TWI317725B - Directly compressible tricalcium phosphate - Google Patents

Description

1317725 玖, invention description: [invention] The present invention relates to tricalcium phosphate for tablet formulations which can be directly compressed. [Background of the Invention]

Tricalcium phosphate is widely used as an excipient in pharmaceutical applications. 0 Establishing a mineral dietary supplement and a recent increase in the price of calcium and phosphorus has led to the manufacture of oral dosage forms such as tablets or lozenges and including chewable oral dosage forms. For example, in the interest of chewable tablets, calcium phosphate is the main ingredient. However, the attempt to use tricalcium phosphate as the main ingredient in the oral dosage form has caused the tablet to exhibit an unsuitable low hardness. In addition, it is made of calcium phosphate. Chewable tablets exhibit an unpleasant mouthfeel that is described as '" like grit and/or A like earthworms. The requirement is to produce a relatively high amount of tricalcium phosphate and exhibit good properties including acceptable hardness. Oral dosage form method - further requirements for such tablets (if designed as chewable tablets) have acceptable organoleptic qualities, including good mouthfeel, no grit, and no bauxite taste [Review of the Invention In a first aspect, the subject matter of the present invention is a compressible triterpene phosphate condensate comprising: a plurality of tricalcium phosphate particles each having an outer surface, and a binder comprising polyethylene An enepyrrole, carrageenan, or guar gum, carried on at least a portion of the outer surface of at least a portion of the tricalcium phosphate particles. In a second aspect, the invention is directed to a compressible phosphoric acid. The method of the tricalcium 1317725 agglomerate comprises the third aspect of spraying the tricalcium phosphate with the aqueous solution comprising the binder of polyethylene, carrageenan or guar gum, and the object of the invention is a A directly compressible calcium dietary supplement composition comprising (based on 1 part by weight of the composition):

Agglomerates of about 20 to 80 parts by weight, comprising a plurality of tricalcium phosphate particles each having an outer surface, and a polyethylene pyrrole supported on at least a portion of the outer surface of at least a portion of the tricalcium phosphate particles _, carrageenan, or gum of Guaya gum, about 79 to 10 parts by weight of the calcium-containing material particles other than the aggregate, about 0.5 to 8 parts by weight of the disintegrator, and about 0.5 to 2 parts Heavy lubricant. In a fourth aspect, the invention is directed to a method of forming an oral dosage form of a calcium dietary supplement composition comprising compressing the above-described directly compressible calcium dietary supplement composition. In a fifth aspect, the method of the present invention is an oral dosage form of a calcium dietary supplement composition, which is prepared by compressing the above-mentioned directly compressible calcium dietary supplement composition. Forms Any tricalcium phosphate that meets the specifications of the United States Pharmacopoeia 26 (HUSP/NF 26") or the Fifth Edition of the National Academy of Sciences (Washington, DC) (FCC Fifth Edition) is suitable for use in the present invention. Body composition. In a specific form, the particles of the tricalcium phosphate particles exhibit a particle size distribution of less than or equal to 2% by weight (more typically less than or equal to 0.6% by weight) having a sieve greater than 14 gauge (about 100 microns) The 1317725 particle size, and less than or equal to 5% by weight (more typically less than or equal to 2% by weight) particles have a particle size less than 325 mesh (about 5 microns).

