WO2016180363A1 - Chitosan citrate and composition containing same - Google Patents
Chitosan citrate and composition containing same Download PDFInfo
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- WO2016180363A1 WO2016180363A1 PCT/CN2016/082002 CN2016082002W WO2016180363A1 WO 2016180363 A1 WO2016180363 A1 WO 2016180363A1 CN 2016082002 W CN2016082002 W CN 2016082002W WO 2016180363 A1 WO2016180363 A1 WO 2016180363A1
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- Prior art keywords
- chitosan
- composition
- citrate
- phosphate
- moiety
- Prior art date
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- 229920001661 Chitosan Polymers 0.000 title claims abstract description 107
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 title claims abstract description 58
- 239000000203 mixture Substances 0.000 title claims abstract description 39
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 claims abstract description 25
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 claims abstract description 25
- 201000005991 hyperphosphatemia Diseases 0.000 claims abstract description 14
- 230000006196 deacetylation Effects 0.000 claims description 29
- 238000003381 deacetylation reaction Methods 0.000 claims description 29
- 229910019142 PO4 Inorganic materials 0.000 claims description 22
- 239000010452 phosphate Substances 0.000 claims description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 238000009739 binding Methods 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 5
- 229920002567 Chondroitin Polymers 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- 229940072056 alginate Drugs 0.000 claims description 5
- 229920000615 alginic acid Polymers 0.000 claims description 5
- 235000010443 alginic acid Nutrition 0.000 claims description 5
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
- 239000002480 mineral oil Substances 0.000 claims description 5
- 235000010446 mineral oil Nutrition 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- 235000019165 vitamin E Nutrition 0.000 claims description 5
- 239000011709 vitamin E Substances 0.000 claims description 5
- 230000037213 diet Effects 0.000 claims description 4
- 235000005911 diet Nutrition 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 abstract description 14
- 229910000019 calcium carbonate Inorganic materials 0.000 abstract description 7
- 239000002694 phosphate binding agent Substances 0.000 abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000011230 binding agent Substances 0.000 description 12
- 239000007836 KH2PO4 Substances 0.000 description 9
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 9
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 9
- 235000013305 food Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229920002101 Chitin Polymers 0.000 description 5
- 238000000159 protein binding assay Methods 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000000038 Hypoparathyroidism Diseases 0.000 description 2
- 229910015667 MoO4 Inorganic materials 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229920006037 cross link polymer Polymers 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Chemical class 0.000 description 1
- 229910052791 calcium Chemical class 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229960002413 ferric citrate Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
Definitions
- Hyperphosphatemia is a syndrome that the serum phosphate level of a subject is above a certain threshold causing deposits throughout the body and endangering circulation.
- hyperphosphatemia such as, renal disease, kidney failure, hypoparathyroidism, etc.
- the patient’s kidney function will be compromised and thereby the phosphate level in the blood becomes markedly elevated.
- phosphate binders are developed for this purpose. Typically, phosphate binders are substances taken orally and effective in the intestinal tract for binding with phosphate and preventing the same from being uptaken.
- Conventional phosphate binders include, for example, various salts of aluminum and calcium, as well as some chemically synthesized cross-linked polymers.
- aluminum or calcium salts and cross-linked polymers may both cause undesirable results and therefore, are not ideal.
- One of the objectives of the present invention is to provide an alternative phosphate-binding agent that may exhibit better phosphate-binding ability and/or fewer side effects than the conventional medicine used clinically.
- Another objective of the present invention is to provide a novel method for treating hyperphosphatemia by using a novel phosphate-binding agent.
- the present invention provides a phosphate-binding composition, comprising 13 to 40 ⁇ g/ ⁇ l of chitosan citrate; and a pharmaceutically acceptable carrier; wherein said ⁇ g/ ⁇ l is based on the total volume of said composition.
- said composition comprises 13 to 26 ⁇ g/ ⁇ l of chitosan citrate.
