Source: http://www.google.de/patents/US7381428
Timestamp: 2013-05-25 03:46:41
Document Index: 149840570

Matched Legal Cases: ['application No. 60', 'application No. 60', 'application No. 60', 'application No. 60', 'Application No. 04761727', 'Application No. 10']

Patent US7381428 - Stabilized lanthanum carbonate compositions - Google PatenteSuche Bilder Maps Play YouTube News Gmail Drive Mehr » Erweiterte Patentsuche | Webprotokoll | Anmelden Erweiterte Patentsuche PatenteStabilized lanthanum carbonate compositions containing a monosaccharide or disaccharide stabilizing agent are disclosed. Subjects having hyperphosphatemia can be treated by administering a pharmaceutical composition containing a therapeutically effective amount of the stabilized lanthanum carbonate ...http://www.google.de/patents/US7381428?utm_source=gb-gplus-sharePatent US7381428 - Stabilized lanthanum carbonate compositions Ver�ffentlichungsnummerUS7381428 B2PublikationstypErteilung Anmeldenummer11/272,569 Ver�ffentlichungsdatum3. Juni 2008Eingetragen9. Nov. 2005 Priorit�tsdatum26. Aug. 2003Auch ver�ffentlicht unterUS20060121127US20080187602 ErfinderPeter Neil DaviesJosephine Christine FerdinandoUrspr�nglich Bevollm�chtigterShire International Licensing B.V. US-Klassifikation424/715514/960424/464514/492Internationale KlassifikationA01N59/00A61K31/28A01N55/02A61K33/24A61K9/20A61K33/00A61J3/10A61K9/00 UnternehmensklassifikationA61K9/2018A61K9/2059A61K9/0056A61J3/10A61K9/2013A61K33/24 Europ�ische KlassifikationA61K 9/20H6F4A61K 9/00M18BA61K 33/24ReferenzenPatentzitate (51)Nichtpatentzitate (51) Referenziert von (5)Externe LinksUSPTO USPTO-Zuordnung EspacenetStabilized lanthanum carbonate compositionsUS 7381428 B2 Zusammenfassung Stabilized lanthanum carbonate compositions containing a monosaccharide or disaccharide stabilizing agent are disclosed. Subjects having hyperphosphatemia can be treated by administering a pharmaceutical composition containing a therapeutically effective amount of the stabilized lanthanum carbonate formulation.
wherein the monosaccharide or disaccharide is dextrates, mannitol, sorbitol, or a mixture thereof and the amount of the monosaccharide or disaccharide is such that lanthanum hydroxycarbonate is not observed in an x-ray powder diffraction (XRPD) pattern of the lanthanum carbonate composition after it has been exposed to 60� C. and 95% relative humidity for at least 7 days.
admixing the lanthanum carbonate in an amount of from 13.4-13.9% to 32.2-33.3% by weight of the composition as elemental lanthanum with a monosaccharide or disaccharide in an amount from 20 to 80% by weight of the composition, wherein the monosaccharide or disaccharide is dextrates, mannitol, sorbitol, or a mixture thereof and the amount of the monosaccharide or disaccharide is such that lanthanum hydroxycarbonate is not observed in an x-ray powder diffraction (XRPD) pattern of the lanthanum carbonate composition after it has been exposed to 60� C. and 95% relative humidity for at least 7 days.
This application is a continuation in part (CIP) of U.S. application Ser. No. 10/926,330 entitled �Pharmaceutical Formulation Comprising Lanthanum Compounds� filed Aug. 26, 2004 and published as U.S. publication No. 2005/0079135 on Apr. 14, 2005 which claims priority to U.S. Provisional application No. 60/497,560, filed Aug. 26, 2003 and U.S. Provisional application No. 60/517,078 filed Nov. 5, 2003. U.S. application Ser. No. 10/926,330, Provisional application No. 60/497,560, and Provisional application No. 60/517,078 are each incorporated by reference herein.
1. FIELD OF THE INVENTION This invention relates to stabilized lanthanum carbonate compositions comprising a monosaccharide or disaccharide stabilizing agent, and to the treatment of subjects having hyperphosphatemia by administering a pharmaceutical composition containing a therapeutically effective amount of a stabilized lanthanum carbonate composition.
