintegration time of no more than 2 minutes. 
     
     
         4 . The composition of  claim 1 , additionally comprising a disintegrant. 
     
     
         5 . The composition of  claim 1 , additionally comprising an agent that decreases disintegrantion time by effervescent and/or other means 
     
     
         6 . The pharmaceutical composition of  claim 1  having a dissolution time of >80% at no more than 20 minutes in gastric media. 
     
     
         7 . The pharmaceutical composition of  claim 1 , which is in form of a compressed tablet, wherein the tablet has a hardness of between 3 Kp and 20 Kp. 
     
     
         8 . The pharmaceutical composition of a  claim 7 , which is in form of a compressed tablet, wherein the tablet has a hardness of between 5 Kp and 15 Kp. 
     
     
         9 . The pharmaceutical composition of  claim 8  having a disintegration time of less than 1 minute and a hardness of between 5 Kp and 7 Kp. 
     
     
         10 . The composition of  claim 1 , wherein the poly(amino acid) is a polypeptide hormone. 
     
     
         11 . The composition of  claim 10 , wherein the hormone is calcitonin. 
     
     
         12 . The composition of  claim 11 , wherein the calcitonin is salmon calcitonin. 
     
     
         13 . The composition of  claim 11  comprising a calcitonin in a therapeutically effective amount in free or salt form that provides a peak plasma concentration (C max ) of no less than 400 pg/mL and/or a reduction in plasma calcium level of >20% in 6 hours in primate animal models, in particular monkeys. 
     
     
         14 . The composition of  claim 13 , wherein the C max  is no less than 800 pg/mL. 
     
     
         15 . The composition of  claim 13 , wherein the C max  is no less than 1000 pg/mL. 
     
     
         16 . The composition of  claim 11 , comprising a therapeutically effective amount of a calcitonin in free or salt form in a dosage range of between 0.15 mg and 2.5 mg. 
     
     
         17 . The composition according to  claim 16 , wherein the dosage range is of between 0.15 mg and 0.4 mg. 
     
     
         18 . The composition of  claim 1 , wherein the delivery agent is 5-CNAC. 
     
     
         19 . The composition of  claim 4 , wherein the disintegrant is crospovidone and/or povidone. 
     
     
         20 . The composition of  claim 1 , wherein the composition additionally comprises one or more of a thickening agent, a stabilizer and a dry binder. 
     
     
         21 . The pharmaceutical composition of  claim 1  where the tablet has a weight of 500 mg. 
     
     
         22 . The pharmaceutical composition of  claim 1 , comprising:
 x. Salmon calcitonin 0.03 to 0.5 wt %   xi. Micronized 5-CNAC 5 to 80 wt %   xii. Avicel PH 102 or 101 0 to 70 wt %   xiii. Crospovidone, NF 0 to 10%   xiv. Magnesium stearate 0 to 1.5 wt %   xv. Cab-o-sil 0 to 1.5%   where the total percentages add up to 100.   
     
     
         23 . A pharmaceutical combination comprising
 xvi. the composition of  claim 1 ; and   xvii. a co-agent, which is a bone resorption inhibitor.   
     
     
         24 . The combination of  claim 23 , where the co-agent is a cathepsin K inhibitor. 
     
     
         25 . A method of manufacturing an oral pharmaceutical composition comprising the steps
 xviii. Blending a poly(amino acid), a carrier and a disintegrant to make a first blend;   xix. optionally blending a dry binder to the first blend to make a second blend;   xx. optionally blending a stabilizer to the second blend to make a third blend; and   xxi. compressing the third blend into a tablet having a hardness of 5 Kp to 20 Kp.   
     
     
         26 . A method of treating a disease caused by abnormal bone resorption in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         27 . The method of  claim 26 , where the disease is osteoporosis. 
     
     
         28 . A method of treating an arthritic disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         29 . The method of  claim 28 , where the disease is osteoarthritis. 
     
     
         30 . A method of determining the absorption properties of a composition according to  claim 1 , comprising
 xxii. determining the dispersion time; and   xxiii. correlating the dispersion time to the dissolution time.   
     
     
         31 . A method of pre-determining peak plasma concentration (C max ) of an active ingredient in a patient to be treated with an oral pharmaceutical composition comprising said active ingredient and a delivery agent which method comprises adjusting the disintegration time of the pharmaceutical composition and/or the dissolution time of the active ingredient such as to provide a favorable microenvironment in the gastro intestinal tract for the dissolution of the active ingredient in the intestine in order to optimize absorption of the active ingredient and to achieve a therapeutically effective peak plasma concentration of the active ingredient in the blood plasma. 
     
     
         32 . The method according to  claim 31 , wherein the active ingredient is calcitonin, particularly salmon calcitonin. 
     
     
         33 . The method according to  claim 32 , wherein the peak plasma concentration is no less than 400 pg/mL. 
     
     
         34 . The method according to  claim 31 , wherein the oral pharmaceutical composition is provided in the form of a tablet and the disintegration time is adjusted by adapting the hardness of said tablet. 
     
     
         35 . The method according to  claim 34 , wherein the hardness is in a range of between 3 Kp and 20 Kp. 
     
     
         36 . The method according to  claim 34 , wherein the disintegration time is less than 10 minutes. 
     
     
         37 . The method according to  claim 36 , wherein the disintegration time is less than 1 minutes. 
     
     
         38 . The method according to  claim 31 , wherein the favourable microenvironment in the gastro intestinal tract for the dissolution of the active ingredient in the intestine is provided by the addition of 5-CNAC to the composition. 
     
     
         39 - 43 . (canceled) 
     
     
         44 . The composition of  claim 4 , wherein said disintegrant is a superdisintegrant.