丹麦专利DK200600252U1 Pharmaceutical composition comprising lanthanum compounds

专利PDF首页>>丹麦专利

专利附录

专利说明

权利要求

类似技术

同族专利

引用文献

法律状态

优先权

专利摘要:

公开号:DK200600252U1
申请号:DK200600252U
申请日:2006-09-26
公开日:2007-01-12
发明作者:Ferdinando Josephine Christine；Haslam Robert Paul；Trespidi Laura Anna
申请人:Shire Holdings Ag；
IPC主号:

专利说明:

DK 2006 00252 U4
BACKGROUND
Hyperphosphataemia is a particular problem in patients with chronic renal insufficiency using dialysis equipment and in approx. 70% of patients with end-stage renal disease (ESRD). This disorder can lead to severe bone problems and calcium metastasis of larger organs and is associated with significant morbidity or mortality. Conventional dialysis does not reduce the levels of phosphate in the blood, so that the levels increase with time. Elevated phosphate levels are processed using a combination of dietary requirements and phosphate binding agents.
Another problem in patients with chronic renal insufficiency is secondary hyperparathyroidism. It is also important in patients with chronic renal insufficiency to avoid and treat secondary hyperparathyroidism.
Certain lanthanum carbonate forms have been used to treat hyperphosphataemia in patients with renal failure (see, for example, JP 1876384). US Patent No. 5,968,976 discloses the preparation and use of certain hydrates of lanthanum carbonate in a pharmaceutical composition for the treatment of hyperphosphataemia.
WO 96/30029 A discloses pharmaceutical compositions containing hydrated lanthanum carbonates for the treatment of hyperphoshataemia, including various well-known oral administration forms.
WO 02/085348 A discloses pharmaceutical compositions containing e.g. lanthanum carbonate for the treatment of conditions characterized by undesirable absorption of oxalate from the gastrointestinal tract, including various well-known oral administration forms.
2 DK 2006 00252 U4 WO 02/00227 A discloses the use of e.g. lanthanum carbonate for the treatment of various bone diseases including various well known oral administration forms.
5 SUMMARY OF PRODUCTION
Because of their kidney problems, patients with end-stage renal disease or chronic kidney disease must limit their intake of fluid. Therefore, there is a need for a formulation of a lanthanum compound which can be ingested without or together with a limited amount of liquid. There is also a need for a chewable formulation. Furthermore, there is a need for a formulation that the patient thinks is tasty, especially under as dry conditions as possible. There is also a need for a formulation that can be compressed into a tablet.
15
This invention relates to a chewable tablet or powder formulation of lanthanum carbonate comprising: a lanthanum carbonate in an amount of from 10 to 40% by weight of lanthanum 20 measured as elemental lanthanum and at least one chewable pharmaceutically acceptable excipient.
This invention relates to a chewable pharmaceutical formulation in a tablet or powder comprising a lanthanum carbonate, comprising: a lanthanum carbonate in an amount of from 10 to 40% by weight of lanthanum as elemental lanthanum and at least one chewable pharmaceutically acceptable excipient.
3 DK 2006 00252 U4
The production also relates to the use of lanthanum carbonate for the preparation of a chewable tablet or powder formulation for the treatment of hyperphosphataemia.
The formulations of the preparation can be used in a method of controlling hyperphosphataemia in a patient, comprising administering a therapeutically effective amount of the lanthanum formulation.
The lanthanum formulation according to the invention may be prepared by a process comprising the steps of: a) powder blending the lanthanum compound and at least one pharmaceutically acceptable excipient in a blender to form a blend; and b) compressing the mixture into a tablet or loading the resulting mixture into a suitable container.
The lanthanum formulation according to the invention may also be prepared by a process comprising the steps of: a) powder blending the lanthanum compound and at least one pharmaceutically acceptable excipient in a blender to form a blend; or b) powder blending of the lanthanum compound and excipients, compressing the resulting combination into a slug material or rolling compacting the resulting combination into a strand material, and grinding the prepared material into a free-flowing mixture; and c) compressing the mixture into a tablet or loading the resulting mixture into a suitable container.
The lanthanum formulation according to the invention may also be prepared by a process comprising the steps of compressing the lanthanum compound into a slug material or rolling compaction into a strand material, and grinding the prepared material into a free flowing material, then admixing it with excipients where the resulting combination is compressed into a tablet or the resulting mixture is filled into a suitable container.
It should be noted that the hydration state of the lanthanum carbonate present in the formulation of the present invention is relevant to the biological properties of the product. Therefore, it is desirable to maintain a steady state of hydration of the lanthanum carbonate, and for example, it is desired to keep the levels of hydration constant throughout the formulation process. This poses a further challenge besides obtaining a tablet or powder which is acceptable to the patient. It is important to mention that lanthanum carbonate has poor flow characteristics. These poor flow characteristics also present a further challenge in the preparation of high-drug formulations, as is the case for lanthanum carbonate, while maintaining a dose size that the patient thinks is acceptable and tasty. With drugs that have a specific hydration status, granulation with water or solvents and drying is not always advisable as this may affect the hydration status of the drug. In some cases, other techniques, such as roll compaction / slugging / -20 milling / compression, can be used to improve flow. If roll compaction / swallowing / grinding / compaction is not suitable, direct compression can be used to make tablets. However, if the drug has poor flow characteristics and is present in high dose, then direct compression can be difficult due to poor flow. If the drug is in a low dose (e.g. 25 100 mg / tablet or less) then a greater amount of excipients may be used to reduce the flow problems, but for lanthanum carbonate hydrate where the drug is present in greater amount, the amount of excipients added is limited to ensure that the tablet is of an appropriate size. Therefore, there is a need for a formulation that allows the hydration status of the lanthanum carbonate 30 to be maintained within desired ranges. In a further embodiment, the manufacturing process does not require the use of a wet granule step. In yet another embodiment, the formulation process for preparing the formulation of the present invention does not involve a drying step.
The formulation can be used in a method of treating hyperphosphataemia in a kidney failure patient, including, but not limited to, a dialysis patient and a final stage renal disease (ESRD) comprising administering a therapeutically effective amount of a lanthanum compound.
The formulation of the preparation can also be used in a method of treating a patient with chronic kidney disease, comprising administering a therapeutically effective amount of a lanthanum compound.