2. BACKGROUND OF THE INVENTION Hyperphosphatemia is a particular problem of patients with chronic renal insufficiency or chronic kidney disease (CKD). Approximately 70% of patients with end stage renal disease (ESRD) on renal dialysis therapy require treatment for hyperphosphatemia. This condition can lead to severe bone problems and metastatic calcification of skin and major organs and is associated with significant morbidity and mortality. Conventional dialysis fails to reduce the levels of phosphate in the blood, so that levels rise in time. Elevated phosphate levels are treated using a combination of dietary restrictions and phosphate-binding agents.
3. SUMMARY OF THE INVENTION In accordance with the present invention, a stabilized lanthanum carbonate composition is provided, comprising a pharmaceutically effective amount of lanthanum carbonate having the general formula La2(CO3)3.xH2O wherein x has a value from 0 to 10, and at least one pharmaceutically acceptable monosaccharide or disaccharide, wherein the monosaccharide or disaccharide is present in an amount of at least about 1% by weight based on the total weight of the composition. As indicated hereinafter, the invention is applicable to the treatment of subjects susceptible to or suffering from hyperphosphatemia, at risk for chronic kidney disease (CKD), having stage one to five CKD, susceptible to or suffering from soft tissue calcification associated with CKD, susceptible to or suffering from secondary hyperparathyroidism, or susceptible to or suffering from other as yet undiscovered conditions requiring control of phosphate absorption. This invention is also applicable to the treatment of subjects described in U.S. application Ser. No. 11/272,563 entitled �Treatment of Chronic Kidney Disease (CKD) Subjects using Lanthanum Compounds� filed on the same day as the present application.
Lanthanum carbonate in the form of a chewable tablet which is one embodiment of the present invention (available as Fosrenol� from Shire Pharmaceuticals, Wayne, Pa.) has been approved by the FDA to treat hyperphosphatemia in ESRD subjects and it currently being marketed.
4. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is an XRPD (x-ray powder diffraction) pattern of substantially pure hydrated lanthanum carbonate having a water content approximately equivalent to 4-5 moles of water.
FIG. 3 illustrates XRPD patterns of hydrated lanthanum carbonate at 60� C./95% RH (relative humidity) for 0, 1, 2, 3, 4, and 7 days.
FIG. 4 illustrates XRPD patterns of hydrated lanthanum carbonate at 60� C./65% RH for 0, 1, 2, 3, 4, 7, 14, and 21 days.
FIG. 5 illustrates XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/D-mannitol at 60� C./65% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 6 illustrates XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/D-sorbitol at 60� C./65% RH for 0, 1, 2, 3, 4, 7, 14, and 21 days.
FIG. 7 illustrates XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/dextrates at 60� C./65% RH for 0, 1, 2, 3, 4, 7, 14, and 21 days.
FIG. 8 illustrates XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/β-cyclodextrin at 60� C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 9 illustrates XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/corn starch at 60� C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 10 illustrates XRPD patterns of a 1:1 (by weight) mixture of anhydrous lanthanum carbonate/D-mannitol at 60� C./95% RH for 0, 1, 2, 3, 4, and 7 days.
FIG. 11 illustrates the XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/anhydrous lactose at 60� C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 12 illustrates the XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/lactose monohydrate at 60� C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 13 illustrates the XRPD patterns of a 1:1 (by weight) mixture of hydrated lanthanum carbonate/microcrystalline cellulose at 60� C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 14 illustrates the XRPD patterns of a 96:4 (by weight) mixture of hydrated lanthanum carbonate/D-mannitol at 60� C./95% RH for 0, 1, 2, 3, 4, 7, and 14 days.
FIG. 15 shows the degradation to lanthanum hydroxycarbonate that occurs in unformulated hydrated lanthanum carbonate and formulated hydrated lanthanum carbonate containing approximately 50% (by weight) dextrates at 25� C./60% RH, 300C/60% RH, and 40� C./75% RH for up to 24 months.