- said chitosan citrate comprises a chitosan moiety; wherein said chitosan moiety is of 50 to 95 %of deacetylation. More preferably, said chitosan moiety is of 55 to 90 %of deacetylation.
- said pharmaceutically acceptable carrier is water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, dimethyl sulfoxide (DMSO) , or a combination thereof.
- said chitosan citrate comprises a chitosan moiety; wherein said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton.
- the present invention also provides a method for binding phosphate in an environment, comprising: contacting said environment with a chitosan citrate; wherein said chitosan citrate comprises a chitosan moiety; wherein said chitosan moiety is of 50 to 95 %of deacetylation.
- the present invention then provides a use of chitosan citrate for preparing a pharmaceutical composition for treating hyperphosphatemia in a subject; wherein said pharmaceutical composition is the composition above.
- the present invention more provides a method for treating hyperphosphatemia in a subject, comprising administering said subject the composition above before, during, or after diet.
- said chitosan moiety is of 55 to 90 %of deacetylation.
- said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton.
- said chitosan citrate is formulated as a composition; wherein said composition comprises 13 to 40 ⁇ g/ ⁇ l of said chitosan citrate; and a pharmaceutically acceptable carrier; wherein said ⁇ g/ ⁇ l is based on the total volume of said composition. More preferably, said composition comprises 13 to 26 ⁇ g/ ⁇ l of said chitosan citrate.
- said pharmaceutically acceptable carrier is water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, dimethyl sulfoxide (DMSO) , or a combination thereof.
- said contacting is conducted by introducing said chitosan citrate into said environment.
- Figure 1 shows the flow chart of preparing the chitosan citrate of the present invention.
- Figure 2 shows the results of the phosphate-binding assay of experiment 1.
- Figure 3 shows the results of the phosphate-binding assay of experiment 2.
- the present invention provides a chitosan citrate for binding phosphate and thereby to relieve hyperphosphatemia symptom.
- said chitosan citrate is formulated as a composition comprising 13 to 40 ⁇ g/ ⁇ l of chitosan citrate and a pharmaceutical carrier; wherein said ⁇ g/ ⁇ l is based on the total volume of said composition.
- said chitosan citrate is of 13 to 26 ⁇ g/ ⁇ l, based on the total volume of said composition.
- said chitosan citrate has a chitosan moiety; wherein said chitosan moiety is of 50 to 95 %of deacetylation.
- the degree of deacetylation is a factor of the ability of phosphate binding of the present chitosan citrate. Without being bound by theory, the more deacetylation gives more active functional groups for phosphate binding and thereby contributes better phosphate-binding ability to the present chitosan citrate.
- said chitosan moiety is of 55 to 90 %of deacetylation.
- the present invention surprisedly proved that the present chitosan citrate exhibits phosphate-binding ability significantly better than chitosan or citric acid alone. That said, even if there is some publications implied the potential application of chitosan or citric acid in phosphate-binding, one can never foresee the significant improvement contributed by the present chitosan citrate in comparison with other chitosan salt (such as chtosan lactate) or citric acid alone.
- said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton; preferably, said weight-average molecular weight is of 20000 to 35000 dalton.
- said pharmaceutically acceptable carrier is water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, dimethyl sulfoxide (DMSO) , or a combination thereof. Those having ordinary skill in the art can choose suitable pharmaceutically acceptable carrier in accordance with its need or administration route.
- the present invention also provides a method for binding phosphate in an environment.
- Said method may be used for removing phosphate from an environment for any desired purposes. Case in point, the method can be conducted to remove phosphate from food containing phosphate so that the food can be edible for patients having feeble kidney function.
- the term “remove” used herein is referred to as “reducing the content” of an object but shall not necessary mean “removing” the object completely.
- the present method for binding phosphate in an environment comprises contacting said environment with a chitosan citrate; wherein said chitosan citrate comprises a chitosan moiety; wherein said chitosan moiety is of 55 to 90 %of deacetylation.