As used herein, '"binder" means any substance which enables the mixture of the acidic component and the alkaline component of the composition of the present invention to be compacted into a bonded solid. Suitable adhesive compounds include, for example, polyvinylpyrrolidone. , gums, gum arabic, tragacanth, gelatin, polysaccharides such as glucose and sucrose, starch, pregelatinized starch, carrageenan, and cellulosic materials including methylcellulose and carboxymethylcellulose, and hydroxyl groups An alkyl cellulose compound such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose, and a mixture of any of the above, in a specific form, polyvinylpyrrolidone is preferably used as a binder The polyvinylpyrrolidone has a number average molecular weight of about greater than or equal to 30,0 0. In one embodiment, the polyvinylpyrrole binder has an average molecular weight of greater than or equal to 60,000, more typically greater than or equal to 80,000 Ο. In another specific form, the gum is used as a binder. Sub-gel refers to the water-soluble component of the leguminous Cyamopsis tetragonolobus-based endosperm, which is attached to the (1,6) bond by (l,4-)-y8-D-mannosetose units (XD-half The linear chain of lactosyl units is composed, and the ratio of D-galactose to D-mannose is about 1:2. The guar gum can be in the form of a white powder which can be dispersed in hot or cold water. For example, carboxymethylguar gum, carboxymethylhydroxypropyl guar gum, cationic hydroxypropyl guar gum, hydroxyalkyl guar gum (including hydroxyethyl guar gum, hydroxypropyl guar gum, hydroxyl Butyl guar gum and higher molecular hydroxyalkyl gums), 1317725 carboxyalkyl gums (including carboxymethyl guar gum, carboxy propyl guar gum, carboxybutyl guar gum and higher Molecular carboxyalkyl guar gum) 〇 之 古 古 为 为 符合 compliant Specification and form a gutta-percha or denatured gum with a viscosity that is low enough to allow the solution to be used in the spray drying procedure

In a specific form, the gum arabic has an average molecular weight of about less than or equal to 2,000,000 Daltons, more typically from about 200,000 Daltons to 2,000 Daltons. In a particular form, the aggregates of the present invention comprise (based on the weight of the composition): about 90 to 99 parts by weight of tricalcium phosphate, more typically from about 93 to 98 parts by weight, and still more typically from about 95 to 97 parts by weight, and from about 10 to 1 Part by weight of the binder, more typically from about 7 to 2 parts by weight, and more typically from about 5 to 3 parts by weight of the tricalcium phosphate and the binder, can be made by any suitable coacervation technique, including agglomerating. Techniques such as fluidized bed drying and high shear mixing, pressure coagulation techniques such as compression, or spray agglomeration techniques such as spray drying in a specific form, a coagulation system of tricalcium phosphate and binder by spraying dry calcium phosphate with a binder The aqueous liquid is formed in a specific form, and the particles having a particle size distribution of less than or equal to 65% by weight (more typically 90% by weight) having a particle size distribution having a sieve larger than 325 (about 50 μm) ) the particle size, and less than or equal 10% by weight (more typically 2% by weight) of the particles have a particle size smaller than 60 mesh (about 200 microns). The aggregate of the tricalcium phosphate and the binder can be used in a suitable mixer with -4 - 1317725 other Ingredients such as calcium-containing material particles, lubricants, dispersing agents, and flow agents are combined to provide the direct compressible tricalcium phosphate composition of the present invention in a specific form, the direct compressible calcium dietary supplement of the present invention The composition 尙 contains one or more particles of a calcium-containing substance other than the aggregate of the present invention. Suitable calcium-containing substances include calcium tongs such as protein calcium, and calcium salts such as calcium carbonate, calcium gluconate, calcium citrate, Tricalcium phosphate or phosphorus dihydrate

Dicalcium acid or anhydrous dicalcium phosphate, and calcium citrate maleate oxime in a particular form, the composition 尙 comprising a particle size distribution of less than or equal to 15% by weight (more typically 2.6) 6% by weight of the particles have a particle size greater than size 40 (about 3 Å 0 microns), and less than or equal to 5% by weight (more typically 0.9% by weight) of the particles have a size less than 325 mesh (about 50 microns). Tricalcium phosphate particles of particle size. In one particular form, the direct compressible calcium dietary supplement composition of the present invention comprises a lubricant. As used herein, "lubricant" means a substance that reduces the friction between the composition of the present invention and the surface of the device used to compact the composition into a compressed form. Suitable lubricants include, for example, fatty acids such as palmitic acid, stearic acid, oleic acid, hydrogenated vegetable oils, triglycerides of fatty acids; metal salts of fatty acids such as zinc stearate and magnesium stearate; glycols such as polyethylene glycol Alcohol; and talc; and mixtures thereof. In one embodiment, the lubricant component of the composition of the present invention comprises magnesium stearate. 0 In a particular form, the composition of the present invention comprises (based on 1 part by weight of the composition) about 〇·〇 5 to 5 parts by weight of the lubricant, more typically from about 0.1 to 3 parts by weight, and still more typically from about 0.2 to 2 parts by weight. In a specific form, the present invention can directly compress calcium dietary supplement 1317725