5. DETAILED DESCRIPTION OF THE INVENTION 5.1. General Definitions As used herein, the terms �treat,� �treating,� or �treatment� mean the prevention, reduction, amelioration, partial or complete alleviation, or cure of hyperphosphatemia, chronic kidney disease (CKD), severe bone problems, soft tissue calcification, secondary hyperparathyroidism, or other as yet undiscovered conditions requiring control of phosphate absorption.
Further, as used herein, the term �subject� refers to a mammal (e.g., any veterinary medicine patient such as a domesticated animal, such as a dog or cat), or a human patient.
The terms �about� or �approximately� mean within an acceptable range for the particular parameter specified as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, �about� can mean a range of up to 20% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
The term �dextrates� as used herein refers to a purified mixture of saccharides that is mostly dextrose (e.g., not less than about 93.0% and not more than about 99.0%, calculated on the dried basis) and that results from a controlled enzymatic hydrolysis of starch. Dextrates can be either anhydrous or hydrated. �Dextrates� can refer to dextrates as defined its official monograph found in National Formulary 21 (printed by Webcom Limited in Toronoto, Canada; 2003). Dextrates are available from JRS Pharma (Patterson, N.Y.) as Emdex�.
As used herein, a �stabilized composition� or �stabilized lanthanum carbonate composition� refers to a composition containing lanthanum carbonate (of any hydration state including anhydrous lanthanum carbonate) and one or more monosaccharides or disaccharides. Preferably, the total amount of monosaccharides, disaccharides, or combination thereof is present in the stabilized composition in an amount of at least about 1% by weight. The lanthanum carbonate in a stabilized lanthanum carbonate composition degrades into lanthanum hydroxycarbonate at a slower rate compared to lanthanum carbonate alone or not in the presence of other materials. For example, after 7 days at 60� C. and 95% relative humidity, lanthanum carbonate in a lanthanum carbonate composition stabilized with at least about 4% monosaccharide, disaccharide, or combination thereof does not detectably (by present analytical techniques) degrade into lanthanum hydroxycarbonate. In contrast, under the same conditions, substantially pure lanthanum carbonate begins to decompose into lanthanum hydroxycarbonate after only 1 day.
A �pharmaceutically effective amount� or �therapeutically effective amount� as used herein is an amount or dose of lanthanum carbonate sufficient (i) to detectably decrease the serum phosphate levels of a subject or (ii) at a minimum, to keep the serum phosphate levels of a subject substantially constant.
�Lanthanum carbonate� as used herein encompasses all hydrated forms of lanthanum carbonate as well as anhydrous lanthanum carbonate.
�Percent� or �%� as used herein refers to the percentage by weight of the total composition.
The term �substantially pure lanthanum carbonate� refers to lanthanum carbonate of about 90% purity or greater, on an anhydrous basis.
The term �symptom(s)� of those at risk for or having hyperphosphatemia, CKD, soft tissue calcification associated with CKD, or secondary hyperparathyroidism may be any functional or structural abnormality experienced by a subject and indicating kidney dysfunction, e.g., those described in Section 5.6, infra. Among other abnormalities, as an example, one or more of the following symptoms may indicate risk for or the presence of CKD: a creatinine concentration of above about 1.6 mg/dL, a blood urea nitrogen (BUN) of above about 20 mg/dL, a blood phosphate level of above about 4.5 mg/dL, any detectable amount of blood in the urine, a urine protein concentration above about 100 mg/dL, a urine albumin concentration above about 100 mg/dL, an intact parathyroid hormone (PTH) concentration in the blood of above about 150 pg/mL, or a glomerular filtration rate (GFR) of below about 90 mL/min/1.73 m2.
5.2. Lanthanum Carbonate The stabilized compositions of the invention can contain lanthanum carbonate having the general formula La2(CO3)3.xH2O, wherein x has a value from 0 to 10. Preferably, x has a value from 3 to 8, desirably from 3 to 6. Most preferably, x may have an average value of about between 4 and 5. The hydration level of the lanthanum compound can be measured by methods well known in the art, such as thermo gravimetric analysis (TGA) or x-ray powder diffraction (XRPD).