The formulation according to the invention may also be used in a method of controlling hyperparathyroidism in a patient with chronic renal failure, comprising administering a therapeutically effective amount of a lanthanum compound, preferably lanthanum carbonate.
The formulation of the preparation may also be used in a method of treating hyperparathyroidism in a patient with chronic renal failure, comprising administering a therapeutically effective amount of a lanthanum compound, preferably lanthanum carbonate.
*
The formulation according to the invention can also be used in a method where the ianthan compound is applied in such a formulation that lanthanum plasma levels are low, for example at least as good as those provided with an average concentration curve where Cmax, Tmax and AUC are preferably less than 1.5 ng / ml, approx. 12 hours, and less than 50 ng * hr / ml, for a dose of 3 g per day (e.g., 1 g three times daily), as obtained in the prior art. In a more preferred embodiment, Cmax and AUC are less than 1.1 ng / ml and less than 32 ng * hr / ml, and in a most preferred embodiment, Cmax and AUC are less than 0.5 ng / ml and less than 20 ng «hr / ml of such a dose. Tmax values are essentially unaffected by dose, and Cmax and AUC values vary linearly with dose. All of these parameters have their highly conventional meanings.
The formulation of the preparation may also be used in a method of treating hyperphosphataemia, comprising administering such a lanthanum carbonate formulation to a patient in need thereof.
In a preferred embodiment, lanthanum carbonate of the general formula is used:
La 2 (CO 3) 3 * x H 2 O where x has a value of from 3 to 8, from 3 to 7, from 3 to 6, preferably from 3 to 5, especially from 3 to 4, more preferably from 3 to 4.5, preferably from 4 to 5, most preferably, 3.4, most preferably x has an average value of 4; for the manufacture of a medicament for the treatment of hyperphosphataemia by administration into the gastrointestinal tract; see, for example, U.S. Patent No. 5,968,976, incorporated herein by reference. The hydration level of the lanthanum carbonate can be measured by methods well known in the art, such as thermal analysis (TGA).
In one aspect, the excipients used in the formulation of the present invention are suitable for administration to patients with renal impairment. In a further aspect, the excipients include diluents, binders and lubricants / lubricants. It is to be understood that other agents, such as explosives, colors, flavors / sweeteners, may be added to the formulation.
7 DK 2006 00252 U4
The diluents can be selected from dextrates, corn syrup, oligosaccharide, isomaltooligosaccharide, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, polydextrose, dextrin, starch, fructose, xylitol, litholactol, maelodextrin, maltodextrin (such as avicel), sucrose-based diluents (such as Nutab, DiPac or Sugar loss), icing sugar, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolyzed starches (such as Emdex or Celutab), dextrose (such as Cerelose), inositol, hydrolyzed solids (such as Maltrons or Morx) ), amylose or glycine.
The diluents may be selected from dextrates, starch, lactose, mannitol, sorbitol, microcrystalline cellulose (such as avicel) sucrose-based diluents (such as Nutab, Di-Pac or Sugartab), icing flour, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolyzed dextrose (or such as Cerelose), inositol, hydrolyzed solids (such as Maltrons or Mor-Rex), amylose or glycine.
In a further embodiment, the diluents may be selected from dextrates, starch, lactose, mannitol, sorbitol, microcrystalline cellulose (such as avicel), sucrose-based diluents (such as Nutab, Di-Pac or Sugartab), calcium sulfate dihydrate, calcium lactate trihydrate, hydrolysed , dextrose (such as Cerelose), inositol, or amylose.
In a further embodiment, the diluent is selected from dextrates, fructose, xylitol, erythritol, maltodextrin, dextrose, maltitol, isomalt or glucose.
In a further embodiment, the diluent is dextrates.
In a further embodiment, lubricant / lubricant and mixer / flow agent may be selected from, for example, magnesium stearate, talcum, polyethylene glycol, silica, colloidal anhydrous silica, hydrogenated vegetable oils, glyceryl behenate or glyceryl monostearate.
In a further embodiment, lubricant / lubricant and mixer / flow agent may be selected from, for example, magnesium stearate, talcum, polyethylene glycol, silica or colloidal anhydrous silica.
In one aspect, the production is directed to a chewable formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (Elemental) 5-50 Diluent (s) (e.g., dextrates (hydrated)) 10-90 Mixing / Flowing Agent (s) - Lubricant (s) (e.g., colloidal anhydrous silica and / or magnesium stearate) 0 In a further aspect, the preparation is directed to a formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (Elemental) 10-40 Diluent (s) (e.g., dextrates (hydrated)) 40-80 Mixing / Flowing Agent (s) - Lubricant) (e.g., colloidal anhydrous silica and / or magnesium stearate) 0.1 In a further aspect, the preparation is directed to a chewable formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (elemental) 20-30 Diluent (s) (e.g., dextrates (hydrated)) 30-60 Mixing / flowing agent (s) - Lubricant (s) (e.g., colloidal anhydrous silica and / or magnesium stearate) 0.1-5.0 In a further aspect, the production is directed to a formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (elemental) 20-30 Diluent (s) (e.g. dextrates (hydrated)) 30-50 Mixing / flowing agent (s) - Lubricant (s) (e.g. colloidal anhydrous silica and / or magnesium stearate) 0.1-5.0 In a further aspect, the production is directed to a formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (elemental) 10-30 Diluent (s) (for example, dextrates (hydrated)) 24-60 10 DK 2006 00252 U4
Mixing / Flow Agent (s) - Lubricate 0.1-5.0 agent (s) (e.g., colloidal anhydrous silica and / or magnesium stearate) In a further aspect, the preparation is directed to a formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (elemental) 20-30 Diluent (s) (e.g., dextrates (hydrated)) 40-60 Mixing / flowing agent (s) - Lubricant (s) (e.g., colloidal anhydrous silica and / or magnesium stearate In a further aspect, the production is directed to a chewable formulation comprising:
Formulation wt% range from approx. to approx. Lanthan (Elemental) 20-27 Diluent (s) (e.g., dextrates (hydrated)) 42-58 Mixing / Flowing Agent (s) - Lubricant (s) (e.g., colloidal anhydrous silica and / or magnesium stearate ) 0.1-4.0
These formulations may also be sprinkled when prepared in a conventional suitable dosage form, for example, beads, crushed tablets, powders, sieved granules; 11 11GB 2006 00252 U4 all are tasty. For patients who have difficulty chewing tablets, the formulation can be sprinkled either on a spoon or on food, if necessary.
Tablets may be coated according to methods well known in the art.
5
It may be advantageous to incorporate an antioxidant, for example ascorbic acid, butylated hydroxyanisole or hydroquinion into the formulations of the preparation to increase their shelf life.
Alternatively, administration may be performed in an uninterrupted regimen; such a regime can be a long-term regime, for example a permanent regime.
In one aspect, the preparation is directed to a pharmaceutical formulation in a tablet containing an amount of elemental lanthanum selected from 250 mg, 500 mg, 15 750 mg and 1000 mg. It can be prepared by a process comprising the steps of: a) dry mixing a lanthanum compound and excipient in a mixer to form a mixture; and b) compressing the mixture into tablets using a single punch or rotary tablet machine.
