Ferroporphyrin solid dispersion and preparation method thereof
10391103 ยท 2019-08-27
Assignee
Inventors
- Larry Yun FANG (Shanghai, CN)
- Jiansheng WAN (Shanghai, CN)
- Kun LI (Shanghai, CN)
- Maojian Gu (Shanghai, CN)
Cpc classification
International classification
A61K31/555
HUMAN NECESSITIES
A61K9/16
HUMAN NECESSITIES
Abstract
Disclosed are a ferroporphyrin solid dispersion, preparation method therefor and a pharmaceutical composition comprising the solid dispersion, wherein the weight ratio of ferroporphyrin to the carrier material in the dispersion is 1:1-1:10. The solid dispersion of the present invention masks the undesirable taste of ferroporphyrin, ameliorates irritation thereof to the digestive tract, and at the same time increases the solubility thereof and improves the bioavailability thereof.
Claims
1. A porphyrin iron solid dispersion, comprising porphyrin iron and a carrier material, wherein said carrier material is selected from one or more of polymers comprising vinylpyrrolidone units, or mixtures thereof; polymers comprising ethylene glycol units; and celluloses or cellulose esters; wherein porphyrin iron is dispersed in said carrier material at molecular level; and wherein the weight ratio of porphyrin iron to the carrier material is 1:1 to 1:10; and wherein the porphyrin iron solid dispersion is prepared by a process including: either feeding a homogenously mixed mixture of porphyrin iron and the carrier material at a said weight ratio, or simply feeding porphyrin iron and the carrier material at a said weight ratio, into a hot melt extruder preheated to about 120 C. to about 180 C.; and cooling, pulverizing, and sieving the extruded mixture, to obtain the porphyrin iron solid dispersion.
2. The porphyrin iron solid dispersion according to claim 1, wherein said polymers comprising vinylpyrrolidone units, or mixtures thereof are selected from one or more of polyvinylpyrrolidone, a mixture of polyvinylpyrrolidone and polyvinyl acetate, and a copolymer of vinylpyrrolidone and vinyl acetate.
3. The porphyrin iron solid dispersion according to claim 1, wherein said polymers comprising vinylpyrrolidone units, or mixtures thereof have a K value of 10-95.
4. The porphyrin iron solid dispersion according to claim 2, wherein the weight ratio of polyvinylpyrrolidone and polyvinyl acetate in said mixture of polyvinylpyrrolidone and polyvinyl acetate is 1:9 to 9:1.
5. The porphyrin iron solid dispersion according to claim 2, wherein the weight ratio of vinylpyrrolidone units and vinyl acetate in said copolymer of vinylpyrrolidone and vinyl acetate is 1:9 to 9:1.
6. The porphyrin iron solid dispersion according to claim 1, wherein said polymers comprising ethylene glycol units are copolymers of polyethylene glycol/vinyl caprolactam/vinyl acetate.
7. The porphyrin iron solid dispersion according to claim 1, wherein said cellulose esters are hydroxypropylmethyl cellulose acetate succinate.
8. The porphyrin iron solid dispersion according to claim 7, wherein in said hydroxypropylmethyl cellulose acetate succinate, the content of the acetate group is 8 wt. % to 12 wt. %, and the content of the succinate group is 6 wt. % to 15 wt. %, based on the weight of said hydroxypropylmethyl cellulose acetate succinate.
9. The porphyrin iron solid dispersion according to claim 1, wherein the solid dispersion further comprises a pharmaceutically acceptable pharmaceutical adjuvant, and the process includes either feeding a homogenously mixed mixture of porphyrin iron and the carrier material and the pharmaceutically acceptable pharmaceutical adjuvant, or simply feeding porphyrin iron and the carrier material and the pharmaceutically acceptable pharmaceutical adjuvant, into the hot melt extruder.
10. A process of preparing a porphyrin iron solid dispersion comprising porphyrin iron dispersed in a carrier material at molecular level, the process including: either feeding a homogenously mixed mixture of porphyrin iron and said carrier material at a weight ratio of 1:1-1:10, and an optional pharmaceutically acceptable pharmaceutical adjuvant, or simply feeding porphyrin iron and said carrier material at said weight ratio and an optional pharmaceutically acceptable pharmaceutical adjuvant, into a hot melt extruder preheated to about 120 C. to about 180 C.; and cooling, pulverizing, and sieving the extruded mixture, to obtain the porphyrin iron solid dispersion; wherein said carrier material is selected from one or more of polymers comprising vinylpyrrolidone units, or mixtures thereof; polymers comprising ethylene glycol units; and celluloses or cellulose esters.