- Said environment may be a container containing a food.
- said environment may be the intestinal tract where the food ingested by a subject can be digested while reacting with the present chitosan citrate.
- said contacting can be achieved by introducing said chitosan citrate into said environment. Nevertheless, the way to achieve said contacting is not limited as long as said chitosan citrate can react with or in said environment to exhibit its phosphate-binding effect.
- the present invention more provides a use of chitosan citrate for preparing a pharmaceutical composition for treating hyperphosphatemia in a subject; wherein said pharmaceutical composition is the composition described above.
- the present invention also provides a method for treating hyperphosphatemia in a subject, comprising administering said subject the composition described above.
- said composition is administered before, during or after diet of said subject.
- treating used herein is referred to as controlling, reducing, and/or avoiding from negative progression of a disease, illness, or symptoms at issue. Accordingly, said “treating hyperphosphatemia” may be construed as controlling, reducing, and/or avoiding from negative progression of hyperphosphatemia symptoms of a subject.
- step (2) After the chitin from step (1) was dried, the chitin was reacted with sodium hydroxide (NaOH; 42.5 wt%) for deacetylation.
- the solid/liquid ratio ie. chitin/sodium hydroxide
- the reaction was maintain under 40 °C. Mixtures containing chitosan of 60%, 87%, and 90 deacetylation were obtained respectively upon different reaction time (15 hours, 25 hours and 30 hours, respectively) .
- CHS60 abd CHS90 the chitosan citrate of 60%deacetylation and chitosan citrate of 90%deacetylation obtained in the previous experiment 1 were tested for their ability of binding phosphate at various concentration.
- calcium carbonate, ferric citrate (Sigma F3388) , citric acid, and chitosan lactate of 87%deacetylation (CH87, purchased from Shin Era Technology Co., LTD. ) were respectively used as control groups in the trials.
- CH87 chitosan lactate of 87%deacetylation
- the data of experiment 3 confirmed the chitosan citrate’s potential in phosphate-binding. It was particularly noted that the phosphate-binding ability of chitosan citrate is much better than chitosan lactate or citric acid alone. In other words, even if chitosan and citric acid both showed some degree of phosphate-binding ability, it was unforeseeable that chitosan citrate is able to exhibit phosphate-binding ability that is significantly better than that of citric acid and other chitosan salts (ex. chitosan lactate) .
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Abstract
Provided is a phosphate-binding composition comprising chitosan citrate as the phosphate-binding agent. The chitosan citrate exhibits excellent phosphate-binding ability comparable to calcium carbonate, which is clinically used nowadays. Thus, the phosphate-binding composition of the present invention is valuable for treating hyperphosphatemia.
Description
Description of Related Art
Hyperphosphatemia is a syndrome that the serum phosphate level of a subject is above a certain threshold causing deposits throughout the body and endangering circulation. There are many different disease may cause hyperphosphatemia, such as, renal disease, kidney failure, hypoparathyroidism, etc. In end-stage of the aforesaid diseases, the patient’s kidney function will be compromised and thereby the phosphate level in the blood becomes markedly elevated.
Patients suffering hypoparathyroidism are advised to have low phosphate diet. However, phosphate is very commonly present in food we eat everyday. That said, it is difficult to avoid foods containing phosphate. Since it is nearly impossible to eat only food containing low phosphate, others strategies shall be adopted for decreasing phosphate uptake. In this regard, phosphate binders are developed for this purpose. Typically, phosphate binders are substances taken orally and effective in the intestinal tract for binding with phosphate and preventing the same from being uptaken.
Conventional phosphate binders include, for example, various salts of aluminum and calcium, as well as some chemically synthesized cross-linked polymers. However, aluminum or calcium salts and cross-linked polymers may both cause undesirable results and therefore, are not ideal.
To sum up, although there are several medicines being used as phosphate binders exist, it is still continuous needs in the art for more options capable of relieving hyperphosphatemia symptom.