For example, a typical dose for an adult may be 750 mg-3000 mg daily. The dose can be divided and taken with each meal, for example 250-1000 mg, for example three times daily. Serum plasma levels can be monitored weekly until an optimal serum phosphate level is conventionally achieved.
Lanthan is a rare earth metal with an atomic number of 57. Lanthan's properties make it a good candidate as a useful phosphate binder. It has a high affinity for phosphorus binding and, in its carbonate salt form, has low solubility which limits gastrointestinal absorption. In addition, the phosphate bond is pH-independent, it has low toxic potential based on LD50, it is tasty, is found in abundance, and has limited effects on serum electrolyte concentrations (Hutchison, AJ et al. (1998) Perit. Dial. Int. 18 (Suppl 2): S38.
It should be understood that the dosage dosages and the duration of administration of the formulation according to the preparation will vary depending on the needs of the particular individual. The exact dose regimen will be determined by the treating physician or veterinarian, will take such factors into account such as body weight, age and symptoms (if any). The formulations may, if desired, incorporate one or more additional active ingredients.
In a further embodiment, the lanthanum formulation is used for veterinary treatment of a non-human animal, for example, a pet suffering from hyperphosphataemia, comprising the step of administering a pharmaceutically acceptable amount of the lanthanum compound to such an animal, e.g. need such treatment.
The use of oral medications for animals has usually been quite difficult due to the animals' reluctance to swallow tablets, pills or drug-fed foods, especially if the drug has an unpleasant taste or odor. For example, when a drug is administered orally as tablets, even if mixed with regular feed, the animal will not have it, and the treatment may either not be performed or should be coerced, but only to a limited and therefore usually inadequate and inconsistent extent.
The success of oral administration of pet medicines has been limited. For example, US Patent No. 5,824,336 discloses the need for a tasty pet food worm composition and is specifically directed to a chewable tablet composition afflubendasol which dogs seem to taste good.
13 DK 2006 00252 U4
In particular, cat owners' veterinary manuals typically warn against breaking pills into powders, For example, in Cat Owner's Home Veterinary Handbook by Carl-son D.G. et al. (1983, First Edition, Howell Book House Inc), this is emphasized on the basis that powders provide an unpleasant taste that is poorly tolerated. Furthermore, it recommends that drugs specifically predicted to be added to a cat's ration are blurred by adding beer yeast, cheese or strong fish oil. This manual also describes more elaborate ways in which tablet and liquid formulations can be administered directly to a cat and specifically how the cat is kept, the mouth opened and the dosage form placed in the cat's mouth to ensure it is eaten.
It is also recognized that control of the pet's diet is more difficult and therefore that control of the intake of phosphates is relatively difficult compared to human subjects.
It is also well known that pet's sense of smell (highly correlated with taste) is particularly sharp in comparison to human subjects. Therefore, there is a need for a palatable agent that can be immediately used to treat hyperphosphataemia and control associated hypercalcaemia especially in pets, including, for example, dogs and cats. As renal disease is often diagnosed in older cats, improved remedies for this condition are strongly required for this species.
It has now been found that lanthanum compounds can be administered to animals, including pets, in an amount that tastes good and is effective in reducing hyperphosphataemia. Furthermore, it has been found that the degree of palatability of the lanthanum compound for such animals allows such compounds to be administered in a dosage form where no specific coatings, masking ingredients and administration procedures are required to encourage ingestion, especially when put into the animal's feed ration. In particular, it has been found that lanthanum compounds can be administered to cats in an amount effective to reduce hyperphosphataemia when these compounds are in particulate form for admixture with feed.
During the dosing regimen, administration may be performed once or several times a day, for example once, twice, three or four times a day.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning which is generally understood by a layman in the field to which this production belongs. All publications, patent applications, patents and other references cited herein are incorporated in their entirety by reference. In the event of conflict, the present description including definitions will govern. Furthermore, the materials, methods and examples are illustrative only and are not intended to be limiting.
Without further elaboration, it is believed that one skilled in the art can fully utilize the present invention using the foregoing description.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the mean serum lanthanum concentration (lanthanum given at maximum tolerated dose for 72 hours).
Figure 2 shows the mean concentration of inorganic phosphorus in urine.
15 DK 2006 00252 U4
EXAMPLES
Example 1 Preparation of Lanthan Carbonate Liquid Tablets (250 mg. 500 mg, 750 mg and 1000 mg).
The preparation process involves sieving and mixing the active ingredient with the excipients followed by direct compression. Specifically, the 10 steps that follow for Formulation A are the 250 mg and 500 mg tablets: a) Pass the lanthanum carbonate, dextrates and colloidal silica through a screen of at least 16 mesh into a suitable blender and blend for approx. 20 minutes.
15 b) Pass talcum (optional) and magnesium stearate through a 30 mesh sieve and add to the blender and blend ice for approx. 5 minutes.
c) Compress the mixture using standard tool 20 for the target compression weight.
The following tablets were prepared as generally described in the example.
16 DK 2006 00252 U4
Table 1A Formulation A
Ingredient 250 mg tablet 500 mg tablet Function Active ingredient Lanthan (III) carbonate hydrate 477.0 mg 954.0 mg Active Other ingredients Dextrates (hydrated) 1247.0 mg 2494.0 mg Diluent Colloidal anhydrous silica 36.0 mg 72 , 0 mg Mix / flow improvement Purified talcum 30.0 mg 60.0 mg Lubricant / lubricant Magnesium stearate 10.0 20.0 Lubricant TOTAL 1800 mg 3600 mg 17 DK 2006 00252 U4
Table 1B Formulation B
250 mg tablet 500 mg tablet 750 mg tablet 1000 mg tablet Dosage form Chewable tablet Chewable tablet Chewable tablet Tablet diameter 13 mm 18 mm 20 mm 22 mm Formulation Lanthan (elemental) 250 mg 500 mg 750 mg 1000 mg Lanthan carbonate hydrate1 477 mg 954 mg 1431 mg 1908 mg Dext rates (hydrated) 533.2 mg 1066.4 mg 1599.6 mg 2132.8 mg Colloidal silicon dioxide 21.2 mg 42.4 mg 63.6 mg 84.4 mg Magnesium stearate 10, 6 mg 21.2 mg 31.8 mg 42.4 mg Total weight 1042 mg 2084 mg 3126 mg 4168 mg Example 2
Summary of studies conducted with Formulation A
1. Summary of Multiple Studies 10 Table 2 summarizes the ranges of mean concentrations of lanthanum in plasma obtained at designated times in several studies of randomized patients among five Fasel l / l II studies.
18 DK 2006 00252 U4