11. A pharmaceutical composition comprising the porphyrin iron solid dispersion according to claim 1, wherein said pharmaceutical composition is in the form of powders, granules, pills, capsules or tablets.
12. A pharmaceutical composition according to claim 11, further comprising a pharmaceutically acceptable pharmaceutical adjuvant selected from one or more of surfactants, diluents, disintegrants, binders, and lubricants.
13. The porphyrin iron solid dispersion according to claim 2, wherein said polymers comprising vinylpyrrolidone units, or mixtures thereof have a K value of 10-95.
14. The porphyrin iron solid dispersion according to claim 1, wherein said polymers comprising vinylpyrrolidone units, or mixtures thereof have a K value of 25-70.
15. The porphyrin iron solid dispersion according to claim 2, wherein the weight ratio of polyvinylpyrrolidone and polyvinyl acetate in said mixture of polyvinylpyrrolidone and polyvinyl acetate is 2:8 to 8:2.
16. The porphyrin iron solid dispersion according to claim 2, wherein the weight ratio of vinylpyrrolidone units and vinyl acetate in said copolymer of vinylpyrrolidone and vinyl acetate is 4:6 to 6:4.
17. The porphyrin iron solid dispersion according to claim 1, wherein said celluloses or cellulose esters are selected from one or more of methyl cellulose, hydroxymethyl cellulose, hydroxylethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose and hydroxypropylmethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, and cellulose acetate phthalate.
18. The porphyrin iron solid dispersion according to claim 1, wherein the weight ratio of porphyrin iron to the carrier material is 1:1 to 1:4.
19. The porphyrin iron solid dispersion according to claim 1, wherein the weight ratio of porphyrin iron to the carrier material is 1:1 to 1:3.
20. The process according to claim 10, wherein the porphyrin iron and the carrier material are at a weight ratio of 1:1-1:4.
21. The process according to claim 10, wherein the porphyrin iron and the carrier material are at a weight ratio of 1:1-1:3.
22. The porphyrin iron solid dispersion according to claim 2, wherein said polymers comprising vinylpyrrolidone units, or mixtures thereof have a K value of 25-70.
23. The porphyrin iron solid dispersion according to claim 9, wherein the pharmaceutically acceptable pharmaceutical adjuvant is selected from one or more of surfactants, diluents, disintegrants, binders, and lubricants.
Description
DESCRIPTION OF THE DRAWINGS
(1) The above and other objects and features of the present invention will be apparent with reference to the following figures.
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EXAMPLES
(10) Examples are provided below in order to describe the present invention in more details. The following examples are for the purpose of illustration only, and are not intended in any way to limit the present invention. A person skilled in the art will readily be aware of various non-critical parameters, and is able to modify or change these parameters to obtain substantially the same results.
Preparation of Porphyrin Iron-KollidonVA 64 Solid Dispersions
Example 1-1. Preparation of Porphyrin Iron-KollidonVA 64 Solid Dispersions
(11) The particular weight ratios in various solid dispersion formulae are shown in Table 1-1.
(12) TABLE-US-00001 TABLE 1-1 Specific composition of various solid dispersion formulae Names of raw materials Amounts of raw materials and adjuvants (g) and adjuvants Formula 1-1 Formula 1-2 Formula 1-3 Formula 1-4 porphyrin iron 35 50 50 20 Kollidon 35 150 150 200 VA 64 Kolliphor None None 20 None TPGS
(13) Preparation process: Porphyrin iron and the carrier materials in the amounts shown in the formulae in Table 1-1 were added to a mixer separately and mixed homogenously. Alternatively, porphyrin iron and the carrier materials in the amounts shown in the formulae in Table 1-1 were fed into the loading hopper of a co-rotating twin screw extruder (Omicron 12, Steer Engineering Private Limited, India). The melting temperature in the co-rotating twin screw extruder was controlled at between about 120 C. and about 180 C., and the rotation speed of the screw was about 50 to about 500 rpm. The extruded mixtures were cooled, pulverized, and sieved, to obtain the solid dispersion.
