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Patiromer

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Patiromer skeletal.svg

Patiromer

1260643-52-4 FREE FORM

CAS 1208912-84-8

(C10 H10 . C8 H14 . C3 H3 F O2 . 1/2 Ca)x

2-​Propenoic acid, 2-​fluoro-​, calcium salt (2:1)​, polymer with diethenylbenzene and 1,​7-​octadiene

RLY5016

RELYPSA INNOVATOR

Patiromer is a powder for suspension in water for oral administration, approved in the U.S. as Veltassa in October, 2015. Patiromer is supplied as patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol. Patiromer sorbitex calcium is an amorphous, free-flowing powder that is composed of individual spherical beads.

Veltassa is a powder for suspension in water for oral administration. The active ingredient is patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion.

Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol.

Mechanism of Action

Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.

patiromer1

Treatment of Hyperkalemia

Hyperkalemia is usually asymptomatic but occasionally can lead to life-threatening cardiac arrhythmias and increased all-cause and in-hospital mortality, particularly in patients with CKD and associated cardiovascular diseases (Jain et al., 2012; McMahon et al., 2012; Khanagavi et al., 2014). However, there is limited evidence from randomized clinical trials regarding the most effective therapy for acute management of hyperkalemia (Khanagavi et al., 2014) and a Cochrane analysis of emergency interventions for hyperkalemia found that none of the studies reported mortality or cardiac arrhythmias, but reports focused on PK (Mahoney et al., 2005). Thus, recommendations are based on opinions and vary with institutional practice guidelines (Elliot et al., 2010; Khanagavi et al., 2014). Management of hyperkalemia includes reducing potassium intake, discontinuing potassium supplements, treatment of precipitating risk factors, and careful review of prescribed drugs affecting potassium homeostasis. Treatment of life-threatening hyperkalemia includes nebulized or inhaled beta-agonists (albuterol, salbutamol) or intravenous (IV) insulin-and-glucose, which stimulate intracellular potassium uptake, their combination being more effective than either alone. When arrhythmias are present, IV calcium might stabilize the cardiac resting membrane potential. Sodium bicarbonate may be indicated in patients with severe metabolic acidosis. Potassium can be effectively eliminated by hemodialysis or increasing its renal (loop diuretics) and gastrointestinal (GI) excretion with sodium polystyrene sulfonate, an ion-exchange resin that exchanges sodium for potassium in the colon. However, this resin produces serious GI adverse events (ischemic colitis, bleeding, perforation, or necrosis). Therefore, there is an unmet need of safer and more effective drugs producing a rapid and sustained PK reduction in patients with hyperkalemia.

In this article we review two new polymer-based, non-systemic oral agents, patiromer calcium (RLY5016) and zirconium silicate (ZS-9), under clinical development designed to induce potassium loss via the GI tract, particularly the colon, and reduce PK in patients with hyperkalemia.

1. Patiromer calcium

This metal-free cross-linked fluoroacrylate polymer (structure not available) exchanges cations through the gastrointestinal (GI) tract. It preferentially binds soluble potassium in the colon, increases its fecal excretion and reduces PK under hyperkalemic conditions.

The development program of patiromer includes several clinical trials. An open-label, single-arm study evaluated a titration regimen for patiromer in 60 HF patients with CKD treated with ACEIs, ARBs, or beta blockers (clinicaltrials.gov identifier: NCT01130597). Another open-label, randomized, dose ranging trial determined the optimal starting dose and safety of patiromer in 300 hypertensive patients with diabetic nephropathy treated with ACEIs and/or ARBs, with or without spironolactone (NCT01371747). The primary outcomes were the change in PK from baseline to the end of the study. Unfortunately, the results of these trials were not published.