La2(CO3)3+H2O→2LaOHCO3+CO2 The hydroxycarbonate product results from electrophilic or nucleophilic attack on the carbonyl moiety of lanthanum carbonate. This process is accelerated in the presence of moisture or heat and appears to be self-catalyzing. Hence, even a very small amount of lanthanum hydroxycarbonate in lanthanum carbonate formulations causes rapid and excessive degradation. Furthermore, there is a need in the art to prevent this degradation since, as noted above, current regulatory requirements preclude detectable decarboxylation for administration to patients. As a result, formulations that eliminate or substantially retard degradation are highly preferred.
Without being bound by any theory, the stabilizing effect of the monosaccharide and disaccharide stabilizing agents of this invention is believed to be attributed to the availability of reactive alcohol �OH groups on such materials; on the other hand, polysaccharides (wherein the alcohol groups are further reacted to link the monosaccharide units) do not exhibit such stabilizing characteristics. Water reacts preferentially with the available alcohol groups on the monosaccharides or disaccharides, leaving the carbonyl groups of the lanthanum carbonate intact so that the anti-hyperphosphatemic agent is not degraded.
5.3. The Monosaccharide and Disaccharide Stabilizing Agent The stabilized compositions of the invention contain at least one monosaccharide or disaccharide. The monosaccharide, disaccharide, or mixture thereof is present in a total amount of at least about 1%, preferably from about 4% to about 90%, and more preferably from about 30% to about 70% by weight of the composition.
Suitable monosaccharides for use as stabilizing agents in the formulation of the present invention include, but are not limited to, glyceraldehyde, erythrose, threose, ribose, lyxose, xylose, arabinose, allose, talsoe, gulose, mannose, glucose (e.g., in the form of corn syrup), idose, galactose, altrose, dihydroxyacetone, erythrulose, ribulose, xyloketose, psicose, tagatose, sorbose, fructose, sorbitol, xylitol, inositol, erythritol, and mannitol in either the D- or L-configuration, including derivatives and analogs thereof. Monosaccharides for use in this inventions can be either cyclic (in either α- or β-form) or acyclic and can be used in the invention as mixtures. Other suitable monosaccharides include dextrose (D-glucose such as Cerelose� available from Fisher Scientific (Hampton, N.H.)).
Suitable disaccharides for use as stabilizers in the present invention include, but are not limited to, sucrose (for example, in the form of Di-Pac� available from Domino Foods in Baltimore, Md., Sugartab� available from JRS Pharma (Patterson, N.Y.), confectioner's sugar, or Nutab), lactose (including anhydrous lactose and lactose monohydrate), maltose, isomaltose, cellobiose, trehalose, maltitol (in the form of Lycasin� available from Roquette (Lestrem, France)), isomalt, lactitol, mixtures, dervatives, and analogs thereof. Disaccharides of this invention also include any combination of two monosaccharides linked by a glycosidic bond. Disaccharides can be either homodisaccharides (i.e., consisting of 2 monosaccharides that are the same) or heterodisaccharides (i.e., consisting of 2 monosaccharides that are different). Furthermore, monosaccharides and disaccharides can be used in the same formulation.
5.4. Excipients The stabilized formulations of the invention may further comprise at least one excipient. The excipients used in the formulation administered by the present invention should be suitable for oral administration to renally impaired subjects. The excipients may include diluents, binders, and lubricants/glidants. Other agents such as disintegrants, colors, and flavors/sweeteners can be added to the formulation.
Suitable diluents can be chosen from, for example, calcium sulfate dihydrate, oligosaccharide, isomaltooligosaccharide, erythritol, polydextrose, dextrins, starch, maltodextrin, calcium lactate trihydrate, microcrystalline cellulose (such as Avicel� available from GFS Chemicals (Powell, Ohio)), hydrolyzed cereal solids (such as Maltrons or Mor-Rex�), amylose, or glycine. Additional diluents can include the mono- and disaccharides stabilizing agents discussed, supra. One or more diluents can be present in a formulation. The total diluent amount can be from about 1% to about 90%, preferably from about 4% to about 90%, and most desirably from about 40% to about 80% by weight of the composition.