Evaluation on the Physical and Chemical Properties of the Porphyrin Iron-KollidonVA 64 Solid Dispersions
Test Example 1-2. Determination of Glass Transition Temperature (Tg) of the Solid Dispersions
(14) >3 mg of the active pharmaceutical ingredient (API) porphyrin iron, extruded blank material prepared from KollidonVA 64, and materials prepared according to the formulae in Table 1-1 were precisely weighted separately, and were subjected to differential scanning calorimetry analysis (mDSC analysis, TA Q2000 Differential Scanning calorimeter). The test results showed that no melting point or Tg value was determined in the scanning of the API porphyrin iron (crystalline type) in the temperature range of 40-180 C., since crystalline porphyrin iron was completely decomposed before the melting point was reached. The blank KollidonVA 64 solid dispersion had a Tg value of 98.73 C. and Formula 1-2 had a Tg value of 101.3 C. The Tg value of Formula 1-2 showed a significant deviation as compared to the blank solid dispersion and also was different from the Tg value of porphyrin iron, indicating that porphyrin iron was in the state of being dispersed at molecular level in the dispersion, it formed a solid dispersion or a solid solution with the carrier adjuvant.
Test Example 1-3. Determination of the Content of Porphyrin Iron in the Solid Dispersions
(15) Sample preparation: an appropriate amount of the solid dispersion of each formula was weighted, and was dissolved in 0.1N aqueous NaOH solution, to prepare a test sample with a porphyrin iron concentration of about 50 g/ml. Analysis was conducted by an HPLC method. The method for determining the content was as follows, and the results were shown in Table 1-2.
(16) TABLE-US-00002 Chromatography column C18 column (3 m, 3.0 50 mm) Mobile phase 0.2% phosphoric acid/methanol = 25:75 Flow rate 1 ml/min Sample disk Room temperature Wavelength 401 nm Sample injection 10 l Analysis period for single About 2 min sample injection
(17) TABLE-US-00003 TABLE 1-2 Content determination results for each solid dispersion formula Formula Formula 1-1 Formula 1-2 Formula 1-3 Formula 1-4 Labelled 93.3 95.7 97.1 96.5 amount (%)
(18) As can be seen from Table 1-2, the labelled amounts of the drug for all formulae were >93%, indicating that the hot melt extrusion process had little influence on the stability of the drug. The relatively lower labelled amounts of the drug were due to about 3%-6% of water contained in the solid dispersions.
Test Example 1-4. Determination of the Apparent Solubility of the Solid Dispersions
(19) Sample preparation: Excess amounts of porphyrin iron solid dispersions of various formulae and physical mixtures of porphyrin iron and carrier materials (prepared by weighting the active pharmaceutical ingredient and the carrier adjuvants in the amounts shown in the formulae and simply mixing them) were weighted separately, and placed in appropriate containers, a phosphate buffer solution having a pH of 6.8 and a volume of about of the volume of the container was added, and then it was placed in a shaking table at 37 C. and was shaken for 24 h. The resultant solution was filtered through a 0.45 m filter membrane, and then the filtrate was collected, further diluted with an appropriate amount of 0.1N NaOH, and analyzed by HPLC after vortex mixing. The analysis method was the same as the method for the content determination for the solid dispersions in Example 1-3. The determination results were shown in Table 1-3.
(20) TABLE-US-00004 TABLE 1-3 Determination results of porphyrin iron solubility for each solid dispersion formula Formula Formula Formula Formula Formula 1-1 1-2 1-3 1-4 API A.sup.1) B.sup.2) A B B A B Solubility <0.2 2.5 239.9 1.2 606.3 126.4 1.1 360.6 (g/ml) Solubility .sup.3) >1200 >3032 >632 >1803 ratio (solid dispersion/API) Solubility .sup. 96 505 79 328 ratio (solid dispersion/ physical mixture) .sup.1)A represents a physical mixture (not a solid dispersion of the present invention) with the same composition as sample B. .sup.2)B represents a solid dispersion of the present invention. .sup.3) means that there is no determined value.