In a double-blind, placebo-controlled trial (PEARL-HF, NCT00868439), 105 patients with a baseline PK of 4.7 mmol/L and HF (NYHA class II-III) treated with spironolactone in addition to standard therapy were randomized to patiromer (15 g) or placebo BID for 4 weeks (Pitt et al., 2011). Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on day 15 if PK was ≤5.1 mmol/L. Patients were eligible for the trial if they had either CKD (eGFR <60 ml/min) or a history of hyperkalemia leading to discontinuation of RAASIs or beta-blockers. Compared with placebo, patiromer decreased the PK (-0.22 mmol/L, while PK increased in the placebo group +0.23 mmol/L, P<0.001), and the incidence of hyperkalemia (7% vs. 25%, P=0.015) and increased the number of patients up-titrated to spironolactone 50 mg/day (91% vs. 74%, P=0.019). A similar reduction in PK and hyperkalemia was observed in patients with an eGFR <60 ml/min. Patiromer produced more GI adverse events (flatulence, diarrhea, constipation, vomiting: 21% vs 6%), hypokalemia (<4.0 mmol/L: 47% vs 10%, P<0.001) and hypomagnesaemia (<1.8 mg/dL: 24% vs. 2.1%), but similar adverse events leading to study discontinuation compared to placebo. Unfortunately, recruited patients had normokalemia and basal eGFR in the treatment group was 84 ml/min. Thus, this study did not answer whether patiromer is effective in reducing PK in patients with CKD and/or HF who develop hyperkalemia on RAASIs.

A two-part phase 3 study evaluated the efficacy and safety of patiromer in the treatment of hyperkalemia (NCT01810939). In a single-blind phase (part A) 243 patients with hyperkalemia and CKD (102 with HF) on RAASIs were treated with patiromer BID for 4 weeks: 4.2 g in patients with mild hyperkalemia (5.1-<5.5 mmol/L, n=92) and 8.4 g in patients with moderate-to-severe hyperkalemia (5.5-<6.5 mmol/L, n=151). Part B was a placebo-controlled, randomized, withdrawal phase designed to confirm the maintained efficacy of patiromer and the recurrent hyperkalemia following that drug’s withdrawal. Patients (n=107) who completed phase A with a normal PK were randomized to continue on patiromer (27 with HF) or placebo (22 with HF) besides RAASIs for 8 weeks. The primary endpoint was the difference in mean PK between the patiromer and placebo groups from baseline to the end of the study or when the patient first had a PK <3.8 or ≥5.5 mmol/L. In part A patiromer produced a rapid reduction in PK that persisted throughout the study in patients with and without HF (-1.06 and -0.98 mmol/L, respectively; both P<0.001 vs. placebo); three-fourths of patients in both groups had normal PK (3.8-<5.1 mmol/L) at 4 weeks. In part B patiromer reduced PK (-0.64 mmol/L) in patients with or without HF (P<0.001). As compared with placebo, fewer patients, with or without HF, presented recurrent hyperkalemia in the patiromer group or required RAASI discontinuation regardless of HF status (Pitt, 2014). Patiromer was well-tolerated, with a safety profile similar to placebo even in HF patients. The most common adverse events were nausea, diarrhea, and hypokalemia.

INDICATIONS AND USAGE

Veltassa is a potassium binder indicated for the treatment of hyperkalemia.

Veltassa should not be used as an emergency treatment for lifethreatening hyperkalemia because of its delayed onset of action.

Patiromer (USAN, trade name Veltassa) is a drug used for the treatment of hyperkalemia (elevated blood potassium levels), a condition that may lead to palpitations and arrhythmia (irregular heartbeat). It works by binding potassium in the gut.[1][2]

Medical uses

Patiromer is used for the treatment of hyperkalemia, but not as an emergency treatment for life-threatening hyperkalemia, because it acts relatively slowly.[2] Such a condition needs other kinds of treatment, for example calcium infusions, insulin plus glucose infusions, salbutamol inhalation, and hemodialysis.[3]

Typical reasons for hyperkalemia are renal insufficiency and application of drugs that inhibit the renin–angiotensin–aldosterone system (RAAS) – e.g. ACE inhibitors, angiotensin II receptor antagonists, or potassium-sparing diuretics – or that interfere with renal function in general, such as nonsteroidal anti-inflammatory drugs (NSAIDs).[4][5]

Adverse effects

Patiromer was generally well tolerated in studies. Side effects that occurred in more than 2% of patients included in clinical trials were mainly gastro-intestinal problems such as constipation, diarrhea, nausea, and flatulence, and also hypomagnesemia (low levels of magnesium in the blood) in 5% of patients, because patiromer binds magnesium in the gut as well.[2][6]

Interactions

No interaction studies have been done in humans. Patiromer binds to many substances besides potassium, including numerous orally administered drugs (about half of those tested in vitro). This could reduce their availability and thus effectiveness,[2] wherefore patiromer has received a boxed warning by the US Food and Drug Administration (FDA), telling patients to wait for at least six hours between taking patiromer and any other oral drugs.[7]

