CN117205164A - Sapropterin hydrochloride tablet and preparation method thereof - Google Patents
Sapropterin hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN117205164A CN117205164A CN202311276216.6A CN202311276216A CN117205164A CN 117205164 A CN117205164 A CN 117205164A CN 202311276216 A CN202311276216 A CN 202311276216A CN 117205164 A CN117205164 A CN 117205164A
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- Prior art keywords
- tablet
- sapropterin hydrochloride
- mixing
- maltitol
- filler
- Prior art date
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- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 title claims abstract description 68
- 229960004617 sapropterin Drugs 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title abstract description 42
- 239000000845 maltitol Substances 0.000 claims abstract description 29
- 235000010449 maltitol Nutrition 0.000 claims abstract description 29
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims abstract description 29
- 229940035436 maltitol Drugs 0.000 claims abstract description 29
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 17
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 17
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 17
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 10
- 239000003205 fragrance Substances 0.000 claims abstract description 4
- 239000003826 tablet Substances 0.000 claims description 76
- 238000002156 mixing Methods 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 24
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 23
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 23
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 23
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 23
- 239000000945 filler Substances 0.000 claims description 19
- 239000000665 guar gum Substances 0.000 claims description 13
- 235000010417 guar gum Nutrition 0.000 claims description 13
- 229960002154 guar gum Drugs 0.000 claims description 13
- 239000007910 chewable tablet Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229940068682 chewable tablet Drugs 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920013818 hydroxypropyl guar gum Polymers 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 10
- 230000001055 chewing effect Effects 0.000 abstract description 6
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 28
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical group CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 16
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 15
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 15
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 12
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- 239000008187 granular material Substances 0.000 description 12
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- 238000007873 sieving Methods 0.000 description 8
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- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 4
- 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
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
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- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000000227 bioadhesive Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
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- 239000003381 stabilizer Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229960002477 riboflavin Drugs 0.000 description 2
- 235000019192 riboflavin Nutrition 0.000 description 2
- 239000002151 riboflavin Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 108010069013 Phenylalanine Hydroxylase Proteins 0.000 description 1
- 102100038223 Phenylalanine-4-hydroxylase Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- 210000004369 blood Anatomy 0.000 description 1
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- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
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- 239000002274 desiccant Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
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- 229940003703 kuvan Drugs 0.000 description 1
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- 229960001855 mannitol Drugs 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 239000002859 orphan drug Substances 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- RKSUYBCOVNCALL-NTVURLEBSA-N sapropterin dihydrochloride Chemical compound Cl.Cl.N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 RKSUYBCOVNCALL-NTVURLEBSA-N 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a sapropterin hydrochloride tablet and a preparation method thereof. The tablet comprises sapropterin hydrochloride, maltitol, hydroxyethylcellulose and other pharmaceutically acceptable auxiliary materials. The tablet has fragrant and sweet smell, easy chewing, high dissolution rate, high bioavailability, good stability, and simple preparation process.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a sapropterin hydrochloride tablet and a preparation method thereof.
Background
Hyperphenylalaninemia (HPA) is an autosomal recessive genetic disease, and patients cannot normally metabolize phenylalanine, such as eating ordinary foods, and a large amount of hyperphenylalaninemia symptoms are accumulated in the body. High concentration phenylalanine in blood can cause irreversible damage to central nervous system, and can cause patients to develop clinical symptoms such as mental retardation, epilepsy, dyskinesia, etc. If the disease is not treated in time, serious damage to the central nervous system of the patient can be caused.
Sapropterin, also known as tetrahydrobiopterin (or BH) 4 ) Is a naturally occurring alkaloid of the pterin family and can be used for replacing deficient BH 4 Thereby restoring the phenylalanine hydroxylase activity. Sapropterin hydrochloride tablet developed by Bayer pharmaceutical company is the only medicine for treating hyperphenylalaninemia and is suitable for BH in response to the treatment of sapropel hydrochloride tablet 4 HPA caused by deficiency is marketed as a rare disease drug in the united states as an orphan drug in 2007 (trade name: kuvan) at the earliest, and is rapidly approved for marketing in the european union in 2008, and is approved into china in 2010 at 9.
The sapropterin hydrochloride has good water solubility (solubility is higher than 1000 mg/mL), but has poor fat solubility, is slightly dissolved in methanol, is slightly dissolved in ethanol, is almost insoluble in diethyl ether, greatly limits the oral bioavailability, is sensitive to temperature, moisture and pH, is rapidly decomposed when meeting water, high temperature and the like, and has poor stability. Compared with intravenous administration route with the same dosage, the BH of 8-11% is only after oral administration 4 Is absorbed in intestinal tract, and most of the intestinal tract is discharged from the feces. In order to improve the oral bioavailability clinically, BH is generally used 4 Fed with food (e.g., high fat foods or high fat and/or high calorie diets); or BH for fasting administration 4 (e.g., 1 hour before a meal or 2 hours after a meal) to maximize the uniformity of oral bioavailability between two administrations.
CN101132776a discloses a tetrahydrobiopterin tablet formulation comprising BH in a stable crystalline form stable at room temperature for more than 8 hours 4 And pharmaceutically acceptable carrier, diluent or excipient, etc., the stability of the obtained preparation is improved, and the preparation can be stored for 6 to 9 months at room temperature, but related substances are obviously increased.
CN101678025a discloses various tetrahydrobiopterin compositions comprising glycerol monooleate, bioadhesive polymer tablets, sustained release tablets, floating dosage forms, bioadhesive granule capsules, proton donor capsules, etc., the bioavailability of the resulting formulation products being improved.