5.5. Additional Active Ingredients 5.5.1. A Combination Formulation Comprising Lanthanum Carbonate and Vitamin D Often, a subject suffering from hyperphosphatemia or the symptoms of CKD is also vitamin D deficient. Levels of 25-hydroxy vitamin D2 are low at values less than about 16 ng/mL and replacement treatment aims for levels of greater than or equal to about 16 ng/mL. Levels of 1, 25-dihydroxy vitamin D2 are low at values less than about 22 pg/mL and replacement treatment aims for levels of greater than about 22 pg/mL. Thus, it becomes desirable to produce and administer to a patient a formulation containing lanthanum carbonate and vitamin D or an analog of vitamin D.
Examples of vitamin D sources which may be used in a formulation of this invention include 1,25 dihydroxy-vitamin D, the active metabolite of vitamin D (calcitriol, rocalcitrol). Examples of suitable vitamin D analogs include doxercalciferol (Hectorol�, available from Bone Care International, Middleton, Wis.) and paricalcitol (Zemplar�, available from Abbott Laboratories, Abbott Park, Ill.). One or more vitamin D sources or vitamin D analogs can be present in a formulation.
5.5.2. A Combination Formulation Comprising Lanthanum Carbonate and a Calcium Source Hyperphosphatemic subjects or subjects having symptoms of CKD often suffer from hypocalcaemia (i.e., a blood calcium concentration below about 8.5 mg/dL). Hence, a formulation of the invention can include lanthanum carbonate and a calcium source.
Examples of forms of calcium include calcium carbonate (e.g., Tums� available from GlaxoSmithKline, Uxbridge, UK), calcium acetate (e.g., PhosLo� available from Nabi Biopharmaceuticals, Boca Raton, Fla.), and CaCl2. One or more calcium sources can be present in a formulation.
5.5.3. A Combination Formulation Comprising Lanthanum and Vitamin K A subject suffering from hyperphosphatemia or the symptoms of CKD can be vitamin K deficient. In another embodiment of the present invention, the formulation of the invention, in combination with vitamin K, is administered to a subject suffering from hyperphosphatemia or the symptoms of CKD to alleviate vitamin K deficiency.
5.6. Subjects Treated with Stabilized Lanthanum Carbonate Formulations Subjects susceptible to or suffering from hyperphosphatemia, at risk for chronic kidney disease (CKD), having stage one to five CKD, susceptible to or suffering from soft tissue calcification associated with CKD, susceptible to or suffering from secondary hyperparathyroidism, or susceptible to or suffering from other as yet undiscovered conditions requiring control of phosphate absorption, can be treated by administering a therapeutically effective amount of a stabilized lanthanum carbonate formulation of the present invention.
5.6.1. Chronic Kidney Disease (CKD) The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (�NKF-K/DOQI� or �K/DOQI,� as referred to herein) has defined chronic kidney disease (CKD) as either (1) having kidney damage as defined by structural or functional abnormalities of the kidney for 3 months or longer with or without a decreased glomerular filtration rate (GFR) or (2) having a GFR of less than 60 mL/min/1.73 m2 for 3 months or longer with or without kidney damage. Structural or functional abnormalities are manifested by symptoms such as either pathologic abnormalities or markers of kidney damage, including abnormalities identified in imaging studies or the composition of blood or urine.
90-120 (with CKD
Kidney damage with normal or elevated
Kidney damage with mildly reduced GFR
Moderately reduced GFR
Severely reduced GFR
5.6.2. Methods of Treating Hyperphosphatemia Subjects susceptible to or suffering from hyperphosphatemia can be treated by administering a therapeutically effective amount of a stabilized lanthanum carbonate formulation of the invention. Hyperphosphatemia as used herein refers to a condition of a patient having blood phosphate levels of above about 4.5 mg/dL.