Pharmacology

Mechanism of action

Patiromer works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange, thus lowering the amount of potassium available for absorption into the bloodstream and increasing the amount that is excreted via the feces. The net effect is a reduction of potassium levels in the blood serum.[2][4]

Lowering of potassium levels is detectable 7 hours after administration. Levels continue to decrease for at least 48 hours if treatment is continued, and remain stable for 24 hours after administration of the last dose. After this, potassium levels start to rise again over a period of at least four days.[2]

Pharmacokinetics

Patiromer is not absorbed from the gut, is not metabolized, and is excreted in unchanged form with the feces.[2]

Physical and chemical properties

The substance is a cross-linked polymer of 2-fluoroacrylic acid (91% in terms of amount of substance) with divinylbenzenes (8%) and 1,7-octadiene (1%). It is used in form of its calcium salt (ratio 2:1) and with sorbitol (one molecule per two calcium ions or four fluoroacrylic acid units), a combination called patiromer sorbitex calcium.[8]

  • 2-fluoroacrylic acid

  • o-divinylbenzene

  • p-divinylbenzene

  • 1,7-octadiene

Patiromer sorbitex calcium is an off-white to light brown, amorphous, free-flowing powder. It is insoluble in water, 0.1 M hydrochloric acid, heptane, and methanol.[2][8]

Hyperkalemia Is a Clinical Challenge

Hyperkalemia may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or conditions that reduce potassium excretion, including CKD, hypertension, diabetes mellitus, or chronic heart failure (HF) (Jain et al., 2012). Additionally, drugs and nutritional/herbal supplements (Table 1) can produce hyperkalemia in up to 88% of hospitalized patients by impairing normal potassium regulation (Hollander-Rodríguez and Calvert, 2006; Khanagavi et al., 2014).

Although the prevalence of hyperkalemia in the general population is unknown, it is present in 1-10% of hospitalized patients depending on how hyperkalemia is defined (McMahon et al., 2012; Gennari, 2002). Hyperkalemia is a common problem in patients with conditions that reduce potassium excretion, especially when treated with beta-adrenergic blockers that inhibit Na+,K+-ATPase activity or RAAS inhibitors (RAASIs) [angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists or renin inhibitors] that decrease aldosterone excretion (Jain et al., 2012; Weir and Rolfe, 2010). The incidence of hyperkalemia with RAASIs in monotherapy is low (≤2%) in patients without predisposing factors, but increases with dual RAASIs (5%) and in patients with risk factors such as CKD, HF, and/or diabetes (5-10%) (Weir and Rolfe, 2010). Thus, hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs.

History

Studies

In a Phase III multicenter clinical trial including 237 patients with hyperkalemia under RAAS inhibitor treatment, 76% of participants reached normal serum potassium levels within four weeks. After subsequent randomization of 107 responders into a group receiving continued patiromer treatment and a placebo group, re-occurrence of hyperkalemia was 15% versus 60%, respectively.[9]

Approval

The US FDA approved patiromer in October 2015.[7] The drug is not approved in Europe as of January 2016.

PATENT

WO 2010132662

PATENT

WO 2010022383

CLIP

https://www.oatext.com/polymer-and-heterocyclic-compounds-their-utility-and-application-as-drug.php

The Structure of some commercially available polymer sequestrant drugs, were as follows:

Were sorbitol, which is frequently dosed with SPS as a laxative the risk of swelling of above drugs Leeds to some improvements to the above drudge polymers to increase of its capacity and reducing its swelling property sevelamer is changed into cross liked N,N, N,N-tetrakis (3-aminopropyl) butane-1,4-diamin (Schemes 6, 7) as illustrated below support the safety profile in clinical studies of up to 52 weeks it is approved for treatment of hyperphosphatemia by FDA in 1998.

Scheme 6. Showing the  network formation of patiromer amine residue

Scheme 7. Synthetic steps of Patiromer

Patiromer is a non-absorbed, potassium-sequestering polymer which is a crosslinked form of poly (fluoroacrylic acid).The fluorine substituent lowers the pKa of the acid group in patiromer compared to acrylic acid such that a higher proportion of acid groups are available for ion binding.

Suspension polymerization during patiromer manufacture allows for the generation of monodisperse uniform polymer particles, with spherical shape, controlled size distribution, and low swelling. The bead particles have a median diameter of around 100 µm. Patiromer was approved by the FDA for the treatment of hyperkalemia in 2015 based on clinical studies showing effective potassium lowering and acceptable safety profile in clinical studies of up to 52 weeks duration.