(21) As can be seen from the solubility determination results in Table 1-3, all solid dispersions of various formulae prepared by a hot melt extrusion process had significant solubilizing effects on porphyrin iron, indicating that KollidonVA 64 had fairly good solubilizing effects on porphyrin iron. As can be seen from the results obtained from a single-variable design of experiment (DOE), there is a certain relationship between the weight ratio of the carrier (KollidonVA 64) to the API porphyrin iron in the solid dispersions and the solubility of porphyrin iron in the solid dispersions, as shown in
Test Example 1-5. In Vitro Dissolution Tests for the Solid Dispersions
(22) Conditions for the Dissolution Tests:
(23) TABLE-US-00005 Dissolution method USP Method II (Paddle) Dissolution medium pH 1.2/pH 6.8 Medium volume 900 ml Rotation speed 100 rpm Temperature 37.5 C. Tested dosage 50 mg (porphyrin iron)/cup
(24) Analysis method for sample dissolution: the same as that for the content determination for the solid dispersions in Example 1-3.
(25) The in vitro dissolution results for the solid dispersions were shown in Table 1-4 and Table 1-5.
(26) TABLE-US-00006 TABLE 1-4 Results of the dissolution tests for solid dispersions of various formulae in the dissolution medium at pH 1.2 Concentrations of dissolved API at various time points (g/ml) Test 5 10 15 30 45 60 samples min min min min min min Physical <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 mixture.sup.1) Formula 1-1 55.1 52.8 55.7 52.8 54.9 54.3 Formula 1-2 52.2 54.0 52.6 54.3 54.0 53.9 Formula 1-3 48.8 51.3 49.6 49.7 49.5 49.1 Formula 1-4 45.4 46.8 49.0 49.8 47.2 49.0 .sup.1)said physical mixture was prepared according to the specific composition of Formula 1-2.
(27) TABLE-US-00007 TABLE 1-5 Results of the dissolution tests for the solid dispersions of various formulae in the dissolution medium at pH 6.8 Concentrations of dissolved API at various time points (g/ml) Test 15 30 45 60 120 180 samples min min min min min min Physical <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 mixture.sup.1) Formula 1-1 56.8 56.1 55.9 56.0 55.8 54.8 Formula 1-2 54.2 54.9 53.6 53.8 53.8 54.5 Formula 1-3 45.9 46.3 44.4 42.5 45.8 47.8 Formula 1-4 55.1 55.4 55.2 54.3 54.9 54.2 .sup.1)said physical mixture was prepared according to the specific composition of Formula 1-2.
(28) As can be seen from Table 1-4 and Table 1-5, as compared to the physical mixture, solid dispersions of various formulae prepared by using KollidonVA 64 as the carrier material could largely increase the concentration of dissolved porphyrin iron and the dissolution rate of porphyrin iron at pH 1.2 and pH 6.8.
Test Example 1-6. Dissolution Tests Under Stimulated In Vivo Conditions
(29) The pH of gastric fluid is about 1.2 and that of intestinal fluid is about 6.8 in human in the fasted conditions. The pH of gastric fluid might be still as low as 1.2 and that of intestinal fluid is about 5.0 due to the influences from foods. In this test example, Formula 1-2, having a maximal solubility, was selected for dissolution tests under stimulated in vivo conditions. The test conditions were shown below.
(30) TABLE-US-00008 Dissolution USP method II (Paddle) method Dissolution A medium of pH 1.2.fwdarw.6.8: 800 ml of a dissolution medium medium of pH 1.2 was sampled over 30 min, and then 100 ml of a prepared buffer solution was immediately added so that the pH of the overall dissolution medium was 6.8. A medium of pH 1.2.fwdarw.5.0: 800 ml of a dissolution medium of pH 1.2 was sampled over 30 min, and then 100 ml of a prepared buffer solution was immediately added so that the pH of the overall dissolution medium was 5.0. Rotation speed 100 rpm Temperature 37.5 C. Tested dosage 60 mg (porphyrin iron)/cup
(31) Analysis method for sample dissolution: the same as that for the content determination for the solid dispersions in Example 1-3.
(32) The in vitro dissolution results for the solid dispersions were shown in Table 1-6 and Table 1-7.