The composition 尙 comprises a dispersing agent, as used herein, A dispersing agent means a substance which is substantially insoluble in water but swellable in water, acts as a dissolving agent to accelerate the compressed form of the composition of the invention in an ice medium. Dispersion and Dissolution 0 Any pharmaceutically acceptable compound which is substantially insoluble in water but swellable in water to accelerate the dissolution and dissolution of a compressed form (e.g., a tablet) formed by the composition of the present invention in an aqueous medium is suitable as Suitable dispersing agents for the composition of the present invention include, for example, sodium carboxymethyl, starch, microcrystalline cellulose, soy protein, alginic acid, cross-linked polyethylene (also known as cross-linked povidone), and Cross-linked thiomethylcellulose sodium (also known as croscarmellose sodium), and mixtures thereof, etc., in a particular form, the dispersing agent of the composition of the invention comprises croscarmellose sodium strontium in a specific form, a combination of the invention The composition comprises (in terms of 100 parts by weight of the composition) about 5 to 5 parts by weight of the dispersing agent, more typically from about 0.1 to 4 parts by weight. In a specific form, the directly compressible calcium dietary supplement composition comprises (based on 100 parts by weight of the composition): about 15 to 75 parts by weight of the inventive agglomerates, more typically from about 30 to 60 parts

9 about 85 to 25 parts by weight of the calcium-containing material particles other than the aggregate, more typically from about 70 to 40 parts by weight, from about 0.05 to about 5 parts by weight of the disintegrator, more typically from about 0.1 to about 4 parts by weight. And from about 0.05 to 5 parts by weight of lubricant, more typically from about 0.1 to 3 parts by weight, still more typically from about 0.2 to 2 parts by weight. 1317725 The direct compressible calcium dietary supplement composition of the present invention is used for forming an oral preparation (such as a tablet and a tablet) by a conventional method, for example, using a tableting machine, so that the anti-scratch effect is the oral dosage form of the present invention. High hardness, low friability and good disintegration properties. The chewable tablet form of the present invention exhibits a very good mouthfeel and a very low astringency and grit feel.

The hardness referred to herein is measured using a Model 2E Schleuniger tablet hardness tester. In a particular form, the oral dosage form of the present invention exhibits a hardness greater than or equal to 15 kilograms ("kp"), more typically about 20 to 30 kilograms of force, more typically about 24 to 28 kilograms of force. In another specific form, the oral dosage form of the invention is in the form of a chewable tablet that exhibits a hardness greater than or equal to kilograms of force, more typically about 12 To 22 kg force, and more typically about 14 to 16 kg force. The friability referred to herein is measured according to the USP 1216 Tablet Fragility Test (USP 25) and is expressed in terms of grinding rate. In a particular form, the oral dosage form of the present invention exhibits a friability of less than 1%, more typically less than about 0.6%, and more typically less than about 0.2%. w The disintegration of w in the text herein is based on the United States Pharmacopoeia. The test method of 7〇1 (USP 26) is measured and the tablet is disintegrated into the time required to pass the smaller segment of the test sieve (seconds) when immersed in 37 ° 2 t: water. In a specific form, the mouth of the present invention The dosage form exhibits a 90 second disintegration effect, more typically less than 60 seconds. The reference to the v'clearing effect herein means that the tablet is separated by 1317725 of the tablet fragment or the tablet body is compressed. Loss of physical integrity due to lamination 0 Examples 1-3 The compressible tricalcium phosphate condensate systems of Examples 1-3 are each prepared by spray drying a slurry containing (based on 100 parts by weight of the slurry) ) 33.6 copies

Polylactic acid trihydrate ("TCP") particles, 64.2 parts by weight of water, and 2.2 parts by weight of three adhesives, namely polyethylene ketone K30 ("PVP30"), polyvinylpyrrolene K90 ("PVP90") One of the guar gums was sprayed in a Niro Mobile Minor laboratory scale dryer with the following conditions: 100% open atomizer turbine air pressure 4 kg/cm 2 heat set 100% The particle size distribution of these tricalcium phosphate particles and the aggregates is shown in Table I below.

