COMPOSITIONS FOR AND METHODS OF TREATING ACID-BASE DISORDERS
Pharmaceutical compositions for and methods of treating an animal, including a human, and methods of preparing such compositions. The pharmaceutical compositions contain nonabsorbable compositions and may be used, for example, to treat diseases or other metabolic conditions in which removal of protons, the conjugate base of a strong acid and/or a strong acid from the gastrointestinal tract would provide physiological benefits such as normalizing serum bicarbonate concentrations and the blood pH in an animal, including a human.
1 . A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition having the capacity to bind at least 5 mEq of a target species as it transits the digestive system to achieve a clinically significant increase in the serum bicarbonate value of at least 1 mEq/l from baseline within a treatment period not greater than 1 month, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
2 . A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a pharmaceutical composition, wherein the pharmaceutical composition given orally binds at least 5 mEq per day on average of a target species in the digestive system, said oral administration achieving a clinically significant increase in the serum bicarbonate value of at least 1 mEq/l from baseline within a treatment period not greater than 1 month, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.
3 . A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition containing a nonabsorbable composition;
wherein said oral administration increases the individual's serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 mEq/l; and
wherein the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or at least one year.
4 . The method of any preceding claim wherein the oral administration is as frequent as at least weekly, at least semi-weekly, or daily within the treatment period.
5 . The method of any preceding claim wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/l.
6 . The method of any preceding claim wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/l.
7 . The method of any preceding claim wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/l.
8 . The method of any preceding claim wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 22 mEq/l but not in excess of 29 mEq/l.
9 . The method of any preceding claim wherein the clinically significant increase is at least 3 mEq/l.
10 . The method of any preceding claim wherein the clinically significant increase is achieved within a treatment period of 2 weeks.
11 . The method of any preceding claim wherein, upon cessation of the treatment, the individual's serum bicarbonate value decreases by at least 2 mEq/l within 1 month of the cessation of treatment.
12 . The method of any preceding claim wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on different days.
13 . The method of any preceding claim wherein the individual is being treated for chronic metabolic acidosis.
14 . The method of any preceding claim wherein the daily dose has the capacity to remove at least 7.5 mEq, 15 mEq or 25 mEq of a target species as it transits the digestive system.
15 . The method of any preceding claim wherein the daily dose is less than 40 g/day, less than 25 g/day, less than 15 g/day, or less than 10 g/day.
16 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) of at least 3 microns.
17 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a particle size range that is (i) large enough to avoid passive or active absorption through the GI tract and (ii) small enough to not cause grittiness or unpleasant mouth feel when ingested as a powder, suspension, gel, and/or tablet.
18 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 5 or less than 2.
19 . The method of any preceding claim wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 3 mEq/g or at least about 10 mEq/g.
20 . The method of any preceding claim wherein the theoretical binding capacity for the target species is the theoretical binding capacity as determined in a SGF assay.
21 . The method of any preceding claim wherein the daily dose has the capacity to remove at least about 10 mEq/day, at least about 15 mEq/day, at least about 20 mEq/day, at least about 25 mEq/day of the target species, or at least about 30 mEq/day of the target species.
22 . The method of any preceding claim wherein the daily dose removes less than 50 mEq/day or less than 35 mEq/day of the target species.
23 . The method of any preceding claim wherein the nonabsorbable composition is a cation exchange material comprising exchangeable cations selected from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof.
24 . The method of any preceding claim wherein the nonabsorbable composition is a cation exchange material comprising exchangeable cations selected from the group consisting of sodium, potassium, and combinations thereof.
25 . The method of any preceding claim wherein the nonabsorbable composition is a cation exchange material optionally containing exchangeable sodium ions provided, however, that the amount of the sodium ions in a daily dose is insufficient to increase the patient's serum sodium ion concentration to a value outside the range of 135 to 145 mEq/l.
26 . The method of any preceding claim wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 1% by weight sodium.
27 . The method of any preceding claim wherein the nonabsorbable composition is an anion exchange material having the capacity to induce an increase in the individual's serum bicarbonate value, at least in part, by delivering a physiologically significant amount of hydroxide, carbonate, citrate or other bicarbonate equivalent, or a combination thereof.
28 . The method of any preceding claim wherein the nonabsorbable composition is an anion exchange material comprising at least 1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof.
29 . The method of any of claims 1 to 27 wherein the nonabsorbable composition is an anion exchange material comprising less than 1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion.
30 . The method of any preceding claim wherein the nonabsorbable composition is an amphoteric ion exchange resin.
31 . The method of any preceding claim wherein the target species comprises protons.
32 . The method of any preceding claim wherein the target species comprises the conjugate base of a strong acid selected from the group consisting of chloride, bisulfate and sulfate ions.
33 . The method of any preceding claim wherein the target species comprises chloride ions.
34 . The method of any preceding claim wherein the target species comprises a strong acid.
35 . The method of any preceding claim wherein the target species comprises hydrochloric acid.
36 . The method of any preceding claim wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a SIB assay.
37 . The method of any preceding claim wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay.
38 . The method of any preceding claim wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay.
39 . The method of any preceding claim wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.25:1, respectively.