PATENT

https://patents.google.com/patent/WO2017109658A1/en

The present invention relates to a new process for the synthesis of Patiromer, an active ingredient recently approved for the treatment of hyperkalemia in adults, also known as hyperpotassemia.
By the term hyperkalemia or hyperpotassemia, an excess of potassium in the organism blood is meant.
Potassium is an important intracellular cation and it is the main determinant of the membrane resting potential. The potassium intracellular concentration is 150 mmol/L, while potassium plasmatic concentration is 3.5-5 mmol/L. Therefore hyperkalemia is defined as the group of electrolyte disorders which lead potassium plasmatic concentration to a value higher than 5 mmol/L.
Hyperkalemia can arise in case of kidney dysfunction which, due to their compromised functionality, are no longer able to remove potassium from the organism.
An additional cause of hyperkalemia is the release of excessive amounts of potassium by the organism cells.
Anyway, the presence of a kidney disease remains the most common cause of hyperkalemia, since kidneys help to control the potassium body balance. In case of dysfunction, kidneys are unable to filter the excess amount of potassium in the blood or to remove it from the organism.
Aldosterone secretion is crucial since said hormone promotes potassium excretion into the filtrate, therefore diseases that reduce the secretion of this hormone, such as Addison’s disease, can cause the onset of hyperkalemia.
The assumption of some drugs can also render much more difficult or unfavourable potassium excretion from kidneys. Moreover, some drugs or nutritional supplements can increase the potassium amount in the organism. In particular, a potassium excess within the diet can contribute to increase its levels into the blood, especially in case of kidney functionality problems.
The following drugs and nutritional supplements have been related to hyperkalemia: antibiotics, among which penicillin G and trimethoprim, azole antifungals, used for treating vaginal yeast infections and other fungal infections, drugs for the treatment of arterial pressure named angiotensin-converting-enzyme inhibitors (ACE- inhibitors), drugs for the treatment of arterial pressure known as beta-blockers, herbal supplements, heparin, non-steroidal anti-inflammatory drugs, (NSAID), potassium supplements and potassium-sparing diuretics, among which triamterene, amiloride (Midamor) and spironolactone (Aldactone).
In addition, several health problems or diseases interfere with potassium transit outside of body cells.
In fact, sometimes, cells release too much potassium, and this may be caused either by the destruction of red blood cells (haemolysis), the breakdown of skeletal muscle cells (rhabdomyolysis), burns, traumas or other tissues injuries, or by uncontrolled diabetes.
The presence of an excessive amount of potassium into the blood can affect cardiac muscle functionality.
Hyperkalemia, as a disease, can be difficult to diagnose, since symptoms can be mild and may be due to many different health problems.
Symptoms of hyperkalemia can include: abnormal heart rhythm (arrhythmia), which can also be extremely dangerous, slow heart rate or weakness.
Heart rhythm changes or cardiac arrhythmia can be potentially life-threatening, since they can lead to the outbreak of an emergency condition known as ventricular fibrillation, wherein the lower chambers of the heart quiver rapidly rather than pump blood properly.
Moreover if hyperkalemia is not pharmacologically treated an extremely high amount of potassium into the blood may cause heart failure and, therefore, death.
Patiromer is a cation exchange polymer, which acts by binding unabsorbed potassium from intestinal mucosa. Said polymer promotes the decrease in potassium absorption and its excretion through the feces.
Patiromer is indicated in the treatment of patients with both acute and chronic kidney failure, when kidneys are unable to maintain potassium blood levels within normal values range and also in cardiac decompensation hyperpotassemia, caused by drugs that inhibit the renin-angiotensin-aldosterone system (ACE-inhibitors, angiotensin inhibitors or sartans, potassium sparing diuretics). Patiromer is a compound of formula (I)
Figure imgf000004_0001