SUMMARY
One of the objectives of the present invention is to provide an alternative phosphate-binding agent that may exhibit better phosphate-binding ability and/or fewer side effects than the conventional medicine used clinically.
Another objective of the present invention is to provide a novel method for treating hyperphosphatemia by using a novel phosphate-binding agent.
In order to achieve the aforesaid objectives, the present invention provides a phosphate-binding composition, comprising 13 to 40 μg/μl of chitosan citrate； and a pharmaceutically acceptable carrier； wherein said μg/μl is based on the total volume of said composition.
Preferably, said composition comprises 13 to 26 μg/μl of chitosan citrate.
Preferably, said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety is of 50 to 95 ％of deacetylation. More preferably, said chitosan moiety is of 55 to 90 ％of deacetylation.
Preferably, said pharmaceutically acceptable carrier is water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, dimethyl sulfoxide (DMSO) , or a combination thereof.
Preferably, said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton.
The present invention also provides a method for binding phosphate in an environment, comprising: contacting said environment with a chitosan citrate； wherein said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety is of 50 to 95 ％of deacetylation.
The present invention then provides a use of chitosan citrate for preparing a pharmaceutical composition for treating hyperphosphatemia in a subject； wherein said pharmaceutical composition is the composition above.
The present invention more provides a method for treating hyperphosphatemia in a subject, comprising administering said subject the composition above before, during, or after diet.
Preferably, said chitosan moiety is of 55 to 90 ％of deacetylation.
Preferably, said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton.
Preferably, said chitosan citrate is formulated as a composition； wherein said composition comprises 13 to 40 μg/μl of said chitosan citrate； and a pharmaceutically acceptable carrier； wherein said μg/μl is based on the total volume of said composition. More preferably, said composition comprises 13 to 26 μg/μl of said chitosan citrate.
Preferably, said pharmaceutically acceptable carrier is water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, dimethyl sulfoxide (DMSO) , or a combination thereof.
Preferably, said contacting is conducted by introducing said chitosan citrate into said environment.
Figure 1 shows the flow chart of preparing the chitosan citrate of the present invention.
Figure 2 shows the results of the phosphate-binding assay of experiment 1.
Figure 3 shows the results of the phosphate-binding assay of experiment 2.
The present invention provides a chitosan citrate for binding phosphate and thereby to relieve hyperphosphatemia symptom. In a preferable embodiment, said chitosan citrate is formulated as a composition comprising 13 to 40 μg/μl of chitosan citrate and a pharmaceutical carrier； wherein said μg/μl is based on the total volume of said composition. In a more preferable embodiment, said chitosan citrate is of 13 to 26 μg/μl, based on the total volume of said composition.
In an alternative embodiment, said chitosan citrate has a chitosan moiety； wherein said chitosan moiety is of 50 to 95 ％of deacetylation. The degree of deacetylation is a factor of the ability of phosphate binding of the present chitosan citrate. Without being bound by theory, the more deacetylation gives more active functional groups for phosphate binding and thereby contributes better phosphate-binding ability to the present chitosan citrate. In a preferable embodiment, said chitosan moiety is of 55 to 90 ％of deacetylation.
The present invention surprisedly proved that the present chitosan citrate exhibits phosphate-binding ability significantly better than chitosan or citric acid alone. That said, even if there is some publications implied the potential application of chitosan or citric acid in phosphate-binding, one can never foresee the significant improvement contributed by the present chitosan citrate in comparison with other chitosan salt (such as chtosan lactate) or citric acid alone.
In an alternative embodiment, said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton； preferably, said weight-average molecular weight is of 20000 to 35000 dalton. In a preferable embodiment, said pharmaceutically acceptable carrier is water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, dimethyl sulfoxide (DMSO) , or a combination thereof. Those having ordinary skill in
the art can choose suitable pharmaceutically acceptable carrier in accordance with its need or administration route.