Table 2 Study No. Lanthan dose interval (mg / day) Duration of treatment (weeks) Interval for lanthanum piezma agent levels (SD), ng / ml 1 375 - 2250 Dose titration (Dell) 4 0.16 (0.31) -0, 69 (0.55) a 375 - 2250 Fixed Maintenance Dose (Part 2) 4 0.39 (0.37) -0.67 (0.98) 3 2 225 - 2250 Fixed Dose Levels 6 0.21 (0.22) -0.86 (0.91) 3 750 - 3000 Adjustable dose levels 49 0.38- (0.25) -0.67 (0.65) 4 375 - 3000 Dose titration for fixed dose levels 10 0.35 (0.44 ) -0.78 (1.05) 5 750 - 3000 Dose titration to fixed dose levels 52 0.4 (0.76) -0.6 (1.15) aU Units are ng / gm. Conversion to ng / ml, multiply plasma concentrations by 1.054, plasma density.
19 DK 2006 00252 U4
The intervals and upper range values for the lanthanum plasma mean levels are similar throughout the Fasell / III studies with the highest mean levels at <1ng / ml. The interval values were as low as the Cmax values determined in previous studies.
2. This study evaluates the primary pharmacology and safety pharmacology of a conventional non-calcium antihyperphosphate anemia treatment, lanthanum carbonate (LC).
Methods LC's in vitro phosphate binding efficiency is assessed at the relevant gastroin testinal pHs of 3, 5 and 7 using aluminum hydroxide (AH) and calcium salts for comparison. In vivo dietary phosphate binding is compared with AH, calcium carbonate (CC) and sevelamer hydrochloride (SH) (1000 mg binder / kg / day) in 5 / 6th renal rectomized rats dosed daily for 6 weeks and using urine phosphate excretion as the primary endpoint. The potential for adverse pharmacological effects of LC on CNS, cardiovascular, respiratory and GI systems is evaluated in mice, rats and dogs at doses up to 2000 mg / kg / day.
results
In vitro, LC is equipotent with AH and significantly more potent than CC or calcium acetate. LC is most effective (97.5% phosphate bound) at pH 3, but also has good efficacy at pH 5 and 7. In 5/6 kidney rectomised rats, LC is equipotent with AH and significantly more potent than CC or SH to reduce urinary phosphate excretion. , a sensitive marker for dietary phosphate binding in this model. At doses up to 2000 mg / kg, LC has no direct effects on serum calcium, vitamin D or PTH levels, and no adverse pharmacological actions on cardiovascular, respiratory or GI systems in mice, rats or dogs. No acute or long-term effects on CNS function occur in mice or dogs in Irwin and neurotoxicity screenings. LC has no pro- or anti-convulsive activity and no effects on locomotor risk activity in mice.
This study indicates that LC is a selective and potent phosphate binder with the same efficacy as aluminum hydroxide and low potential for adverse safety pharmacology.
3. This preclinical study is being conducted to investigate long-term toxicity of conventional lanthanum carbonate (LC).
methods
Single- and multiple-dose oral and iv toxicity studies with LC in mice, rats and dogs use doses up to 2000 mg / kg / day (po) (x17 a human dose of 1000 mg time) and 1 mg / kg / day ( iv). LC plasma levels are up to 20,000 times that of dialysis patients. The duration of the studies varies from up to 1 year in dogs and 2 years (lifetime exposure) in rodents. Studies in 5/6 renal rectomised rats evaluated the possible influence of renal impairment on the toxicity profile. The studies include clinical assessments, ECG, ophthalmoscopy, haematology, urine analysis, serum chemistry, plasma and tissue LC exposure, and histopathological examination of more than 40 tissues. Full programs are also being carried out to assess genetic toxicity, reproductive toxicity and carcinogenicity.
Results LC are well tolerated with no impact on appearance, growth or survival in the lifetime studies. Adaptive changes in the rodent's stomach (not observed in dogs) are the only findings at high oral doses.
21 DK 2006 00252 U4
Rats with impaired renal function have comparable tissue exposure to normal rats and also tolerate LC very well. Histomorphometry reveals no potential for direct bone toxicity. Some indirect effects on mineralization are due to phosphate depletion caused by excessive dietary binding at high doses. Lanthan is not genotoxic or carcinogenic and does not adversely affect any stage of reproduction.
4. This study is performed to compare conventional lanthanum carbonate (LC) with other therapies (calcium or aluminum salts, or 10 sevelamer hydrochloride).
methods
This 2-year randomized multicenter open-label parallel group trial consists of a 1 to 3-week flushing period, a 6-week titration T phase, and a long-term maintenance phase. Hemodialysis patients with serum phosphorus> 5.9 mg / dL (> 1.9 mmol / L) receive either LC (375-3000 mg / day elemental lanthanum) or their pre-study phosphate binder. The primary purpose of the study is to evaluate safety and tolerance 20 over 2 years. The main efficacy endpoint is serum phosphorus control £ 5.9 mg / dL.
Results 25 A total of 647 patients received LC and 642 received standard therapy (calcium agents: 78%; sevelamer: 16%). Mean total treatment exposure is higher with standard therapy than with LC (422.2 ± 258.5 vs. 304.1 ± 253.8 days). Treatment-emergent complications occur with greater frequency in the standard therapy group than in the LC group with hypercalcaemia (10.4 vs. 3.4%), 30 diarrhea (27.4 vs. 19.8%), abdominal pain (20.9 vs. 14.1%) and dyspepsia (14, 8 vs. 8.2%). Serious complications are also more frequent in the standard treatment group (65.4 vs. 51.0%). However, this is probably complicated by the difference in treatment exposure between groups. Lanthan plasma remains very low throughout treatment (mean level: 0.5-0.6 ng / mL). A similar number of patients in both groups have effective poshphor control during maintenance therapy (46.3% vs. 41.3%; standard therapy vs. LC after 2 years).
LC is tolerated at least as well as other common long-term phosphate binders and exhibits similar efficacy in maintaining serum phosphate control over a 2-year period.
5. This study compares the efficacy, safety and tolerability of conventional lanthanum carbonate (LC) with calcium carbonate (CC) in a randomized, open-label, multicenter trial.
methods
After a flushing period of 1 to 3 weeks, hemodialysis patients with hyperphosphataemia (serum phosphorus> 1.80 mmol / L [5.6 mg / dL]) are randomized to receive LC (375-3000 mg / day lanthanum; n = 533) or CC (1500-9000 mg / day calcium; n = 267) Patients are then titrated to a maintenance dose of both drugs, providing optimal phosphate control (serum phosphorus <1.80 mmol / L) within 5 weeks. -treated patients who have controlled serum phosphorus levels after titration receive maintenance therapy for an additional 20 weeks.
results
Control of serum phosphorus levels is achieved in similar ratios between patients treated with LC and CC (Week 9: 67.9% vs. 65.8%; Week 25: 65.8% vs. 63.9%). LC is associated with a significantly greater decrease in calcium x phosphorus product than CC at Week 9 (-1.80 vs. -1.35 mmol2 / L2; P = 0.009) and a greater decrease at Week 25 (-1.59 vs. -1.26 mmol2 / L2). Lanthan plasma levels are very low throughout LC treatment: 0.49 ng / mL at the highest lanthanum dose administered at Week 25. Complications generally have mild or moderate potency, and occur in 77.7% of patients receiving LC, and 79.8% of patients receiving CC. Hypercalcaemia occurs significantly more frequently in patients receiving CC (20.2%) compared to those receiving LC (0.4%).
LC exhibits equivalent efficacy with CC to control semen phosphorus in end-stage renal disease patients. LC is well tolerated with a lower risk of hypercalcaemia than CC.