wherein m is the number of 2-fluoro-2-propanoate groups and

m is equal to 0.91
n and p are the number of crosslinking groups
n + p is equal to 0.09 and
* is an extended polymeric network
disclosed in WO2010/022380, WO2010/022381 , WO2010/022383 and marketed as Patiromer sorbitex calcium under the brand name Veltassa®.
Few patent documents describe the synthesis of Patiromer.
WO 2010/022380, WO 2010/022381 , WO 2010/022383 disclose a process for the synthesis of Patiromer by polymerization reaction among methyl-2-fluoroacrylate, 1 ,7-octadiene and divinylbenzene, as crosslinking agents, using lauroyi peroxide as radical initiator and an aqueous layer consisting of polyvinyl alcohol, phosphates, sodium chloride, sodium nitrite and water as a stabilizer of the polymerization mixture; it is followed by the removal of the alkyl group and by the formation of the carboxylate salt obtained by hydrolysis of the product, by treatment with an aqueous solution of calcium hydroxide, or by hydrolysis with sodium hydroxide at a temperature of 95°C and subsequent salt exchange by washing with an aqueous solution of calcium chloride.
WO 2005/097081 discloses a process for the synthesis of polyfluoroacrylates comprising the polymerization reaction between methyl-2-fluoroacrylate and divinylbenzene as crosslinking agent, using lauroyi peroxide and azo-bis- isobutylnitrile as radical initiators and polyvinyl alcohol as a stabilizer.
WO 2010/132662 discloses a polymerization process carried out among methyl-2- fluoroacrylate, 1 ,7-octadiene and divinylbenzene, as crosslinking agents, in the presence of a radical initiator, lauroyi peroxide and an aqueous layer consisting of polyvinyl alcohol, water and sodium chloride. The hydrolysis reaction follows, carried out by reaction with sodium hydroxide and subsequent reaction with calcium chloride to give Patiromer of formula (I).
We have now found a process for the synthesis of Patiromer of formula (I) comprising a polymerization reaction using a water soluble radical initiator together with a dispersing agent inert to radical polymerizations.
Surprisingly we have found that the use of a water soluble radical initiator together with an inert dispersing agent and the reaction conditions of the process of the present invention allow to obtain a polymer, such as Patiromer of formula (I), with a large surface area, much easier processability, purification and grinding. Moreover, the process of the present invention provides for a hydrolysis reaction of the polymerization product which occurs at a temperature significantly lower than those reported in the art, thus decreasing the risk of polymer degradation.
Therefore, object of the present invention is a process for the synthesis of Patiromer of formula (I)
Figure imgf000005_0001
wherein m is the number of 2-fluoro-2-propanoate groups and
m is equal to 0.91
n and p are the number of crosslinking groups
n + p is equal to 0.09 and
* is an extended polymeric network
comprising:
the polymerization reaction among methyl-2-fluoroacrylate of formula (VI), 1 ,7- octadiene of formula (V) and divinylbenzene of formula (IV),
Figure imgf000005_0002
(VI) (V) (IV) to obtain a compound of formula (III)
Figure imgf000006_0001

wherein m, n, p and * are as defined above, characterized in that the polymerization reaction to obtain the compound of formula (III) is carried out in the presence of a water-soluble radical initiator and of an inert dispersing agent.

In the process object of the present invention, the water-soluble radical initiator can be a nitrogen compound, preferably 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044), 2,2′-azobis[2-(2-imidazolin-2-yl)propane] disulfate dihydrate (VA-046B), 2,2′-azobis(2-methylpropionamidine) dihydrochloride (V-50), 2,2′-azobis[N-(2-carboxyethyl)-2-methylpropionamidine] hydrate (VA-057), more preferably 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044).
EXAMPLE 1. Synthesis of methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene.
Methyl-2-fluoroacrylate (75.24 g, 0.723 mol), 1 ,7-octadiene (4.18 g, 37.93 mmol), divinylbenzene (4.18 g, 32.10 mmol) and polysorbate 20 (TWEEN® 20, 0.60 mL) were loaded into a reaction flask and the reaction mixture was left under mechanical stirring for five minutes. Demineralised water (490 mL) and a solution composed of 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA044, 1.67 g, 5.16 mmol) and demineralised water (10 mL) were then added, the temperature was brought to about 65°C and the reaction mixture was maintained under these conditions for about four hours. Finally, the reaction was brought to 95°C for 2 hours. When the reaction was completed, the temperature was brought to room temperature, the resultant product was filtered, washed with demineralised water (2 x 150 mL) and acetone (2 x 200 mL). The product was dried in vacuum oven at a temperature of 30°C to give 73.50 g of methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene.
13C-NMR of methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene: reported in Figure 1.
EXAMPLE 2. Synthesis of lithium salt of the methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene.
Methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene (30 g), isopropyl alcohol (150 mL) and a solution of demineralised water (150 mL) and lithium hydroxide (17.62 g, 0.74 mol) were loaded into a reaction flask. The temperature was brought to about 40°C and the reaction mixture was maintained under these conditions for about thirty-six hours. When the reaction was completed, the resultant product was filtered and washed with demineralised water (4 x 100 mL), acetone (4 x 100 mL) and dried into vacuum oven at a temperature of 30°C to give 29.80 g of lithium salt of the methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene.
13C-NMR of lithium salt of methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7-octadiene: reported in Figure 2.
Lithium content: 6.2%.
EXAMPLE 3. Synthesis of Patiromer.
Lithium salt of methyl-2-fluoroacrylate polymer with divinylbenzene and 1 ,7- octadiene (29.80 g), as obtained in example 2, demineralised water (150 mL), and a solution of demineralised water (150 mL) and calcium chloride (70 g, 0.63 mol) were loaded into a reaction flask and the reaction mixture was left at room temperature for about four hours. When the reaction was completed, the product was filtered, washed with demineralised water (2 x 50 mL), acetone (1 x 50 mL) and dried in vacuum oven at a temperature of 30°C, to give 27.90 g of Patiromer.
13C-NMR of Patiromer: reported in Figure 3.
Calcium content: 16.1 %.

