PARTIALLY PRE-GELATINIZED CASSAVA STARCH AS PHARMACEUTICAL EXCIPIENT

Abstract

A hybrid composition of partially pre-gelatinized cassava starch powder is herein disclosed. The hybrid composition is obtained by a pre-compaction process and a wet-granulation process, and the partially pre-gelatinized cassava starch including birefringent portions and non-birefringent portions. The hybrid composition is formulated for use in, for example, tablets, and may be used as a multi-functional excipient in various powder formulations.

Claims

1. A hybrid composition of partially pre-gelatinized cassava starch powder, the hybrid composition being obtained by a pre-compaction process and a wet-granulation process, and the partially pre-gelatinized cassava starch comprising birefringent portions and non-birefringent portions.

2. The hybrid composition of claim 1, wherein a ratio of the birefringent portions to the non-birefringent portions is in the range of 10:90 to 90:10.

3. The hybrid composition of claim 1, wherein the optical rotational range is between −15 degrees and +15 degrees under polarized light.

4. The hybrid composition of claim 1, wherein the bulk density is between 0.4 grams per milliliter and 0.75 grams per milliliter.

5. The hybrid composition of claim 1, wherein the cold water solubility is between 1 percent and 35 percent.

6. The hybrid composition of claim 1, wherein the Carr's index is between 15 and 40.

7. The hybrid composition of claim 1, wherein an average particle size of the birefringent portions and non-birefringent portions is greater than 50 microns (with a range of 5 to 300 microns).

8. The hybrid composition of claim 1, further comprising a low cyanogenic glycosidic content near or less than 1 part per million.

9. The hybrid composition of claim 1, wherein the moisture content is between 7% and 15%.

10. The hybrid composition of claim 1, formulated for oral ingestion in a tablet, a capsule, a pressed compact or loose powder.

11. The hybrid composition of claim 1, formulated in a cosmeceutical or industrial pressed compact or loose powder.

12. A powder formulation comprising: the hybrid composition of claim 1; and acetysalicylic acid.

13. The powder formulation of claim 11, wherein the hybrid composition is present in the amount of 5 percent weight to 75 percent weight.

14. A powder formulation comprising: the hybrid composition of claim 1; and guaifenesin.

15. The powder formulation of claim 13, wherein the hybrid composition is present in the amount of 5 percent weight to 75 percent weight.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIGS. 1(a) and 1(b) depict digital microscopy specimens, taken under polarized light, of pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG, FIG. 1(b)) as compared to Starch 1500® (FIG. 1(a)) at a magnification of 40X.

[0026] FIGS. 2(a) and (2b) depict a particle size analysis for pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG) as compared to Starch 1500® useful in accordance with the present invention (Malvern laser diffraction Instrument was employed for this analysis).

[0027] FIG. 3 depicts the Average Tablet Hardness (Compression profile) of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Tablet compression was performed using Picola D-8 Rotary Tablet press.

[0028] FIG. 4 depicts the Tablet ejection profile of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Tablet compression was performed using Picola D-8 Rotary Tablet press.

[0029] FIG. 5 depicts a friability profile of Guaifenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Tablet friability test was performed using Pharma Test PT Dual Drum Tablet Friabilator.

[0030] FIG. 6 depicts a disintegration profile of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Disintegration was performed using Pharma Test Disintegration Tester PT ZAUTO2.

[0031] FIG. 7 depicts a dissolution profile of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Dissolution was performed using Purified Water, USP and Distek Evolution 6100 Dissolution System.

[0032] FIG. 8 depicts accelerated drug stability profiles for Acetylsalicylic acid Tablets using (a) Starch 1580GG; and (b) Starch 1500®.

[0033] FIG. 9 depicts accelerated drug stability profiles for Guaifenesin Tablets using (a) Starch 1580GG; and (b) Starch 1500®.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The following detailed description is of the best currently contemplated modes of carrying out exemplary embodiments of the present invention. The description is not to be taken in a limiting sense but is made merely for the purpose of illustrating the general principles of the present invention, since the scope of the present invention is best defined by the appended claims.