40 . The method of any preceding claim wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.5:1, respectively.
41 . The method of any preceding claim wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1:1, respectively.
42 . The method of any preceding claim wherein the nonabsorbable composition is a neutral composition having the capacity to bind both protons and anions.
43 . The method of any preceding claim wherein the nonabsorbable composition is a neutral composition having the capacity to bind both protons and anions selected from the group consisting of polymers functionalized with propylene oxide, polymers functionalized with Michael acceptors, expanded porphyrins, covalent organic frameworks, and polymers containing amine and/or phosphine functional groups.
44 . The method of any preceding claim wherein the nonabsorbable composition (i) removes more chloride ions than bicarbonate equivalent anions (ii) removes more chloride ions than phosphate anions, and (iii) remove more chloride ions than the conjugate bases of bile and fatty acids.
45 . The method of any preceding claim wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant species.
46 . The method of any preceding claim wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant cationic species.
47 . The method of any preceding claim wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant anionic species.
48 . The method of any preceding claim wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum potassium levels of a statistically significant number of individuals.
49 . The method of any preceding claim wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum phosphate levels of a statistically significant number of individuals.
50 . The method of any preceding claim wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum low density lipoprotein (LDL) levels of a statistically significant number of individuals.
51 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1:
wherein R 1 , R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R 1 , R 2 and R 3 is other than hydrogen.
52 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1:
wherein R 1 , R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R 1 , R 2 and R 3 is other than hydrogen, and the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C., and (ii) an equilibrium swelling ratio in deionized water of about 2 or less.
53 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising the residue of an amine corresponding to Formula 1:
wherein R 1 , R 2 and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2 and R 3 is other than hydrogen, the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, and the crosslinked amine polymer binds a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, in an interfering ion buffer at 37° C. wherein the interfering ions are phosphate ions and the interfering ion buffer is a buffered solution at pH 5.5 of 36 mM chloride and 20 mM phosphate.
54 . The method of any preceding claim wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C.
55 . The method of any preceding claim wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked amine polymer is prepared by radical polymerization of an amine corresponding to Formula 1a:
wherein R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
56 . The method of any preceding claim wherein the pharmaceutical composition is a nonabsorbable composition comprising a crosslinked amine polymer containing the residue of an amine corresponding to Formula 1b and the crosslinked amine polymer is prepared by substitution polymerization of the amine corresponding to Formula 1 b with a polyfunctional crosslinker:
wherein R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, R 6 is aliphatic and R 61 and R 62 are independently hydrogen, aliphatic, or heteroaliphatic.
56 . The method of any preceding claim wherein the daily dose is administered once-a-day (QD).
57 . The method of any preceding claim wherein the the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and outer layer.
58 . A composition for use in a method of treating metabolic acidosis in an adult human patient, wherein (i) the method of treatment is as defined in any preceding claim or (ii) the composition is as defined in any preceding claim.
59 . A composition for use in a method of treating metabolic acidosis in an adult human patient wherein in said treatment 0.1-12 g of said composition is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay.
60 . A composition for use in a method of treating metabolic acidosis in an adult human patient, said patient having a serum bicarbonate level of less than 20 mEq/L prior to treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient.
61 . A composition for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient's serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient.
62 . A method of increasing serum bicarbonate levels in an individual afflicted with an acid-base disorder, the method comprising oral administration of a pharmaceutical composition to increase the individual's serum bicarbonate levels wherein:
(i) the pharmaceutical composition binds a target species in the individual's digestive system when given orally, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids and
(ii) the pharmaceutical composition increases the serum bicarbonate level by at least 1 mEq/l in a placebo controlled study, said increase being the difference between the cohort average serum bicarbonate level in a first cohort at the end of the study, relative to the cohort average serum bicarbonate level in a second cohort at the end of the study, wherein the first cohort's subjects receive the pharmaceutical composition and the second cohort's subjects receive a placebo, wherein the first and second cohorts each comprise at least 25 subjects, each cohort is prescribed the same diet during the study and the study lasts at least two weeks.
63 . The method of claim 61 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 10 g/day.
64 . The method of any of claims 62 to 63 wherein the potential renal acid load (PRAL value) of the diet is, on average, 0.82 mEq/d).
65 . The method of any of claims 62 to 64 wherein eligible subjects for the study have chronic kidney disease (CKD Stage 3-4; eGFR 20-<60 ml/min/1.73 m 2 ) and a baseline serum bicarbonate value at the start of the study between 12 and 20 mEq/L.
66 . The method of any of claims 62 to 65 wherein the pharmaceutical composition increases the serum bicarbonate level by at least 3 mEq/l in the placebo controlled study.
67 . The method of any of claims 62 to 66 wherein the target species is a strong acid.
68 . The method of any of claims 62 to 67 wherein the pharmaceutical composition is not absorbed when ingested.
69 . A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition containing a nonabsorbable composition;
wherein said oral administration increases the individual's serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 mEq/l; and
wherein the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or at least one year.
70 . The method of claim 69 wherein the treatment decreases the individual's anion gap by at least 1 mEq/L.