References

  • 1 Henneman, A; Guirguis, E; Grace, Y; Patel, D; Shah, B (2016). “Emerging therapies for the management of chronic hyperkalemia in the ambulatory care setting”. American Journal of Health-System Pharmacy 73 (2): 33–44. doi:10.2146/ajhp150457. PMID 26721532.
  • 2FDA Professional Drug Information for Veltassa.
  • 3Vanden Hoek TL, Morrison LJ, Shuster M, Donnino M, Sinz E, Lavonas EJ, Jeejeebhoy FM, Gabrielli A; Morrison; Shuster; Donnino; Sinz; Lavonas; Jeejeebhoy; Gabrielli (2010-11-02). “Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care”. Circulation 122 (18 Suppl 3): S829–61. doi:10.1161/CIRCULATIONAHA.110.971069. PMID 20956228.
  • 4Esteras, R.; Perez-Gomez, M. V.; Rodriguez-Osorio, L.; Ortiz, A.; Fernandez-Fernandez, B. (2015). “Combination use of medicines from two classes of renin-angiotensin system blocking agents: Risk of hyperkalemia, hypotension, and impaired renal function”. Therapeutic Advances in Drug Safety 6 (4): 166. doi:10.1177/2042098615589905. PMID 26301070.
  • 5Rastegar, A; Soleimani, M (2001). “Hypokalaemia and hyperkalaemia”. Postgraduate Medical Journal 77 (914): 759–64. doi:10.1136/pmj.77.914.759. PMC 1742191. PMID 11723313.
  • 6Tamargo, J; Caballero, R; Delpón, E (2014). “New drugs for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors — hype or hope?”. Discovery medicine 18 (100): 249–54. PMID 25425465.
  • 7″FDA approves new drug to treat hyperkalemia”. FDA. 21 October 2015.
  • 8RxList: Veltassa.
  • 9Weir, Matthew R.; Bakris, George L.; Bushinsky, David A.; Mayo, Martha R.; Garza, Dahlia; Stasiv, Yuri; Wittes, Janet; Christ-Schmidt, Heidi; Berman, Lance; Pitt, Bertram (2015). “Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors”. New England Journal of Medicine 372 (3): 211. doi:10.1056/NEJMoa1410853. PMID 25415805.
Patiromer skeletal.svg
Systematic (IUPAC) name
2-Fluoropropenoic acid, cross-linked polymer with diethenylbenzene and 1,7-octadiene
Clinical data
Trade names Veltassa
AHFS/Drugs.com entry
Legal status
Routes of
administration		 Oral suspension
Pharmacokinetic data
Bioavailability Not absorbed
Metabolism None
Onset of action 7 hrs
Duration of action 24 hrs
Excretion Feces
Identifiers
CAS Number 1260643-52-4
1208912-84-8 (calcium salt)
ATC code None
PubChem SID 135626866
DrugBank DB09263
UNII 1FQ2RY5YHH
KEGG D10148
ChEMBL CHEMBL2107875
Synonyms RLY5016
Chemical data
Formula [(C3H3FO2)182·(C10H10)8·(C8H14)10]n

[Ca91(C3H2FO2)182·(C10H10)8·(C8H14)10]n (calcium salt)

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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