The present invention also provides a method for binding phosphate in an environment. Said method may be used for removing phosphate from an environment for any desired purposes. Case in point, the method can be conducted to remove phosphate from food containing phosphate so that the food can be edible for patients having feeble kidney function. The term “remove” used herein is referred to as “reducing the content” of an object but shall not necessary mean “removing” the object completely.
The present method for binding phosphate in an environment comprises contacting said environment with a chitosan citrate； wherein said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety is of 55 to 90 ％of deacetylation. Said environment may be a container containing a food. In an alternative embodiment, said environment may be the intestinal tract where the food ingested by a subject can be digested while reacting with the present chitosan citrate.
In an embodiment, said contacting can be achieved by introducing said chitosan citrate into said environment. Nevertheless, the way to achieve said contacting is not limited as long as said chitosan citrate can react with or in said environment to exhibit its phosphate-binding effect.
The present invention more provides a use of chitosan citrate for preparing a pharmaceutical composition for treating hyperphosphatemia in a subject； wherein said pharmaceutical composition is the composition described above.
The present invention also provides a method for treating hyperphosphatemia in a subject, comprising administering said subject the composition described above. In an embodiment of the preset invention, said composition is administered before, during or after diet of said subject.
The term of “treating” used herein is referred to as controlling, reducing, and/or avoiding from negative progression of a disease, illness, or symptoms at issue. Accordingly, said “treating hyperphosphatemia” may be construed as controlling, reducing, and/or avoiding from negative progression of hyperphosphatemia symptoms of a subject.
Experiment 1: Preparation of the present chitosan citrate.
In this example, an exemplary procedure of the present invention was exhibited for preparing the present chitosan citrate. The preparation was conducted through the following steps and described in Figure 1:
(1) Chitin extracted from crab (or shrimp) shells with molecular weight of more than 140,000 dalton was obtained and degraded by hydrogen peroxide (35 wt ％) at 20℃ for 72 hours. After the degradation, the weight-average molecular weight (according to standard measurement of CHS-E11-03 of Shin Era Technology Co., LTD. by using BROOKFIELD programmable DV-II +Viscometer) of the chitin was changed into about 23,000 dalton.
(2) After the chitin from step (1) was dried, the chitin was reacted with sodium hydroxide (NaOH； 42.5 wt％) for deacetylation. The solid/liquid ratio (ie. chitin/sodium hydroxide) was 1: 45. The reaction was maintain under 40 ℃. Mixtures containing chitosan of 60％, 87％, and 90 deacetylation were obtained respectively upon different reaction time (15 hours, 25 hours and 30 hours, respectively) .
(3) Then, chitosan of 60％deacetylation and chitosan of 90％deacetylation were processed respectively as follows:
3-1 Chitosan of 60％deacetylation was pressed to separate NaOH therein. Then, the pressed chitosan of 60％deacetylation
was neutralized with 10 wt％H2SO4 and purified by dialysis (Spectrum Labs Hollow Fiber) to remove Na2SO4. Then citric acid (40 wt％) was added in to react with the chitosan. The reaction was conducted at 30 ℃ for 2 hours. After the reaction, chitosan citrate of 60％deacetylation was obtained and spray dried to provide powder thereof.
3-2 Chitosan of 90％deacetylation was pressed to separate NaOH therein. Then, the chitosan of 90％deacetylation was washed with water and neutralized with 10 wt％H2SO4. After that, the chitosan of 90％deacetylation was again pressed to separate from the liquid therein. Then citric acid (40 wt％) was added in to react with the chitosan. The reaction was conducted at 30 ℃ for 24 hours. After the reaction, chitosan citrate of 90％deacetylation was obtained and spray dried to provide powder thereof.
(4) The obtained chitosan citrates were formulated as aqueous solution of various concentrations for the subsequent phosphate-binding assay.
Experiment 2: Phosphate binding assay 1.