5.6.3. Methods of Treating Chronic Kidney Disease (CKD) A subject having a symptom or symptoms of chronic kidney disease (CKD) can be treated by administering to the subject a therapeutically effective amount of a stabilized lanthanum carbonate formulation of the present application. As indicated above, the subject treated may be at risk for CKD or have any of stages one to five CKD as defined above. Subjects at risk for CKD or who have any of stages one to five CKD who may be treated may have one or more of the following symptoms: a blood phosphate level of above about 4.5 mg/dL, a plasma creatinine concentration of above about 1.6 mg/dL, a BUN of above about 20 mg/dL, any detectable amount of blood in the urine, a urine protein concentration above about 100 mg/dL, a urine albumin concentration above about 100 mg/dL, an intact parathyroid hormone concentration in the blood above about 150 pg/mL, an abnormal GFR, or combination thereof.
5.6.4. Methods of Preventing Calcification A subject having a symptom or symptoms of CKD can be treated for calcification of soft tissue associated with CKD by administering to the subject a therapeutically effective amount of a stabilized lanthanum carbonate formulation of the present invention.
5.6.5. Methods of Treating Secondary Hyperparathyroidism A subject suffering from or having one or more symptoms of secondary hyperparathyroidism can be treated by administering to the subject a therapeutically effective amount of a stabilized lanthanum carbonate formulation of the present application.
5.7. Administration of a Stabilized Lanthanum Carbonate Formulation The lanthanum carbonate formulation can be orally administered to subjects in accordance with this invention in dosage forms varying from about 125 to about 2000 mg lanthanum carbonate as elemental lanthanum per meal. A typical dosage for an adult can be, e.g., 375 mg-6000 mg daily. More preferably, the dosage is 375-3750 mg/day. The dose can be divided and taken with each meal, for example a 250, 500, 750, or 1000 mg tablet, e.g., three times per day. Serum plasma levels can be monitored weekly and dosages can be modified until an optimal serum phosphate level is reached. Administration may be conducted in an uninterrupted regimen; such a regimen may be a long term regimen, e.g., a permanent regimen, for treating chronic conditions.
The lanthanum carbonate formulation is administered such that plasma levels of lanthanum are low, e.g., at least as low as those provided by a mean concentration curve where Cmax, Tmax, and AUC are preferably less than 1.5 ng/ml, about 12 hours, and less than 50 ng�hr/ml, respectively, for a dose of 3 g per day (e.g., 1 g three times per day). Preferably, the Cmax and AUC are less than 1.1 ng/ml and less than 32 ng�hr/ml, and desirably, Cmax and AUC are less than 0.5 ng/ml and less than 20 ng�hr/ml, for such dosage. Tmax values are essentially unaffected by dose and Cmax and AUC values vary linearly with dosage for oral dosages up to about 1500 mg/day. Cmax and AUC values plateau for dosages above about 1500 mg/day. All of these parameters have their common meanings.
6. EXAMPLES For the purposes of the Examples, the term �hydrated lanthanum carbonate� refers to lanthanum carbonate having a water content approximately equivalent to 4-5 moles of water.
6.1. Example 1 Preparation of Stabilized Hydrated Lanthanum Carbonate Chewable Tablets (250 mg, 500 mg, 750 mg, and 1000 mg) The manufacturing process involves sieving and blending the active ingredient with the excipients followed by direct compression. More specifically the steps are as follows:
Hydrated lanthanum
Improves blending
Hydrated lanthanum carbonate
Colloidal silicon dioxide (e.g., Aerosil �
6.2. Example 2 Stabilized Lanthanum Carbonate Chewable Tablet Formulation Containing Sorbitol Stabilizing Agent The following lanthanum carbonate chewable tablet formulation comprising sorbitol can be manufactured as described in Example 1.
6.3. Example 3 Stabilized Lanthanum Carbonate Chewable Tablet Formulation Containing Mannitol Stabilizing Agent The following lanthanum carbonate chewable tablet formulation comprising mannitol can be manufactured as described in Example 1.
6.4. Example 4 Stabilized Lanthanum Carbonate Chewable Tablet Formulation Containing Xylitol Stabilizing Agent The following lanthanum carbonate chewable tablet formulation comprising xylitol can be manufactured as described in Example 1.
6.5. Example 5 The Stabilization of Lanthanum Carbonate Formulations with Monosaccharide and Disaccharide Stabilizing Agents Excipient compatibility studies of hydrated lanthanum carbonate having a water content approximately equivalent to 4-5 moles of water and anhydrous lanthanum carbonate were performed to determine whether different classes of saccharide excipients would retard or prevent the appearance of decarboxylation products in thermally- and moisture-stressed solid lanthanum carbonate mixtures.