6. This study reports the results of a 6-month open-label extension of a previous 6-month, randomized clinical trial comparing conventional LC with calcium carbonate (CC).
methods
After 6 months of randomized treatment in the initial trial, patients receiving CC for 6 months are switched to a 5-week titration with LC (CC / LC group) to control serum phosphorus at £ 1.8 mmol / L (5 , 6 mg / dL). Those who initially receive LC in the randomized trial continue to receive LC at their established maintenance dose (LC / LC group; total treatment duration, 49 weeks).
Results A total of 518 patients participated in the extended study: 185 in the CC / LC group and 333 in the LC / LC group. In general, 375 patients (72.4%) completed the study: 113 (61.1%) in the CC / LC group, and 262 (78.7%) in the LC / LC- 24 DK 2006 00252 U4 group. Serum phosphorus levels are maintained at approx. 1.8 mmol / L (5.6 mg / dl) in both groups over 24 weeks; endpoint averages were 1.76 mmol / L in the LC / LC group and 1.83 mmol / L in the CC / LC group. At the end of the extended period, serum phosphorus is controlled in 63.3% of the LC / LC group, compared to 58.3% in the CC / LC group. The most common treatment-emergent complications are gastrointestinal, while those believed to be related to study therapy are reported by 17% of LC / LC patients and 31% of CC / LC patients. 0.3% of patients in the LC / LC group and 2.7% of patients in the CC / LC group report hypercalcaemic episodes.
LC is well and effectively tolerated for a period of at least 1 year. The reduced incidence of hypercalcaemia observed with LC in short-term trials is maintained for 1 year.
7. Safety and efficacy are assessed in a large-scale randomized 1-year trial on the effects on bone parameters resulting from prolonged treatment with conventional lanthanum carbonate (LC) or calcium carbonate (CC).
methods
Patients with chronic renal failure undergoing hemodialysis or continuous outpatient peritoneal dialysis are randomized (1: 1) to receive either LC (up to 3750 mg / day lanthanum; n = 49) or CC (up to 9000 mg / day calcium; n = 49) for 50 weeks. Safety assessments include complications, life signs and lanthanum plasma. Efficacy assessment includes serum phosphorus and parathyroid hormone (PTH).
25 DK 2006 00252 U4
results
All 98 patients were included in the treatment-oriented efficacy and safety population. Complication profiles were similar with LC and CC, but hypercalcaemic events {serum calcium> 2.65 mmol / L) were much less frequent with LO (6%) than with CC (35%). There were no clinically relevant changes in life signs during LC or CC therapy. Lanthan plasma levels were similar in the LC and CC treated patients (range, 0.31-0.11 ng / mL) at the bottom line, and were higher in LC treated patients (<0.03-1.95 ng / mL) 10 than in CC-treated patients (all <0.03 ng / mL) at end point.
Lanthan plasma reached steady state early in the study in LC-treated patients, and was similar between Weeks 8 and 52. LC and CC provided similar serum phosphorus control. Bottom line mean (± SD) values were 1.72 ± 0.39 and 1.87 ± 0.52 mmol / L, and endpoint values were 1.79 ± 0.47 and 1.65 ± 0.54 mmol / L with LC and CC respectively. Serum PTH remained stable with LC
over 1 year of dropped with CC.
LC was found to be equally well tolerated and showed equivalent efficacy fullness with CC, but with greatly reduced risk of hypercalcaemia over 1 20 years of treatment. As in other long-term studies, extended LC therapy did not result in lanthanum plasma accumulation.
8. This study evaluated the efficacy and safety of conventional lanthanum carbonate (LC) in an ethnic Chinese population. Twenty-five LC tablets giving 500 mg of lanthanum were evaluated. These higher-strength tablets could reduce overall pill loading - an important issue affecting patient prescription compliance.
26 DK 2006 00252 U4
methods
The study included 3 parts: a 1- to 3-week screening and irrigation phase, a 4-week open-label dose titration phase with LC, and a 4-5-week, double-blind, maintenance phase in which patients were randomized (1: 1) to get LC or placebo. LC was administered as chewable tablets giving 250 or 500 mg of lanthanum. Male and female hemodialysis patients who had phosphorus levels> 5.6 mg / dL (1.8 mmol / L) participated after rinsing their previous phosphate binder. The study included 103 10 patients. The primary efficacy endpoint was the serum phosphorus level achieved during the last week of double-blind therapy. The control of serum phosphorus to 5.6 mg / dL (1.8 mmol / L) was the major secondary efficacy endpoint. Other secondary efficacy measures included the serum phosphorus profile during titration and serum parathyroid hormone, calcium and calcium x phosphorus product levels. LC's safety and tolerance profile was assessed by monitoring complications and signs of life at each study visit. Full biochemical and hematological screenings were also performed and lanthanum plasma levels were measured throughout the study.
20 9. Renal osteodystrophy (ROD) is an important complication of hyperphosphataemia associated with significant patient morbidity. Aluminum-based phosphate binders have been associated with bone toxicity and thus have contributed to the existing difficulties of ROD. This study was designed to demonstrate the lack of similar toxicity for conventional lanthanum carbonate (LC) and to compare its long-term effects on bone with potassium carbonate (CC).
27 DK 2006 00252 U4
Procedures A total of 98 patients were randomized to treatment with either LC (n = 49) or CC (n = 49) for 1 year. Tetracycline-labeled bone biopsies were sampled at the bottom line and after 1 year of open-label treatment and full histomorphometry analyzes were performed. Bone caliphosphatase activity and serum parathyroid hormone (PTH) and calcitriol levels were also measured.
results
Bottom line bone biopsies and after 1 year of treatment were available from 33 LC and 30 CC treated patients. None of the groups exhibited aluminum-like bone toxicity. After 1 year, 5/7 LC- and 3/7 CC-treated patients with osteomalacia or paralytic bone at the baseline and 4/5 LC and 3/6 CC-treated patients with high turnover at the baseline had progressed away from these serious types of ROD. Only one patient in the LC group progressed toward paralytic bone vs. six in the CC group. There were no significant differences in bone alkaline phosphatase activities or serum calcium citriol levels between the treatment groups or at the end of the study (vs. bottom line). Serum PTH levels remained stable in the LC group, whereas reductions were seen in the CC group with greater variation in data range.
During 1 year, dialysis patients treated with LC showed greater evolution than the more severe types of ROD compared to CC-treated patients. Other bone status parameters showed no significant change in LC-treated patients. LC may therefore have an advantage over conventional phosphate binders in the treatment of ROD.
DK 2006 00252 U4 28
The foregoing examples can be replicated with similar success by substituting the genetically or specifically described reactants and / or working conditions according to the preparation for the ones used in the previous examples.
From the foregoing description, one skilled in the art can readily ascertain the essential characteristics of this invention and, without departing from its idea and scope, may make various alterations and modifications to the invention to adapt it to different uses and conditions.