(33) TABLE-US-00009 TABLE 1-6 Results of the dissolution test for Formula 1-2 during medium transition pH 1.2.fwdarw.6.8 Dissolution at various time points (%) pH 1.2 pH 6.8 Test 5 10 15 30 45 60 120 180 sample min min min min min min min min Formula 1-2 103.0 106.5 104.7 104.3 109.3 108.6 106.5 106.7
(34) TABLE-US-00010 TABLE 1-7 Results of the dissolution test for Formula 1-2 during medium transition pH 1.2.fwdarw.5.0 Dissolution at various time points (%) pH 1.2 pH 5.0 Test 5 10 15 30 45 60 120 180 sample min min min min min min min min Formula 1-2 81.2 84.9 85.5 83.5 92.3 95.1 93.3 93.2
(35) As can be seen from Table 1-6 and Table 1-7, the dissolution of Formula 1-2 under both stimulated in vivo fasted conditions (pH 1.2.fwdarw.6.8 medium transition) and fed conditions (pH 1.2.fwdarw.5.0 medium transition) were above 80%, indicating that the transition from gastric fluid to intestinal fluid of different pH had little influence on the dissolution of the solid dispersion of Formula 1-2.
Test Example 1-7. Stability Test for the Solid Dispersions
(36) A certain amount of the API porphyrin iron and the solid dispersion of Formula 1-2 were placed in 30 mL brown glass vials, and the method of the sample stability test was the same as the method for the content determination for the solid dispersions in Example 1-3. The test results were shown in Table 1-8 and Table 1-9.
(37) TABLE-US-00011 TABLE 1-8 Content determination results of the stability study for the porphyrin iron-KollidonVA 64 solid dispersion (open) Test period Test 0 1 3 7 35 Samples conditions day day days days days API 25 C. 100.9% 98.0% 98.7% 100.9% 98.8% Formula 1-2 60% RH 100.5% 97.6% 97.9% 98.6% 97.8% API 40 C. 100.9% 99.0% 99.8% 100.8% 100.6% Formula 1-2 75% RH 100.5% 98.3% 96.2% 96.9% 97.6%
(38) TABLE-US-00012 TABLE 1-9 Content determination results of the stability study for the porphyrin iron-KollidonVA 64 solid dispersion (sealed) Test period Test 0 1 3 7 14 35 Samples conditions day day days days days days API 25 C. 100.9% 99.5% 102.0% 100.5% 98.9% 102.2% Formula 1-2 60% RH 100.5% 98.8% 101.6% 99.6% 97.6% 100.8% API 40 C. 100.9% 99.6% 102.7% 100.8% 99.2% 102.7% Formula 1-2 75% RH 100.5% 98.8% 100.4% 98.2% 98.1% 96.6%
(39) As can be seen from Table 1-8 and Table 1-9, for the API porphyrin iron and the porphyrin iron-KollidonVA 64 solid dispersion, after being placed at 25 C. 60% RH and 40 C. 75% RH for 35 days, the contents of porphyrin iron were within the confidence interval of 96%-104% of the analysis method established for the content determination for the solid dispersions in Example 1-3. The slightly lower labelled amounts of the drug were due to about 3% water contained in the solid dispersion. The test results indicated that porphyrin iron was very stable in the porphyrin iron-KollidonVA 64 solid dispersion.
Preparation of Porphyrin Iron-Soluplus Solid Dispersions
Example 2-1. Preparation of Porphyrin Iron-Soluplus Solid Dispersion
(40) Formula: The specific composition of each solid dispersion formula was shown in Table 2-1.
(41) TABLE-US-00013 TABLE 2-1 Specific composition of each solid dispersion formula Names of raw materials and Amounts of raw materials and adjuvants (g) adjuvants Formula 2-1 Formula 2-2 Formula 2-3 porphyrin iron 35 30 20 Soluplus 35 90 200
(42) Preparation process: Porphyrin iron and the carrier material in the amounts shown in the formulae in Table 2-1 were added to a mixer separately and mixed homogenously. Alternatively, porphyrin iron and the carrier material in the amounts shown in the formulae in Table 2-1 were fed into a loading hopper of a co-rotating twin screw extruder (Omicron 12, Steer Engineering Private Limited, India). The melting temperature in the screw extruder was controlled at about 120 C. to about 180 C., and the rotation speed of the screw was about 50 to about 500 rpm. The extruded mixtures were cooled, pulverized, and sieved, to obtain the solid dispersions.