6.5.1. Materials and Methods 6.5.1.1 Samples and Reagents Substantially pure hydrated lanthanum carbonate and anhydrous lanthanum carbonate samples were utilized for this study. Test excipients (D-mannitol, D-sorbitol, dextrates, f-cyclodextrin, corn starch, anhydrous lactose, lactose monohydrate, and microcrystalline cellulose) were purchased from commercial suppliers and used as received.
6.5.1.2 Mixture Preparation Weighed samples of hydrated lanthanum carbonate/excipient (1:1 or 96:4 by weight) or anhydrous lanthanum carbonate/excipient (1:1 by weight) were sealed into scintillation vials and placed onto a Turbula mixer. Samples were mixed for ten minutes to ensure sample homogeneity.
6.5.1.3 Humidity Chamber Preparation Saturated salt solutions of Na2SO4.10H2O (�95% RH (relative humidity)) or NaNO3 (65% RH) were prepared and placed into sealed chambers. The chambers were placed into a 60� C. oven overnight and the presence of solids was confirmed after 24 hours. These chambers were then subsequently used for the stressing studies of the various excipient/lanthanum carbonate mixtures. The lower humidity conditions were utilized for the D-sorbitol and dextrates excipients because they deliquesce under the more extreme conditions of 60� C./95% RH.
6.5.1.4 X-Ray Powder Diffractometer (XRPD) XRPD analyses were performed using a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Kα radiation. Samples were prepared for analysis by placing them in an aluminum holder with a silicon insert.
6.5.2. Results and Discussion 6.5.2.1 Characterization of Test Materials The unstressed, substantially pure hydrated lanthanum carbonate was crystalline by XRPD (FIG. 1). Excipients and anhydrous lanthanum carbonate used in this study were characterized by XRPD for specificity purposes, and their patterns are displayed in FIG. 2. All excipients exhibit sufficient specificity to allow the monitoring of lanthanum hydroxycarbonate (HC) formation.
6.5.2.2 Stress Studies of Hydrated Lanthanum Carbonate At the experimental onset, the hydrated lanthanum carbonate was stressed under two conditions, 60� C./95% RH and 60� C./65% RH, in order to establish a baseline for monitoring decarboxylation. Individual samples were pulled after 1, 2, 3, 4, and 7 days and immediately analyzed by XRPD. In addition, pulls were made at 14 and 21 days under the 60� C./65% RH condition.
FIG. 3 (60� C./95% RH conditions) and FIG. 4 (60� C./65% RH conditions) summarize the results. Under the 60� C./95% RH conditions, the decarboxylation product, HC, was initially seen after one day. When hydrated lanthanum carbonate was placed under 60� C./65% RH stress conditions, HC was again initially seen after a single day (FIG. 4).
6.5.2.3 Stress Studies of Hydrated Lanthanum Carbonate/D-Mannitol (60� C./65% RH Conditions) The 1:1 (by weight) mixtures of hydrated lanthanum carbonate/D-mannitol were stressed and analyzed over a two week period. The results are shown in FIG. 5. No decarboxylation of the hydrated lanthanum carbonate was seen over the entire length of the experiment.
6.5.2.4 Stress Studies of Hydrated Lanthanum Carbonate/D-Sorbitol (60� C./65% RH Conditions) The 1:1 (by weight) mixtures of hydrated lanthanum carbonate/D-sorbitol were stressed over a three week period. Results are summarized in FIG. 6. No decarboxylation of the hydrated lanthanum carbonate was seen over the entire length of the experiment.
6.5.2.5 Stress Studies of Hydrated Lanthanum Carbonate/Dextrates (60� C./65% RH Conditions) The 1:1 mixtures (by weight) of hydrated lanthanum carbonate/dextrates were stressed over a three week period. Results are summarized in FIG. 7. No decarboxylation of the hydrated lanthanum carbonate was seen over the entire length of the experiment.