权利要求:
Claims (31)
[1]
1. Chewable tablet or powder formulation of lanthanum carbonate, characterized in that it comprises a lanthanum carbonate in an amount of 10 to 40% by weight of lanthanum measured as elemental lanthanum and at least one chewable pharmaceutically acceptable excipient.
[2]
Chewable formulation according to claim 1, characterized in that it comprises a lanthanum carbonate in an amount of 20 to 30% by weight of lanthanum measured as elemental lanthanum.
[3]
Chewable formulation according to claim 1, characterized in that it comprises a lanthanum carbonate in an amount of 10 to 30% by weight of lanthanum measured as elemental lanthanum.
[4]
Chewable formulation according to claim 1, characterized in that it comprises a lanthanum carbonate in an amount of 20 to 27% by weight of lanthanum measured as elemental lanthanum.
[5]
Chewable formulation according to claim 1, characterized in that the tablet contains lanthanum carbonate in an amount corresponding to more than about 10%. 200 mg of elemental lanthanum.
[6]
Chewable formulation according to claim 1, characterized in that the tablet contains lanthanum carbonate in an amount corresponding to approx. 250 mg of elemental lanthanum or more.
[7]
Chewable formulation according to claim 1, characterized in that the tablet contains lanthanum carbonate in an amount corresponding to approx. 500 mg of elemental lanthanum or more. 30 DK 2006 00252 U4
[8]
Chewable formulation according to claim 1, characterized in that the tablet contains lanthanum carbonate in an amount corresponding to approx. 750 mg of elemental lanthanum or more.
[9]
Chewable formulation according to claim 1, characterized in that the tablet contains lanthanum carbonate in an amount corresponding to approx. 1000 mg of elemental lanthanum or more.
[10]
Chewable formulation according to claim 1, characterized in that the tablet contains lanthanum carbonate in an amount corresponding to from approx. 200 mg to approx. 1000 mg of elemental lanthanum.
[11]
Chewable formulation according to any one of claims 1 to 10, characterized in that the lanthanum carbonate is lanthanum carbonate of the general formula: 1.82 (003) 3 · XH 2 O where x has a value from 3 to 8.
[12]
Chewable formulation according to claim 11, characterized in that x has a value from 3 to 7.
[13]
Chewable formulation according to claim 11, characterized in that x has a value from 3 to 6.
[14]
Chewable formulation according to claim 11, characterized in that x has a value from 3 to 5.
[15]
Chewable formulation according to claim 11, characterized in that x has a value from 4 to 5. 31 DK 2006 00252 U4
[16]
Chewable formulation according to claims 1 to 15, characterized in that the excipient is selected from the group consisting of diluents and mixture flow lubricants.
[17]
The chewable formulation of claim 16 comprising at least one diluent selected from the group consisting of dextrates, corn syrup, oligosaccharide, isomaltooligosaccharide, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, polydextrose, dextrin, starch, xylitol, maltodextrin, maltitol, isomalt, lactose, sorbitol, microcrystalline cellulose, sucrose-based diluents, icing sugar, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolyzed starches, dextrose, inositol, hydrolyzed granules, hydrolyzed granules.
[18]
Chewable formulation according to claim 17, comprising at least one diluent selected from the group consisting of dextrates, fructose, xylitol, erythritol, maltodextrin, dextrose, maltitol, isomalt and glucose.
[19]
Chewable formulation according to claim 17, characterized in that the diluent is selected from dextrates and sorbitol.
[20]
Chewable formulation according to any one of claims 1 to 16, comprising dextrates as a diluent in an amount of from 10% by weight to approx. 90% by weight based on the total weight of all ingredients.
[21]
The chewable formulation of any one of claims 1 to 16, comprising dextrates as a diluent in an amount of from 40% by weight to approx. 80% by weight based on the total weight of all ingredients.
[22]
Chewable formulation according to any one of claims 1 to 16, comprising dextrates as a diluent in an amount of from 30% by weight to approx. 60% by weight based on the total weight of all ingredients. 32 DK 2006 00252 U4
[23]
Chewable formulation according to any one of claims 1 to 16, comprising dextrates as a diluent in an amount of from 40% by weight to approx. 60% by weight based on the total weight of all ingredients. 5
[24]
Chewable formulation according to any one of claims 1 to 16, comprising dextrates as a diluent in an amount of from 24% by weight to approx. 60% by weight based on the total weight of all ingredients.
[25]
Chewable formulation according to any one of claims 1 to 16, comprising dextrates as a diluent in an amount of from 42% by weight to approx. 58% by weight based on the total weight of all ingredients.
[26]
Chewable formulation according to any one of claims 1 to 25, comprising a blend flow lubricant selected from the group consisting of magnesium stearate, talcum, polyethylene glycol, silica, colloidal anhydrous silica, hydrogenated vegetable oils, glyceryl behenate and glyceryl monstearate.
[27]
The chewable formulation of claim 26 comprising colloidal anhydrous silica as a blend flow lubricant.
[28]
The chewable formulation of claim 26 comprising 2% by weight of colloidal anhydrous silica as a blend flow lubricant.
[29]
Chewable formulation according to claim 26 comprising a blend flow lubricant in an amount of 0.1 to 5.0% by weight.
29 DK 2006 00252 U4 Bruas model requirements:
[30]
Chewable pharmaceutical formulation in a tablet or powder comprising a lanthanum carbonate, characterized in that it comprises a lanthanum carbonate in an amount of from 10 to 40% by weight of lanthanum as elemental lanthanum and at least one chewable pharmaceutically acceptable excipient. DK 2006 00252 U4 33
[31]
Use of a lanthanum carbonate to prepare a chewable tablet or powder formulation for the treatment of hyperphosphataemia, characterized in that lanthanum carbonate is used in an amount of 10 to 40% by weight of lanthanum as measured as elemental lanthanum.