Evaluation on the Physical And Chemical Properties of the Porphyrin Iron-Soluplus Solid Dispersions
Test Example 2-2. Determination of the Content of Porphyrin Iron in the Solid Dispersions
(43) Sample preparation: an appropriate amount of the solid dispersion of each formula was weighted and dissolved in 0.1N aqueous NaOH solution, to prepare a test sample with a porphyrin iron concentration of about 50 g/ml. Analysis was conducted by a HPLC method. The analysis method for the content determination was the same as that for the content determination for the solid dispersions in Example 1-3. The results were shown in Table 2-2.
(44) TABLE-US-00014 TABLE 2-2 Content determination results for each solid dispersion formula Formula Formula 2-1 Formula 2-2 Formula 2-3 Labelled 94.7 92.0 93.5 amount (%)
(45) As can be seen from Table 2-2, the labelled amounts of the drug for all formulae after being extruded were above 90%, indicating that the hot melt extrusion process had little influence on the stability of the drug. The slightly lower labelled amounts of the drug were due to about 3%-6% of water contained in the solid dispersions.
Test Example 2-3. Determination of the Apparent Solubility of the Solid Dispersions
(46) Sample preparation: Excess amounts of the porphyrin iron solid dispersions of various formulae and physical mixtures of porphyrin iron and the carrier material (prepared by weighting the active pharmaceutical ingredient and the carrier adjuvant in the amounts shown in the formulae and simply mixing them) were weighted separately, and placed in appropriate containers, a phosphate buffer solution having a pH of 6.8 and a volume of about of the volume of the container was added, and then it was placed in a shaking table at 37 C. and was shaken for 24 h. The resultant solution was filtered through a 0.45 m filter membrane, and then the filtrate was collected, further diluted with an appropriate amount of 0.1N NaOH, and analyzed by HPLC after vortex mixing. The analysis method was the same as the method for the content determination for the solid dispersions in Example 1-3. The determination results were shown in Table 2-3.
(47) TABLE-US-00015 TABLE 2-3 Solubility determination results for each solid dispersion formula Formula Formula Formula Formula 2-1 2-2 2-3 API A.sup.1) B.sup.2) A B A B Solubility <0.2 <0.6 33.8 1.3 28.1 <0.6 69.7 (g/ml) Solubility .sup.3) >169 >140 >348 ratio (solid dispersion/API) Solubility .sup. >56 22 >116 ratio (solid dispersion/ physical mixture) .sup.1)A represents a physical mixture (not a solid dispersion of the present invention) with the same composition as sample B. .sup.2)B represents a solid dispersion of the present invention. .sup.3) means that there is no determined value.
(48) As can be seen from the solubility determination results in Table 2-3 and
Test Example 2-4. In Vitro Dissolution Tests for the Solid Dispersions
(49) The conditions for the dissolution tests were the same as the dissolution tests of the solid dispersions in Example 1-5.
(50) The analysis method for sample dissolution was the same as that for the content determination for the solid dispersions in Example 1-3. The results were shown in Table 2-4 and Table 2-5.
(51) TABLE-US-00016 TABLE 2-4 Results of the dissolution tests for the solid dispersions of various formulae in the dissolution medium at pH 1.2 Concentrations of dissolved API at various time points (g/ml) Test 5 10 15 30 45 60 samples min min min min min min Formula 2-1 2.4 2.3 1.89 2.6 3.9 2.9 Formula 2-2 6.6 12.2 6.8 5.2 6.6 3.4 Formula 2-3 37.0 34.1 36.0 36.5 34.9 36.5
(52) TABLE-US-00017 TABLE 2-5 Results of the dissolution tests for the solid dispersions of various formulae in the dissolution medium at pH 6.8 Concentrations of dissolved API at various time points (g/ml) Test 15 30 45 60 120 180 samples min min min min min min Formula 2-1 1.8 2.7 3.0 2.5 3.4 2.8 Formula 2-2 4.2 3.3 3.1 3.2 1.8 2.3 Formula 2-3 1.9 2.3 1.9 2.2 2.2 2.2
(53) As can be seen from Table 2-4 and Table 2-5, each formula containing Soluplus can increase the concentration of dissolved porphyrin iron and the dissolution rate of porphyrin iron.