[0035] In one embodiment of the present invention, food grade cassava flour and cassava starch are produced using raw cassava tubers as starting material. The raw tubers/roots are collected and washed. The roots are peeled and washed thoroughly in clean water to remove pieces of peel, sand and other dirts. Peeling may be manual or mechanical with clean stainless-steel knives and remove woody tips. The rind is completely removed to ensure low fiber and white color of the finished product. This embodiment includes such techniques to avoid excessive waste of roots during peeling. Further, the roots are crushed properly in clean stainless-steel crusher to obtain uniformly smooth mash. The crushed mash must be uniformly smooth without lumps. In case of non-uniform mash, the material is crushed again until smooth or near smooth mash is obtained. The smoothness of the mash determines the quality, yield, and market value of the finished cassava flour. The mash is loaded into sacks and pressed to remove as much moisture as possible. Pressing is completed when water is no longer dripping from the sacks. Complete dewatering facilitates drying. Pressing should be done immediately after crushing to avoid the onset of fermentation. The pressing time depends on the efficiency of the press and moisture content of the mash. Drying may be conducted using conventional ovens, flash dryers and natural sun drying method. Milling is conducted to obtain fine-textured flour using hammer mill or disc attrition mill.

[0036] In another embodiment, the native cassava roots/tubers are placed in a dry sieve. A mechanical device with appropriate grating and blade design is used for cleaning sediment and impurities on raw material. Cleaning efficiencies affect significantly the quality of final starch. Through the collision of raw materials and friction between corner angles of the drum, sand and debris are separated completely. Sewage and sediment are discharged to bottom of the shell through drum gap. Then cleaned raw material is slowly moved to discharging outlet and transported to collector. Further, cleaned cassava tubers and roots are placed into a mechanical rotary or manual sieve for fiber separation. Starch slurry which gets through screen net goes into disc separator for concentration, and fiber enters to fiber pulp dehydrator for further dewatering. Next, the dewatered cassava starch is exposed to further refining process using mechanical hydrocyclone equipment to separate fiber, protein, toxins, impurities, and other contents. The cassava starch slurry is further cleaned and concentrated in this process. Subsequently, the refined cassava starch is dried using a mechanical dryer having the wet starch fed into the feeding inlet through lift under negative pressure. Hot air stream is provided by steam, electrical or gas boiler and wet starch mixes inside and comes out through solid-gas separator, with final cassava starch having moisture content between 7 to 15%.

[0037] In another embodiment, the dried cassava starch having moisture content between 7 to 15% is wet-granulated using appropriate granulator possessing either low, medium or high shear blades and such processing is furthered with supplemental compaction using mechanical compactor having single or twin vertical and/or horizontal screw and suitable nip angle and pre-break to produce compacts of durable strength using compaction force ranging from 4 to 25 kN. This present invention shows that: [0038] 1. Granulating cassava starch with water or starch paste (range 0.5 to 25% w/w), with or without thermal application, significantly increases the mean particle size more than native cassava starch. [0039] 2. Granulating cassava starch with water or starch paste (range 0.5 to 25% w/w), with or without thermal application, shows less birefringence than native starch. [0040] 3. Compacting granulated cassava starch using compaction forces in the range of 4 to 25 kN, with or without thermal application, shows far less birefringence than non-compacted, granulated starch and/or native starch. [0041] 4. Compaction, with or without thermal application, also increases fractures and potential bonding sites in swollen granules.

[0042] In another embodiment, the dried cassava starch having moisture content of about 7-15% is pre-compacted using mechanical compactor having single or twin vertical and/or horizontal screw and suitable nip angle and pre-break to produce compacts of durable strength using compaction force ranging from 4 to 25 kN; and such processing is furthered with supplemental wet-granulation using appropriate granulator having low, medium, or high shear. The present invention shows that: [0043] 1. Granulating pre-compacted cassava starch with water or starch paste (range 0.5 to 25% w/w), with or without thermal application, significantly increases the mean particle size more than native cassava starch. [0044] 2. Granulating pre-compacted cassava starch with water or starch paste (range 0.5 to 25% w/w), with or without thermal application, shows less birefringence than native starch. [0045] 3. Pre-compacting cassava starch using compaction forces in the range of 4 to 25 kN, with or without thermal application, shows far less birefringence than non-compacted, granulated starch and/or native starch. [0046] 4. Pre-compacting, with or without thermal application, also increases fractures and potential bonding sites in swollen granules.