类似技术:

公开号 | 公开日 | 专利标题

DK200600252U4|2007-11-23|Pharmaceutical composition comprising lanthanum compounds

KR101553719B1|2015-09-16|Liquid compositions of calcium acetate

MXPA02005486A|2002-11-29|Nutritional composition.

KR20070090904A|2007-09-06|Oral compositions for absorption of phosphorus compounds

JP2018030873A|2018-03-01|Capsule formulation and powder formulation containing lanthanum compound

NZ567519A|2011-04-29|Treatment of chronic kidney disease | subjects using lanthanum compounds

DE20321698U1|2008-12-24|A medicament for increasing the bioavailability of alendronate or another bisphosphonate by administering a pre-dose of a vitamin D derivative

JP2001048792A|2001-02-20|Purgantia

CN106913552A|2017-07-04|A kind of polycarbophil Biocal and preparation method thereof

WO2015001329A1|2015-01-08|Chewable tablet

RU2288725C2|2006-12-10|Solid medicinal formulation eliciting antacid effect

PL196058B1|2007-11-30|Calcium lactate effervescent tablet and method for manufacture of calcium lactate effervescent tablets

同族专利:

公开号 | 公开日

IL173755D0|2006-07-05|

ES2343354T3|2010-07-29|

KR100830764B1|2008-05-20|

AU2009202429B2|2012-03-22|

HK1084338A1|2006-07-28|

PT2172205E|2014-07-17|

JP4896719B2|2012-03-14|

EP2172205A1|2010-04-07|

EP2792363A1|2014-10-22|

HUE029382T2|2017-02-28|

EA012798B1|2009-12-30|

AU2009202429A1|2009-07-09|

US20050079135A1|2005-04-14|

EP2172205B1|2014-06-18|

KR20060118420A|2006-11-23|

ES2532389T3|2015-03-26|

DE602004025950D1|2010-04-22|

EP2133084A3|2010-02-03|

ZA200602213B|2009-04-29|

FIU20060387U0|2006-09-22|

CA2536959A1|2005-03-03|

IS8353A|2006-03-15|

NO342559B1|2018-06-18|

DK2172205T3|2014-07-14|

PL2133084T3|2015-08-31|

ES2478258T3|2014-07-21|

EP1660104A4|2006-10-18|

IS2893B|2014-09-15|

US7465465B2|2008-12-16|

PL1660104T3|2010-08-31|

CN1871018A|2006-11-29|

JP2010248247A|2010-11-04|

HUE024906T2|2016-02-29|

AT9809U1|2008-04-15|

ES2592803T3|2016-12-01|

WO2005018651A1|2005-03-03|

FI7568U1|2007-07-17|

DE202004021169U1|2007-03-01|

US20090017133A1|2009-01-15|

AU2004266050B2|2009-06-18|

SI2172205T1|2014-10-30|

JP2007503400A|2007-02-22|

CZ17621U1|2007-06-25|

DK2792363T3|2016-09-26|

EA200970709A1|2010-04-30|

PT2792363T|2016-09-26|

PL2172205T3|2015-01-30|

BRPI0413394A|2006-10-17|

SI2133084T1|2015-07-31|

NZ545633A|2009-07-31|

CY1118211T1|2017-06-28|

EP2792363B1|2016-06-29|

PT2133084E|2015-04-16|

CA2536959C|2011-08-02|

SI2792363T1|2016-11-30|

MXPA06002257A|2006-05-17|

SG145765A1|2008-09-29|

SI1660104T1|2010-08-31|

PL2792363T3|2017-01-31|

AU2004266050A1|2005-03-03|

DK1660104T3|2010-06-21|

CN1871018B|2011-11-02|

DK2133084T3|2015-04-13|

CY1110241T1|2015-01-14|

EP2133084B1|2015-02-18|

EP1660104B1|2010-03-10|

PT1660104E|2010-06-15|

DK200600252U4|2007-11-23|

EA200600479A1|2006-08-25|

AT460169T|2010-03-15|

EP1660104A1|2006-05-31|

NO20061347L|2006-05-15|

IL235371A|2018-08-30|

EP2133084A2|2009-12-16|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US4822594A|1987-01-27|1989-04-18|Gibby Wendell A|Contrast enhancing agents for magnetic resonance images|

US4877735A|1987-06-19|1989-10-31|Takeda Chemical Industries, Ltd.|Process for producing 2-keto-L-gulonic acid|

DE3724188C2|1987-07-17|1995-05-18|Heinz Dr Gries|Metal-containing oligosaccharide polysulfates, process for their preparation and pharmaceutical compositions containing them|

US20040043971A1|1995-04-03|2004-03-04|Bone Care International, Inc.|Method of treating and preventing hyperparathyroidism with active vitamin D analogs|

JP2640570B2|1992-01-13|1997-08-13|ファイザーインク．|Manufacturing tablets with increased strength|

CZ290406B6|1994-05-20|2002-07-17|Janssen Pharmaceutica N. V.|Anthelmintic composition and use thereof|

US5562921A|1994-07-15|1996-10-08|Sherman; Bernard C.|Stable solid pharmaceutical compositions containing enalapril maleate|

JP3591886B2|1994-09-05|2004-11-24|シーシーアイ株式会社|Rare earth element accumulating microorganism|

GB9506126D0|1995-03-25|1995-05-10|Johnson Matthey Plc|Pharmaceutical composition and method|

TW506836B|1996-06-14|2002-10-21|Janssen Pharmaceutica Nv|Fast-dissolving galanthamine hydrobromide tablet|

US6074672A|1996-06-28|2000-06-13|Chesebrough-Pond's Usa Co., Division Of Conopco, Inc.|Powdered cosmetic compositions containing silicone elastomers|

GB9720061D0|1997-09-19|1997-11-19|Crosfield Joseph & Sons|Metal compounds as phosphate binders|

US20010014352A1|1998-05-27|2001-08-16|Udit Batra|Compressed tablet formulation|

GB9816899D0|1998-08-05|1998-09-30|Boots Co Plc|Therapeutic agents|

US6270790B1|1998-08-18|2001-08-07|Mxneil-Ppc, Inc.|Soft, convex shaped chewable tablets having reduced friability|

JP2000173537A|1998-09-29|2000-06-23|Toshiba Lighting & Technology Corp|Low pressure mercury-vapor discharge lamp and lighting system|

US6248363B1|1999-11-23|2001-06-19|Lipocine, Inc.|Solid carriers for improved delivery of active ingredients in pharmaceutical compositions|

US6160016A|1999-12-22|2000-12-12|Wisconsin Alumni Research Foundation|Phosphorus binder|

GB0008392D0|2000-04-05|2000-05-24|Unilever Plc|Process for the production of a deodorant or antiperspirant product|

GB0015745D0|2000-06-27|2000-08-16|Shire Holdings Ag|Treatment of bone diseases|

US20020057059A1|2000-07-28|2002-05-16|Kazuhisa Ogishi|Fluorescent lamp, self-ballasted fluorescent lamp and lighting apparatus|

JP2002047210A|2000-08-04|2002-02-12|Nihon Medi Physics Co Ltd|Composition for preventing urinary calculus|

JP4612180B2|2000-12-19|2011-01-12|株式会社ヤクルト本社|Skin preparation|

DE60136096D1|2000-12-19|2008-11-20|Yakult Honsha Kk|EXTERNAL SKIN PREPARATIONS AND METHOD FOR THEIR PRODUCTION|

JP4612183B2|2000-12-27|2011-01-12|株式会社ヤクルト本社|External composition for skin and method for producing the same|

US20020122823A1|2000-12-29|2002-09-05|Bunick Frank J.|Soft tablet containing dextrose monohydrate|

NZ526871A|2001-01-25|2006-01-27|Squibb Bristol Myers Co|Pharmaceutical dosage forms of epothilones for oral administration|

NZ528818A|2001-04-23|2008-09-26|Shire Int Licensing Bv|Use of rare earth metal ions for the prevention of kidney stone disease|

GB0201607D0|2002-01-24|2002-03-13|Gamlen Michael J D|Formulation for the administration of medicinal substances|

EP1499300B1|2002-04-29|2009-03-18|Supernus Pharmaceuticals, Inc.|Pharmaceutical formulations with improved bioavailability|

WO2003094933A2|2002-05-08|2003-11-20|Shire Holding Ag|Use of lanthanum for the treatment of hypercalcemia and bone metastasis|

US20040161474A1|2002-05-24|2004-08-19|Moerck Rudi E.|Rare earth metal compounds methods of making, and methods of using the same|

WO2004037274A1|2002-10-22|2004-05-06|Genzyme Corporation|Amine polymers for promoting bone formation|

US7381428B2|2003-08-26|2008-06-03|Shire International Licensing B.V.|Stabilized lanthanum carbonate compositions|

SG145765A1|2003-08-26|2008-09-29|Shire Holdings Ag|Pharmaceutical formulation comprising lanthanum compounds|

US7459502B2|2003-11-03|2008-12-02|Ilypsa, Inc.|Pharmaceutical compositions comprising crosslinked polyamine polymers|

US7449605B2|2003-11-03|2008-11-11|Ilypsa, Inc.|Crosslinked amine polymers|

US7608674B2|2003-11-03|2009-10-27|Ilypsa, Inc.|Pharmaceutical compositions comprising cross-linked small molecule amine polymers|

US7385012B2|2003-11-03|2008-06-10|Ilypsa, Inc.|Polyamine polymers|

US7545784B2|2004-02-11|2009-06-09|Yahoo! Inc.|System and method for wireless communication between previously known and unknown users|