Table I Example #TCP only Example 1 Example 2 Example 3 Adhesive -- PVP30 PVP90 Guiya gum flow rate (g / sec) 19.7 37.3 22.3 Bulk density (g / ml) 0 .391 0.512 0.436 0.463 Plug density (g / ml ) 0.536 0.640 0.545 (K 634 particle size (accumulated retention %) US sieve number (micron) 8 1317725

60 0 0 · 1 0.1 0.1 80 0.1 0.1 0.1 0.1 100 0.1 0.1 0.1 0.1 140 65.6 0.1 0.1 0.1 200 85.6 0.1 0.1 0.1 270 96 . 8 7.2 4 22.8 325 98.4 14.4 12 36 i{t£V Disk 100 100 100 100 Example IB-3B and Comparative Example C1B The following examples of the aggregates of Examples 1-3 and tricalcium phosphate, a dissolving agent (AC-DI-S0L manufactured by FMC Biopolymer Co., Ltd.), and a lubricant (magnesium stearate) The relative amounts listed in the figure (both component weight/100 parts weight formula) were mixed to make a direct compressible formula of Comparative Example C1B and Examples IB, 2B and 3B. Comparative Example 1B Example 2B Example 3B Example C1B TCP 97.47 82.36 82.36 82.36 TCP-C (Example 1) - 15.11 -- TCP - C (Example 2 ) —— - 15.11 —— TCP-C (Example 3) —— —— —— 15.11 Dispersing agent (AC-DI-SOL) 2,02 2.02 2.02 2.02 Magnesium stearate 0.51 0.51 0.51 0.51 -9- 1317725 Total 100 100 100 100

Example 1C-3C and Comparative Example C1C The directly compressible compositions of Example C1B and Examples 1B, 2B and 3B were each

0.312吋X in the self-pressing machine (Manesty Betapress)

0.7 50 吋 cylindrical mold was compressed to prepare tablets of Comparative Example C1C and Examples 1C, 2C and 3C. The hardness of each tablet was measured with a 2E Schleuniger tablet hardness tester and expressed in kilograms (kp) The friability of each tablet was measured according to the United States Pharmacopoeia 12 16 Tablet Fragility Test (USP 25) and expressed in % Grinding Rate. The disintegration of each tablet was measured according to USP Test Method No. 701 (USP 26) and the tablets were disintegrated into smaller pieces that passed through the test sieve while immersed in 37 ° 2 ° C water using a designated device. Time required (seconds

) indicates the ingot conditions, % cut-off rate, and tablet properties (i.e., thickness, hardness, friability, and dispersibility) of each of Comparative Examples C1C and Examples 1C, 2C, and 3C under various different tableting conditions. The effects are listed in the following table HI to Vl〇800 800 800 2.0 2.5 3.0 Table 111 Comparative Example C1C Preload (lbs) 400 Forces (tons) 1.5 Throwing Force (lbs) 80 Tablet Properties—10—1317725

Weight (mg) 1361 1363 1362 Hardness (kg force) 6.6 10.0 10.3 Thickness (吋) 0.303 0.295 0.291 Fragility (%) - One - Scratch (%) 0 1 98 Table IV Example ic Preload (lbs 400 800 800 force (ton) 1.5 2.0 2.5 throwing force (lbs) —— - - tablet nature weight (mg) 1356 1375 1385 hardness (kg force) 7.9 10.9 13.2 thickness (吋) 0.303 0.300 0.293 friability (% ) — —— Scratch action (%) 0 0 0 Table V Example 2C Preload (lbs) 400 800 800 Force (tons) 1.5 2.0 2.5 Throwing force (lbs) -- 100 100 800 3.0 1395 16.5 0.289 800 3.0 tablets Nature one 11-100 1317725