In this experiment, the chitosan citrate of 60％deacetylation and chitosan citrate of 90％deacetylation (hereinafter referred to as CHS60 and CHS90 respectively) obtained in the previous experiment 1 were tested for their ability of binding phosphate in comparison with calcium carbonate. Please see the experiment design in the following table 1. Co-incubation of KH2PO4 and the present chitosan citrate or calcium carbonate of indicated concentration was conducted for 2 hours under pH 7～8 and room temperature (about 28℃) .
Table 1: Experiment Design.
*after mixing with KH2PO4 the final concentration of the binding agent in the reaction is 6.6 μg/μl.
After the aforesaid incubation, 2 μl of the mixture of each group (and KH2PO4 without reaction with binding agents) was mixed with 120 μl of acetate buffer (0.1 N acetic acid and 0.025 N of CH3COONa) , 12 μl of ascorbic acid (1 wt％) , and 12 ml of NH4MoO4 (1％, in 0.05 N H2SO4) at room temperature for 20 to 30 minutes. After that, the OD700 of the mixture was detected by spectrometer. The experiments were repeated three times for determine the standard deviation. The binding ability was shown in the following table 2 and Figure 2.
Table 2
*The phosphate binding ability was calculated by the formula: (OD700 of mixture after binding reaction) / (OD700 of KH2PO4 without reaction with binding agents) *100％.
The data above showed that the present chitosan citrate can provide comparable effects in phosphate-binding in comparison with calcium carbonate. Calcium carbonate is clinically used as phosphate-binding agent in the field. Thus, the data above implied the potential of the present chitosan citrate to be an alternative option of calcium carbonate.
Experiment 3: Phosphate binding assay 2.
Experiment 2 set forth above has demonstrated the present chitosan citrate’s potential as phosphate-binding agent. The research proceeded to the next stage to compare the phosphate-binding ability of the present chitosan citrate and other phosphate-binding agents.
In this experiment, the chitosan citrate of 60％deacetylation and chitosan citrate of 90％deacetylation (hereinafter referred to as CHS60 abd CHS90 respectively) obtained in the previous experiment 1 were tested for their ability of binding phosphate at various concentration. Moreover, calcium carbonate, ferric citrate (Sigma F3388) , citric acid, and chitosan lactate of 87％deacetylation (CH87, purchased from Shin Era Technology Co., LTD. ) were respectively used as control groups in the trials. Please see the experiment design shown in the following table 3. Co-incubation of KH2PO4 and those binding agents respectively was conducted for 2 hours under pH 7～8 and room temperature (about 28℃) .
Table 3: Experiment Design.
1. after mixing with KH2PO4 the final concentration of the binding agent in the reaction is 6.6 μg/μl.
2. after mixing with KH2PO4 the final concentration of the binding agent in the reaction is 13.2 μg/μl.
*the concentration indicated is the final concentration in the reaction.
After the aforesaid incubation, 2 μl of the mixture of each group (and KH2PO4 without reaction with binding agents) was mixed with 120 μl of acetate buffer (0.1 N acetic acid and 0.025 N of CH3COONa) , 12 μl of ascorbic acid (1 wt％) , and 12 ml of NH4MoO4 (1％, in 0.05 N H2SO4) at room temperature for 20 to 30 minutes. After that, the OD700 of the mixture was detected by spectrometer. The experiments were repeated three time for determine the standard deviation. The binding ability was shown in the following table 4 and Figure 3.
Table 4
*The phosphate binding ability was calculated by the formula: (OD700 of mixture after binding reaction) / (OD700 of KH2PO4 without reaction with binding agents) *100％.
The data of experiment 3 confirmed the chitosan citrate’s potential in phosphate-binding. It was particularly noted that the phosphate-binding ability of chitosan citrate is much better than chitosan lactate or citric acid alone. In other words, even if chitosan and citric acid both showed some degree of phosphate-binding ability, it was unforeseeable that chitosan citrate is able to exhibit phosphate-binding ability that is significantly better than that of citric acid and other chitosan salts (ex. chitosan lactate) .