[0047] Making reference to the FIGURES, the present invention references U.S. Pat. No. 4,072,535 (Starch 1500® based on pre-compacted, partially pre-gelatinized corn starch) for exemplary, comparative review, as well as a predicate.

[0048] FIGS. 1(a) and 1(b), depicts digital microscopy specimens, taken under polarized light, of pre-compacted (Starch 1580GG) as compared to Starch 1500® at a magnification of 40×.

[0049] FIGS. 2(a) and 2(b) depict a particle size analysis for pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG) as compared to Starch 1500° useful in accordance with the present invention (Malvern laser diffraction Instrument was employed for this analysis).

[0050] As shown below, Table 1 depicts the formulation design using Guiafenesin, USP (GUA) as active pharmaceutical ingredient. The pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG) was compared to Starch 1500® as a binder/disintegrant in the formulation.

TABLE-US-00001 TABLE 1 Preparation of Guiafenesin Tablet Blend Amount/tablet Phase (% w/w) Function A. Wet granulation Guaifenesin, USP 70.00 Active Ingredient Starch 1580 GG (or 16.00 Binder Starch 1500 as predicate) B. Dry mixing Microcrystalline cellulose 9.48 Diluent Starch 1580 GG (or 4.00 Disintegrant Starch 1500 ® as predicate) Stearic acid 0.50 Lubricant Colloidal silicon dioxide 0.02 Glidant/Flow agent % Total 100.00

[0051] As shown below, Table 2 depicts the compression parameters for Guiafenesin tablets. The pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG) was compared to Starch 1500® as a binder/disintegrant in the formulation.

TABLE-US-00002 TABLE 2 Compression Parameters for Guiafenesin Tablets STARCH Binder (Starch) Type STARCH 1500 ® 1580GG Upper Compression Force (KN) 17 17 Ejection force (N) 100 106 Avg. Weight of Tablets (mg) 439.78 428.64 Avg. Hardness (N) 152.6 111.83 Friability (%) 0.25 0.44 Avg. Disintegration time (Sec) <100 <60

[0052] FIG. 3 depicts the Average Tablet Hardness (Compression profile) of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Tablet compression was performed using Picola D-8 Rotary Tablet press.

[0053] FIG. 4 depicts the Tablet ejection profile of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Tablet compression was performed using Picola D-8 Rotary Tablet press.

[0054] FIG. 5 depicts a friability profile of Guaifenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Tablet friability test was performed using Pharma Test PT Dual Drum Tablet Friabilator.

[0055] FIG. 6 depicts a disintegration profile of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Disintegration was performed using Pharma Test Disintegration Tester PT ZAUTO2.

[0056] FIG. 7 depicts a dissolution profile of Guiafenesin tablets prepared according to the formulation based on using Starch 1580GG (as a binder/disintegrant), as compared to Starch 1500®. Dissolution was performed using Purified Water, USP and Distek Evolution 6100 Dissolution System.

[0057] As shown below, Table 3 depicts the formulation design using Acetylsalicylic acid, USP (ASA) as active pharmaceutical ingredient. The pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG) was compared to Starch 1500® as a binder in the formulation.

TABLE-US-00003 TABLE 3 Preparation of Aspirin (Acetylsalicylic acid) Tablet Blend Amount/tablet Phase (% w/w) Function Direct Compression Blend Acetylsalicylic acid, USP 50.00 Active Ingredient Microcrystalline cellulose 29.50 Diluent Starch 1580 GG (or Starch 1500® as 20.00 Binder predicate) Magnesium stearate 0.50 Lubricant % Total 100.00

[0058] As shown below, Table 4 depicts the direct compression parameters for Acetylsalicylic acid (Aspirin) tablets. The pre-compacted and wet-granulated hybrid composition of cassava starch (Starch 1580GG) was compared to Starch 1500® as a binder in the formulation.