Weight (mg) - - 1361 1358 1358 Hardness (kg force) - - 11.9 14.4 19.0 Thickness (吋) - - 0.299 0.284 0.283 Fragility (%) - - 0.23 0.16 0.14 Scratch effect (%) - - 0 0 0 Dissolution (seconds) - - 31 33 38

Table Υ Example 3C Preload (Body). 400 800 800 800 Force (ton) 1. 5 2.0 2.5 3.0 Throwing force (lbs) Tablet properties - 100 100 100 Weight (mg) -- 1361 1362 1364 Hardness (kg force ) -· 11.1 14.6 17.0 Thickness (吋) -- 0.303 0.291 0.287 Fragility (%) -- 0.25 0.16 0.13 Scratch effect (%) -- 0 0 0 Dissolution (seconds) — 32 41 46

The results show that the tablet comprising the tricalcium phosphate agglomerate of the present invention has an increased hardness compared to a similar tablet made with conventional tricalcium phosphate. Example 4 The directly compressible composition of Example 4A is prepared by mixing the following Manufactured from -12 to 1317725 to: 45.41 parts by weight according to the procedure described in Example 3 above, 47.68 parts by weight of TRI-TAB (trademark) tricalcium phosphate (Rhodia), 4.01 parts by weight of additional binder (carboxyl group Methylcellulose (PH102) FMC Company. 17 parts of vitamin D3 100,

2. 〇 2 parts of heavy dissolving agent (4 (3-01-801/_,?^« (: company), 0.24 parts of sodium lauryl sulfate, NF 21 (SLS, Stepanol WA-100 (Stepan)) And 0.48 parts of a heavy lubricant (magnesium stearate). The mixture of Example 4A was compressed in a tablet press (Manesty Betapress) using a 0.312 X X 0.750 bar tablet press to make a tablet of Example 4B.

The hardness, thickness, friability, scission, and dissociation properties of the tablet of Example 4B were tested according to the methods listed in Examples 1C-3C and Comparative Example C1C. 0 The ingot conditions and test results are listed below. Table V 〇 Table V Example 4B Force (tons) 1.0 1.5 2.0 2.5 3.0 Ejection force (lbs) 70 100 120 140 160 Tablet nature Weight (mg) 1414 1412 1415 1413 1413 Hardness (kg force) 14.7 19.9 27.3 28.8 31.8 Thickness (吋) 0.331 0.316 0.304 0,296 0,290 — 13 — Γ317725 Fragility (%) 0.355 0.247 0.195 0.176 0.177 Scratch effect (%) 0 0 0 0 0 Dissolution (seconds) 25 34 38 42 46 Example 5 Example 5 Chewable tablets (each nominal 5/8 inch diameter, 0.3 inch thickness and 2000 mg weight) are the following mixtures in a tablet press ("D" Express Press") using a 5/8 inch oblate tool. Compressed to make 42.59 parts of the aggregates according to the procedure outlined in Example 1 above, 51.69 parts by weight of additional adhesive (Xylitab 200 (Danisco) 1.74 parts of heavy fragrance (SD Cherry N&A (Virginia Dare) the company)

1.78 parts by weight of Prosweet #875 (Virginia Dare), 0.. 16 parts by weight of Aspar tame (trademark) (S ear 1 e company), and 2.06 parts of magnesium stearate bismuth 5 The hardness of the force was measured as listed in Examples 1C - 3C above and Comparative Example C1C. It was found that the tablet of Example 5 showed minimal sandiness and bauxite taste in an informal taste test 0 - 14-

Claims (1)