US7335795B2|2004-03-22|2008-02-26|Ilypsa, Inc.|Crosslinked amine polymers|

JP4964122B2|2004-03-30|2012-06-27|レリプサ，インコーポレイテッド|Ion binding composition|

US8192758B2|2004-03-30|2012-06-05|Relypsa, Inc.|Ion binding compositions|

US7854924B2|2004-03-30|2010-12-21|Relypsa, Inc.|Methods and compositions for treatment of ion imbalances|

US8282960B2|2004-03-30|2012-10-09|Relypsa, Inc.|Ion binding compositions|

JP4869229B2|2004-07-27|2012-02-08|シアファーマシューティカルズ，インク．|Pharmaceutical composition for treating hyperphosphatemia using lanthanum hydroxycarbonate|

AR061727A1|2006-06-30|2008-09-17|Schering Corp|DIETILE SYNTHESIS [[5- -PIRIDIN -2IL] METHYL] PHOSPHONATE|

US8974824B2|2008-03-26|2015-03-10|Mylan Laboratories Ltd.|Lanthanum composition|GB9720061D0|1997-09-19|1997-11-19|Crosfield Joseph & Sons|Metal compounds as phosphate binders|

GB0015745D0|2000-06-27|2000-08-16|Shire Holdings Ag|Treatment of bone diseases|

NZ528818A|2001-04-23|2008-09-26|Shire Int Licensing Bv|Use of rare earth metal ions for the prevention of kidney stone disease|

US20040161474A1|2002-05-24|2004-08-19|Moerck Rudi E.|Rare earth metal compounds methods of making, and methods of using the same|

US20060083791A1|2002-05-24|2006-04-20|Moerck Rudi E|Rare earth metal compounds methods of making, and methods of using the same|

US7381428B2|2003-08-26|2008-06-03|Shire International Licensing B.V.|Stabilized lanthanum carbonate compositions|

SG145765A1|2003-08-26|2008-09-29|Shire Holdings Ag|Pharmaceutical formulation comprising lanthanum compounds|

JP4869229B2|2004-07-27|2012-02-08|シアファーマシューティカルズ，インク．|Pharmaceutical composition for treating hyperphosphatemia using lanthanum hydroxycarbonate|

US7700608B2|2004-08-04|2010-04-20|Shire Holdings Ag|Quinazoline derivatives and their use in the treatment of thrombocythemia|

JP2008516971A|2004-10-15|2008-05-22|アルテアーナノ，インコーポレーテッド|Phosphate binder that reduces the burden of tablets|

ITME20040015A1|2004-12-07|2005-03-07|Vincenzo Savica|CHEWING GUM, RUBBER CANDIES, TABLETS, SLOW TABLETS OF CHELANTI PHOSPHATE AND / OR PHOSPHORUS SALIVAR AND CAPSULES WITH SLOW RELEASE OF CHELANTS PHOSPHATE AND / OR PHOSPHORUS AT GASTROENTERIC LEVEL.|

EP1698233A1|2005-03-01|2006-09-06|Bayer HealthCare AG|Reduction of digestibility of phosphorus in animal nutrition|

US20080058250A1|2005-08-17|2008-03-06|Allison Wren|Treatment of chronic renal failure and other conditions in domestic animals:compositions and methods|

ES2311443T1|2005-08-17|2009-02-16|Altairnano, Inc|HYPERPHOSPHATEMY IN DOMESTIC ANIMALS: COMPOSITIONS AND PROCEDURES OF TREATMENT.|

US20070104799A1|2005-11-09|2007-05-10|Shire International Licensing B.V.|Treatment of chronic kidney diseasesubjects using lanthanum compounds|

MY157620A|2006-01-31|2016-06-30|Cytochroma Dev Inc|A granular material of a solid water-soluble mixed metal compound capable of binding phosphate|

CN100398112C|2006-03-24|2008-07-02|辽宁诺康生物制药有限责任公司|Medicine for treating hyperphosphatemia and its preparing method|

GB0714670D0|2007-07-27|2007-09-05|Ineos Healthcare Ltd|Use|

GB0720220D0|2007-10-16|2007-11-28|Ineos Healthcare Ltd|Compound|

US8974824B2|2008-03-26|2015-03-10|Mylan Laboratories Ltd.|Lanthanum composition|

EP2389070B1|2009-01-21|2013-07-31|Mylan Inc.|Disintegrable formulations of lanthanum carbonate|

WO2010106557A2|2009-03-20|2010-09-23|Panacea Biotec Limited|Stable pharmaceutical formulations comprising anhydrous lanthanum carbonate and process for preparation thereof|

GB0913525D0|2009-08-03|2009-09-16|Ineos Healthcare Ltd|Method|

AU2010313075A1|2009-10-26|2012-05-31|Alkem Laboratories Ltd.|Pharmaceutical compositions of lanthanum carbonate and process for the preparation thereof|

GB201001779D0|2010-02-04|2010-03-24|Ineos Healthcare Ltd|Composition|

MX350075B|2010-05-12|2017-08-25|Spectrum Pharmaceuticals Inc|Lanthanum carbonate hydroxide, lanthanum oxycarbonate and methods of their manufacture and use.|

EP2441436A1|2010-10-13|2012-04-18|Fresenius Medical Care Deutschland GmbH|Easy to administer phosphate binder formulation|

US8697132B2|2010-12-01|2014-04-15|Shire Llc|Capsule and powder formulations containing lanthanum compounds|

US8263119B2|2010-12-01|2012-09-11|Shire Llc|Capsule formulations containing lanthanum compounds|

CN103127041A|2012-02-23|2013-06-05|南京卡文迪许生物工程技术有限公司|Medicinal composition with lanthanum acetate, preparation method and application thereof|

DE102012209411A1|2012-06-04|2013-12-05|Fim Biotech Gmbh|Mineral compound for the reduction of inorganic phosphates, in particular in the context of renal replacement therapy|

CN104473963B|2014-12-24|2017-10-10|厦门科明达科技有限公司|The preparation method of rare earth chemistry medicine lanthanum carbonate chewable tablets|

JP2016147827A|2015-02-12|2016-08-18|株式会社三和化学研究所|Pharmaceutical formulations containing lanthanum carbonate hydrate|

US10058569B2|2015-06-24|2018-08-28|Lupin Limited|Lanthanum carbonate compositions|

JP6093829B1|2015-10-02|2017-03-08|バイエル薬品株式会社|Pharmaceutical composition comprising a lanthanum compound|

CN107213126B|2017-05-17|2020-06-23|西安棣加生物科技有限公司|Method for preparing oral rapidly disintegrating tablet for treating hyperphosphatemia by 3D printing technology|

CN108969497A|2018-10-12|2018-12-11|沈阳华泰药物研究有限公司|A kind of lanthanum carbonate tablet composition and preparation method thereof|

WO2021101461A1|2019-11-21|2021-05-27|Santa Farma İlaç Sanayi̇ A.Ş.|Oral solid pharmaceutical compositions comprising lanthanum carbonate octahydrate|

法律状态:
2014-09-12| UUP| Utility model expired|Expiry date: 20140826 |

优先权:

申请号 | 申请日 | 专利标题

US49756003P| true| 2003-08-26|2003-08-26|

US51707803P| true| 2003-11-05|2003-11-05|

[返回顶部]