TABLE-US-00004 TABLE 4 Compression Parameters for Acetylsalicylic acid (Aspirin) Tablets Binder (Starch) Type STARCH 1500 ® STARCH 1580GG Upper Compression Force (KN) 17 17 Ejection force (N) N/A N/A Avg. Weight of Tablets (mg) 396 401 Avg. Hardness (N) 75.2 73.4 Friability (%) 0.44 0.59 Avg. Disintegration time (Sec) <60 <60

[0059] As shown below, Table 5 depicts the Drug Stability Study Report for Guiafenesin Tablets at accelerated condition. The tablets were produced using pre-compacted and wet-granulated hybrid composition of Cassava starch (Starch 1580GG) a binder/disintegrant in the formulation.

TABLE-US-00005 TABLE 5 Drug Stability Study Report: Guiafenesin Tablets Starch Type 1580GG Cassava Conditions: 40 Deg C. 75% RH Initial 1 month 2 month 3 month Appearance (Smooth/White) No No No No Change Change Change Change Weight gain/loss No No No No Change Change Change Change % Assay (Limit: 63-77%; 70.67 68.68 68.50 68.30 Target = 70%)

[0060] As shown below, Table 6 depicts the Drug Stability Study Report for Guiafenesin Tablets at accelerated condition. The tablets were produced using Corn starch (Starch 1500®) a binder in the formulation.

TABLE-US-00006 TABLE 6 Drug Stability Study Report: Guiafenesin Tablets Starch Type 1500 ® Corn Conditions: 40 Deg C. 75% RH Initial 1 month 2 month 3 month Appearance (Smooth/White) No Change No Change No No Change Change Weight gain/loss No Change No Change No No Change Change % Assay (Limit: 63-77%; 69.00 69.46 68.82 69.25 Target = 70%)

[0061] As shown below, Table 7 depicts the Drug Stability Study Report for Acetylsalicylic acid Tablets at an accelerated condition. The tablets were produced using pre-compacted and wet-granulated hybrid composition of Cassava starch (Starch 1580GG) a binder in the formulation.

TABLE-US-00007 TABLE 7 Drug Stability Study Report: Acetylsalicylic acid (Aspirin) Tablets Starch Type 1580GG Cassava Conditions: 40 Deg C. 75% RH Initial 1 month 2 month 3 month Appearance (Smooth/White) No No No No Change Change Change Change Weight gain/loss No No No No Change Change Change Change % Assay (Limit: 45-55%; 54.03 47.26 48.23 49.75 Target = 50%)

[0062] As shown below, Table 8 depicts the Drug Stability Study Report for Acetylsalicylic acid Tablets at an accelerated condition. The tablets were produced using Corn starch (Starch 1500®) a binder in the formulation.

TABLE-US-00008 TABLE 8 Drug Stability Study Report: Acetylsalicylic acid (Aspirin) Tablets Starch Type 1500 ® Corn Conditions: 40 Deg C. 75% RH Initial 1 month 2 month 3 month Appearance (Smooth/White) No No No No Change Change Change Change Weight gain/loss No No No No Change Change Change Change % Assay (Limit: 45-55%; 51.89 49.85 47.01 51.99 Target = 50%)

[0063] FIG. 8 depicts accelerated drug stability profiles for Acetylsalicylic Acid Tablets using Starch 1580GG; and Starch 1500®. The results demonstrated that Acetylsalicylic Acid product formulated with either Starch 1580GG or Starch 1500® could provide similar presumptive shelf-life.

[0064] FIG. 9 depicts accelerated drug stability profiles for Guaifenesin Tablets using Starch 1580GG: and Starch 1500®. The results demonstrated that Guaifenesin product formulated with either Starch 1580GG or Starch 1500® could provide similar presumptive shelf-life.

[0065] The present invention has been described in terms of exemplary embodiments solely for the purpose of illustration. Persons skilled in the art will recognize from this description that the invention is not limited to the embodiments described but may be practiced with modifications and alterations limited only by the spirit and scope of the claims to the present invention.