, 1317725 修ii: Patent Application Announcement 1. 1. A compressible tricalcium phosphate aggregate containing (according to 100 parts by weight of the agglomerate): 90 to 99 parts by weight each having an outer The surface tricalcium phosphate particles, and one of 10 to 1 part by weight, carried on at least a portion of the outer surface of at least a portion of the tricalcium phosphate particles, comprising polyvinylpyrrolidone, carrageenan, or guar gum The adhesive is prepared by spray drying an aqueous slurry containing the tricalcium phosphate particles and the binder. 2. The agglomerate of claim 1 wherein the binder comprises polyvinylpyrrolidone having a number average molecular weight of greater than or equal to 30,000. 3. The agglomerate of claim 1, wherein the binder comprises a mixture of gums, denatured gums or the like. 4. A directly compressible calcium dietary supplement composition comprising (based on 100 parts by weight of the composition): 20 to 80 parts by weight of the aggregate of claim 1 of the patent, 79 to 10 parts by weight One or more calcium-containing substances other than the aggregate The particles, 0.5 to 8 parts by weight of the disintegrating agent, and 0.5 to 2 parts by weight of the lubricant. 5. The composition of claim 4, wherein one or more of the particles of the calcium-containing material other than the agglomerate are selected from the group consisting of calcium chelates, calcium salts, and the like. 6. The composition of claim 4, wherein one or more of the particles of the calcium-containing material other than the aggregate comprise particles having a particle size distribution of less than or equal to 15% by weight. The particles having a particle size greater than 40 mesh No. 1317725 and less than or equal to 5% by weight have tricalcium phosphate particles having a particle size smaller than that of No. 325 mesh. 7. The composition of claim 4, wherein the lubricant is a mixture of a fatty acid, a hydrogenated vegetable oil, a fatty acid triglyceride, a fatty acid metal salt, a glycol 'talc, and the like. Elected in the middle. 8. The composition of claim 4, wherein the dispersing agent is composed of carboxymethyl sodium cellulose, starch, microcrystalline cellulose, soy protein, alginic acid, crosslinked polyvinylpyrrolidone, and Selected from sodium carboxymethylcellulose, and mixtures thereof. 9. A method of making a calcium dietary supplement composition for oral dosage form comprising compressing a directly compressible calcium dietary supplement composition of claim 4 of the scope of the patent application. An oral dosage form of a calcium dietary supplement composition prepared by compressing a dietary supplement composition of claim 4 of the patent application. 11. An oral dosage form calcium dietary supplement composition as claimed in claim 10, wherein the oral dosage form of the calcium dietary supplement composition exhibits a hardness of greater than or equal to 10 kilograms of force. An oral dietary calcium dietary supplement composition according to claim 10, wherein the oral dosage form of the calcium dietary supplement composition exhibits a hardness of greater than or equal to 15 kg. An oral dietary calcium dietary supplement composition according to claim 10, wherein the oral dosage form of the calcium dietary supplement composition exhibits less than 1% friability. 1 4 , a chewable oral dosage form of a calcium dietary supplement composition, 1317725, prepared by compressing a composition comprising compressible tricalcium phosphate aggregates, the compressible tricalcium phosphate aggregate Included (with 100 parts by weight of the agglomerate) 90 to 99 parts by weight of each of the tricalcium phosphate particles having an outer surface, and 10 to 1 part by weight of one of the at least one portion of the tricalcium phosphate a binder comprising polyvinylpyrrolidone, carrageenan, or guar gum on at least a portion of the outer surface of the particle, by spraying an aqueous slurry comprising the tricalcium phosphate particles and the binder Dried to make. The calcium dietary supplement composition of the alpha dosage form of claim 14 wherein the oral dosage form calcium dietary supplement composition exhibits a force greater than or equal to 10 kilograms. The oral dietary calcium dietary supplement composition of claim 14, wherein the oral dosage form of the calcium dietary supplement composition exhibits a hardness of from 1 2 to 22 kg. The oral dietary calcium dietary supplement composition of claim 14, wherein the oral dosage form of the calcium dietary supplement composition exhibits a hardness of from 14 to 16 kilograms.