6.5.2.6 Stress Studies of Hydrated Lanthanum Carbonate/β-Cyclodextrin (60� C./95% RH Conditions) The 1:1 (by weight) mixtures of hydrated lanthanum carbonate/O-cyclodextrin were stressed and analyzed over a two week period. The results are summarized in FIG. 8. The presence of the decarboxylation product HC was initially detected after 1 day of stressing.
6.5.2.7 Stress Studies of Hydrated Lanthanum Carbonate/Corn Starch (60� C./95% RH Conditions) The 1:1 (by weight) mixtures of hydrated lanthanum carbonate/corn starch were set up for stressing over a two week period. The results are summarized in FIG. 9. The presence of the decarboxylation product HC was initially detected after 1 day of stressing.
6.5.2.8 Stress Studies of Anhydrous Lanthanum Carbonate/D-Mannitol (60� C./95% RH Conditions) The 1:1 (by weight) mixtures of anhydrous lanthanum carbonate/D-mannitol were stressed and analyzed over a two week period. The results are summarized in FIG. 10. No decarboxylation of the anhydrous lanthanum carbonate was seen over the entire length of the experiment.
6.5.2.9 Stress Studies of Hydrated Lanthanum Carbonate/Anhydrous Lactose and Hydrated Lanthanum Carbonate/Lactose Monohydrate (60� C./95% RH Conditions) 1:1 (by weight) mixtures of hydrated lanthanum carbonate/anhydrous lactose and hydrated lanthanum carbonate/lactose monohydrate were stressed and analyzed over a two week period. The results are summarized in FIGS. 11 and 12 for hydrated lanthanum carbonate/anhydrous lactose and hydrate lanthanum carbonate/lactose monohydrate, respectively. No detectable decarboxylation of the hydrated lanthanum carbonate was observed in either mixture over the entire length of the experiment.
6.5.2.10 Stress Studies of Hydrated Lanthanum Carbonate/Microcrystalline Cellulose (60� C./95% RH Conditions) The 1:1 (by weight) mixture of hydrated lanthanum carbonate/microcrystalline cellulose showed evidence of the decarboxylation of hydrated lanthanum carbonate after a single day of stressing at 60� C. and 95% relative humidity. The results are summarized in FIG. 13.
6.5.2.11 The Stabilization of Hydrated Lanthanum Carbonate in a 96:4 (by Weight) Hydrated Lanthanum Carbonate/D-Mannitol Mixture A study of a 96:4 (by weight) hydrated lanthanum carbonate/D-mannitol mixture was performed using the methods described above. This mixture was stressed at 60� C. and 95% relative humidity for 14 days. The results are summarized in FIG. 14.
6.5.3. Conclusions The results show that mono- and disaccharides, such as mannitol, sorbitol, lactose and dextrates, offer a stabilizing protection to formulations containing lanthanum carbonate (anhydrous and hydrated) in reducing or eliminating the decarboxylation to lanthanum hydroxycarbonate. Polysaccharides such as corn starch, beta-cyclodextrins and microcrystalline cellulose, do not offer such protection and so decarboxylation was seen in formulations containing such materials at a similar rate to the unformulated drug substance exposed to the same conditions.
6.6. Example 6 Decarboxylation Rates of Hydrated Lanthanum Carbonate Under Ambient Conditions Unformulated hydrated lanthanum carbonate and formulated hydrated lanthanum carbonate tablets containing approximately 50% (by weight) dextrates were exposed to the standard ICH stability conditions of 25� C./60% RH, 30� C./60% RH and 40� C./75% RH for a period up to 2 years. Samples were removed periodically over this time and tested for their lanthanum hydroxycarbonate content using x-ray powder diffraction.
FIG. 15 shows the decarboxylation rates of unformulated hydrated lanthanum carbonate and demonstrates significant degradation of the unformulated hydrated lanthanum carbonate at the standard ICH stability conditions of 25� C./60% RH, 30� C./60% RH and 40� C./75% RH. The degradation at the 25� C./60% RH condition results indicates the need to store the unformulated drug substance in refrigerated conditions in order to slow the degradation rate. In contrast, no decarboxylation can be detected in similarly stored tablets formulated with about 50% (by weight) dextrates as shown in FIG. 15.
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