Preparation of Porphyrin Iron-HPMCAS Solid Dispersions
Example 3-1. Preparation of Porphyrin Iron-HPMCAS (AQOAT AS-M) Solid Dispersions
(54) Formula: The specific composition of each solid dispersion formula was shown in Table 3-1.
(55) TABLE-US-00018 TABLE 3-1 Specific composition of each solid dispersion formula Names of raw materials Amounts of raw materials and adjuvants (g) and adjuvants Formula 3-1 Formula 3-2 Formula 3-3 porphyrin iron 35 50 20 HPMCAS 35 150 200
(56) Preparation process: Porphyrin iron and the carrier material in the amounts shown in the formulae in Table 3-1 were added to a mixer separately and mixed homogenously. Alternatively, porphyrin iron and the carrier material in the amounts shown in the formulae in Table 3-1 were fed into a loading hopper of a co-rotating twin screw extruder (Omicron 12, Steer Engineering Private Limited, India). The melting temperature in the screw extruder was controlled at about 120 C. to about 180 C., and the rotation speed of the screw was about 50 to about 500 rpm. The extruded mixtures were cooled, pulverized, and sieved, to obtain the solid dispersions.
Evaluation on the Physical and Chemical Properties of the Porphyrin Iron-HPMCAS Solid Dispersions
Test Example 3-2. Determination of the Content of Porphyrin Iron in the Solid Dispersions
(57) Sample preparation: an appropriate amount of the solid dispersion of each formula was weighted, and dissolved in 0.1N aqueous NaOH solution, to prepare a test sample with a porphyrin iron concentration of about 50 g/ml. Analysis was conducted by a HPLC method. The analysis method for the content determination was the same as that for the content determination for the solid dispersions in Example 1-3. The results were shown in Table 3-2.
(58) TABLE-US-00019 TABLE 3-2 Content determination results for each solid dispersion formula Formula Formula 3-1 Formula 3-2 Formula 3-3 Labelled 95.6 85.5 91.7 amount (%)
(59) As can be seen from Table 3-2, the labelled amounts of the drug for all formulae after being extruded were above 85%, indicating that the hot melt extrusion process had little influence on the stability of the drug. The slightly lower labelled amounts of the drug were due to about 3%-6% of water contained in the solid dispersions.
Test Example 3-3. Determination of the Apparent Solubility of the Solid Dispersions
(60) Sample preparation: Excess amounts of the porphyrin iron solid dispersions of various formulae and the physical mixture of porphyrin iron and the carrier material (prepared by weighting the active pharmaceutical ingredient and the carrier adjuvant in the amounts shown in the formulae and simply mixing them) were weighted separately, and placed in appropriate containers, a phosphate buffer solution having a pH of 6.8 and a volume of about of the volume of the container was added, and then it was placed in a shaking table at 37 C. and was shaken for 24 h. The resultant solution was filtered through a 0.45 m filter membrane, and then the filtrate was collected, further diluted with an appropriate amount of 0.1N NaOH, and analyzed by HPLC after vortex mixing. The analysis method was the same as the method for the content determination for the solid dispersions in Example 1-3. The determination results were shown in Table 3-3.
(61) TABLE-US-00020 TABLE 3-3 Solubility determination results for each solid dispersion formula Formula Formula Formula Formula 3-1 3-2 3-3 API A.sup.1) B.sup.2) A B A B Solubility <0.2 <0.2 71.1 <0.2 66.0 <0.2 54.0 (g/ml) Solubility .sup.3) >355 >330 >270 ratio (solid dispersion/API) Solubility .sup. >355 >330 >270 ratio (solid dispersion/ physical mixture) .sup.1)A represents a physical mixture (not a solid dispersion of the present invention) with the same composition as sample B. .sup.2) B represents a solid dispersion of the present invention. .sup.3) means that there is no determined value.