Claims (14)
- A phosphate-binding composition， comprising13 to 40 μg/μl of chitosan citrate； anda pharmaceutically acceptable carrier；wherein said μg/μl is based on the total volume of said composition.
- The composition of claim 1， wherein the composition comprises 13 to 26 μg/μl of chitosan citrate.
- The composition of claim 1， wherein said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety is of 50 to 95 ％ of deacetylation.
- The composition of claim 3， wherein said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety is of 55 to 90 ％ of deacetylation.
- The composition of claim 1， wherein said pharmaceutically acceptable carrier is water， alcohol， glycerol， chitosan， alginate， chondroitin， Vitamin E， mineral oil， dimethyl sulfoxide (DMSO) ， or a combination thereof.
- The composition of claim 1， wherein said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton.
- A method for binding phosphate in an environment， comprising：contacting said environment with a chitosan citrate； wherein said chitosan citrate comprises a chitosan moiety； wherein said chitosan moiety is of 50 to 95 ％ of deacetylation.
- The method of claim 7， wherein said chitosan moiety is of 55 to 90 ％ of deacetylation.
- The method of claim 7， wherein said chitosan moiety has a weight-average molecular weight of 15000 to 40000 dalton.
- The method of claim 7， wherein said chitosan citrate is formulated as a composition； wherein said composition comprises 13 to 40 μg/μl of said chitosan citrate； and a pharmaceutically acceptable carrier； wherein said μg/μl is based on the total volume of said composition.
- The method of claim 10， wherein said pharmaceutically acceptable carrier is water， alcohol， glycerol， chitosan， alginate， chondroitin， Vitamin E， mineral oil， dimethyl sulfoxide (DMSO) ， or a combination thereof.
- The method of claim 7， wherein said contacting is conducted by introducing said chitosan citrate into said environment.
- A use of chitosan citrate for preparing a pharmaceutical composition for treating hyperphosphatemia in a subject； wherein said pharmaceutical composition is of the composition of claim 1.
- A method for treating hyperphosphatemia in a subject， comprising administering said subject a composition of claim 1 before， during， or after diet.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019105401A1 (en) * | 2017-11-29 | 2019-06-06 | Shin Era Technology Co. Ltd. | Enteric coated pharmaceutical composition and use thereof |
| CN114246323A (en) * | 2021-12-27 | 2022-03-29 | 江苏康庭生物科技有限公司 | Preparation method of chitosan citrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120277183A1 (en) * | 2008-04-08 | 2012-11-01 | Cypress Pharmaceutical, Inc. | Phosphate-binding chitosan and uses thereof |
| US20140044831A1 (en) * | 2011-04-20 | 2014-02-13 | Lars Christian Kure Steenberg | Chewing Gum Comprising Chitosan For Use In Reduction Of The Level Of Free Phosphorus Compounds In The Digestive Juice |
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- 2016-05-13 TW TW105114873A patent/TW201703774A/en unknown
- 2016-05-13 WO PCT/CN2016/082002 patent/WO2016180363A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120277183A1 (en) * | 2008-04-08 | 2012-11-01 | Cypress Pharmaceutical, Inc. | Phosphate-binding chitosan and uses thereof |
| US20140044831A1 (en) * | 2011-04-20 | 2014-02-13 | Lars Christian Kure Steenberg | Chewing Gum Comprising Chitosan For Use In Reduction Of The Level Of Free Phosphorus Compounds In The Digestive Juice |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019105401A1 (en) * | 2017-11-29 | 2019-06-06 | Shin Era Technology Co. Ltd. | Enteric coated pharmaceutical composition and use thereof |
| CN111727037A (en) * | 2017-11-29 | 2020-09-29 | 世展科技股份有限公司 | Enteric-coated pharmaceutical composition and use thereof |
| CN114246323A (en) * | 2021-12-27 | 2022-03-29 | 江苏康庭生物科技有限公司 | Preparation method of chitosan citrate |
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