(62) As can be seen from the solubility determination results in Table 3-3 and
Test Example 3-4. In Vitro Dissolution Tests of the Solid Dispersions
(63) The conditions for the dissolution tests were the same as the dissolution tests of the solid dispersions in Example 1-5.
(64) The analysis method for sample dissolution was the same as that for the content determination for the solid dispersions in Example 1-3. The results were shown in Table 3-4 and Table 3-5.
(65) TABLE-US-00021 TABLE 3-4 Results of the dissolution tests for the solid dispersions of various formulae in the dissolution medium at pH 1.2 Concentrations of dissolved API at various time points (g/ml) Test 5 10 15 30 45 60 samples min min min min min min Formula 3-1 <0.3 <0.3 <0.3 <0.3 <0.3 <0.3 Formula 3-2 1.0 1.1 1.1 1.1 1.2 1.2 Formula 3-3 <0.3 <0.3 <0.3 <0.3 <0.3 <0.3
(66) TABLE-US-00022 TABLE 3-5 Results of the dissolution tests for the solid dispersions of various formulae in the dissolution medium at pH 6.8 Concentrations of dissolved API at various time points (g/ml) Test 15 30 45 60 120 180 samples min min min min min min Formula 3-1 44.7 44.3 42.4 43.6 43.3 44.4 Formula 3-2 44.7 49.5 50.7 50.6 25.8 26.1 Formula 3-3 47.9 49.2 48.1 47.3 48.5 49.0
(67) As can be seen from Table 3-4 and Table 3-5, the HPMCAS solid dispersion of each formula can increase the concentration of dissolved porphyrin iron and the dissolution rate of porphyrin iron in the medium at pH 6.8. The dissolved amounts in the medium at pH 1.2 were very few, since HPMCAS was an enteric material.
Example 4. Clinical Tests on the Mouthfeel and Gastrointestinal Tract Irritation of Porphyrin Iron Solid Dispersions
(68) In order to evaluate the mouthfeel and gastrointestinal tract irritation of porphyrin iron solid dispersions, 6 healthy volunteers were enrolled in tests on the mouthfeel and gastrointestinal tract irritation for the samples such as Formula 1-1, Formula 1-2, Formula 1-4, Formula 2-2, Formula 3-2 and the API of porphyrin iron. The test results were summarized in Table 4-1.
(69) Test procedure for mouthfeel and gastrointestinal tract irritation: 6 healthy volunteers, who had no bad habits such as smoking and drinking and had certain sensory evaluation practice, were enrolled. Each volunteer took a sample into his or her mouth and ingested it with warm water at 10:00 am every day, and recorded his or her actual feeling after 20 minutes. The tests were carried out for 6 consecutive days, and each volunteer took all samples one by one.
(70) TABLE-US-00023 TABLE 4-1 Results of the mouthfeel and gastrointestinal tract irritation test for the porphyrin iron solid dispersions Feeling of Feeling of Samples Mouthfeel stomach burning nausea Formula 1-1 Heavy bitterness, no other Slight stomach Slight nausea (porphyrin iron:Kollidon undesirable tastes burning feeling feeling VA 64 = 1:1) Formula 1-2 Bitterness, heavy aftertaste, No obvious No obvious (porphyrin iron:Kollidon no other undesirable tastes stomach burning nausea feeling VA 64 = 1:3) feeling Formula 1-4 Agglomerating in mouth, No stomach No nausea (porphyrin iron:Kollidon slight bitterness, no other burning feeling feeling VA undesirable tastes 64 = 1:10) Formula 2-2 Pleasant taste, no obvious No stomach No nausea (porphyrin iron:Soluplus = undesirable tastes, good burning feeling feeling 1:3) palatability Formula 3-2 Obvious granular sensation No obvious No obvious (porphyrin iron:HPMCAS = in mouth, no obvious stomach burning nausea feeling 1:3) undesirable tastes feeling API Heavy blood smell, Obvious Obvious nausea undesirable tastes stomach burning feeling feeling
(71) The results in Table 4-1 showed that by preparing porphyrin iron and KollidonVA 64, Soluplus and HPMCAS into solid dispersions, the blood smell and undesirable tastes of porphyrin iron can be effectively masked and removed, and the stomach burning feeling and nausea feeling of porphyrin iron can be reduced significantly or even avoided, such that the compliance of patients can be improved.