US20110144117a discloses formulations of tetrahydrobiopterin containing antioxidants, which contain sulfhydryl compounds as antioxidants, such that an aqueous solution of tetrahydrobiopterin or metabolic precursors thereof is stored for at least one month.
US9216178B discloses dry-mixed powder formulations of tetrahydrobiopterin pharmaceutical formulations, the resulting powder being contained in a single or dual compartment pouch for the prevention of moisture contact drying, stable BH 4 Or BH 4 Related dry mix compounds, the pouch also contains a desiccant.
CN112057423a is a granule medicine containing sapropterin hydrochloride, which is composed of sapropterin hydrochloride, lipophilic surfactant and/or waxy skeleton material, stabilizer, bleaching aid or bioadhesive, etc., and the preparation method of using co-micronization or hot-melting granulation is not beneficial to improving stability of sapropterin hydrochloride sensitive to moisture and temperature.
Chewable dosage forms are intended for young or elderly patients who have difficulty swallowing whole tablets or capsules, and such dosage forms are intended to be easy to chew, have a pleasant taste and have a gritty feel. While sapropterin hydrochloride has a certain pungent smell, the common tablet can be taken by young patients with difficulty in swallowing and compliance; meanwhile, the oral absorption and bioavailability are poor, and the time node of oral administration is easy to be influenced by food, so that the oral administration is not controlled, the sapropterin hydrochloride chewing dosage form is developed to improve the compliance or the compliance of patients, and the preparation is also more preferably suitable for patients needing long-term medication.
Disclosure of Invention
In view of the shortcomings of the sapropterin hydrochloride preparation in the prior art, the invention provides sapropterin hydrochloride tablets. The tablet has fragrant and sweet smell, easy chewing, high dissolution rate, high bioavailability, good stability, and simple preparation process.
The inventor mixes sapropterin hydrochloride with maltitol and hydroxyethylcellulose, then adds partial filler, and adds the rest filler, disintegrating agent, aromatic agent, lubricant and the like into mixed tabletting after dry granulation. The mixture of maltitol and hydroxyethylcellulose is used as an adhesive in the prescription, so that the problem of material flowability generated by directly tabletting the material is solved; meanwhile, the stability of the sapropterin hydrochloride tablet is obviously improved, and maltitol and hydroxyethylcellulose can quickly form colloid after the auxiliary materials absorb water in the long-term placement process of the preparation, so that sapropterin hydrochloride is prevented from being degraded when meeting water, and the increase of degradation impurities is avoided; in addition, the dissolution rate and bioavailability of the tablet are also improved.
Specifically, the invention aims at realizing the following technical scheme:
a sapropterin hydrochloride tablet, which comprises sapropterin hydrochloride, maltitol, hydroxyethylcellulose and other pharmaceutically acceptable auxiliary materials.
Preferably, in the tablet, the weight ratio of sapropterin hydrochloride to maltitol to hydroxyethylcellulose is 1:0.04 to 0.25.
Preferably, in the tablet, the weight ratio of maltitol to hydroxyethylcellulose is 1:1 to 3.
Preferably, in the tablet, the pharmaceutically acceptable other auxiliary materials are filler, disintegrant, aromatic and lubricant.
Further preferably, in the tablet, the filler is microcrystalline cellulose, spray-dried lactose or aerosil.
More preferably, in the tablet, the filler is microcrystalline cellulose PH112 or microcrystalline cellulose PH113.
Further preferably, in the tablet, the disintegrant is sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, guar gum, or croscarmellose sodium.
Further preferably, in the tablet, the flavoring agent is vanillin, ethyl vanillin, menthol or peppermint oil; more preferably, the fragrance is ethyl vanillin or menthol.
Further preferably, in the tablet, the lubricant is magnesium stearate, zinc stearate, sodium stearyl fumarate, polyethylene glycol or hydrogenated vegetable oil.
Preferably, the tablet comprises the following components in percentage by weight:
in a preferred embodiment, the tablet comprises the following components in weight percent:
the invention provides a preparation method of sapropterin hydrochloride tablets, which comprises the following steps:
mixing sapropterin hydrochloride with maltitol and hydroxyethyl methylcellulose, adding partial filler, mixing, granulating, adding rest filler, disintegrating agent and aromatic agent, mixing, adding lubricant, mixing, and tabletting.
Preferably, in the preparation method, the filler is 30 to 50% by weight of the filler in part.
Preferably, in the preparation method, the tabletting pressure is 5.0-12.0 KN; further preferably, the tabletting pressure is 6.0-10.0 KN.
The sapropterin hydrochloride tablet prepared by the invention is a chewable tablet.
Sapropterin hydrochloride has a plurality of crystal forms such as A, B, F, J, K, wherein the B crystal form is the most stable, and is suitable for formulation development.
Compared with the prior art, the invention has the following outstanding advantages:
1. aiming at the characteristic that sapropterin hydrochloride API is sensitive to water and temperature, maltitol and hydroxyethylcellulose are used as an adhesive and a stabilizer, so that the degradation of the API is prevented, and the stability of the preparation is improved;
2. the invention uses dry granulation technology and filler batch adding method, the stability of the prepared tablet is higher, and the content uniformity is high;
3. the invention does not need to add a stabilizer or an antioxidant additionally, and avoids damage to liver and kidney functions caused by long-term administration.
Detailed Description
The invention is further described below by way of specific embodiments, which in no way limit the scope of the invention, and various modifications or improvements may be made by those skilled in the art in light of the basic idea of the invention, but are within the scope of the invention without departing from the basic idea of the invention.
Example 1
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, 40% microcrystalline cellulose PH112, guar gum and ethyl vanillin, granulating by dry method, sieving with 1mm sieve, adding residual microcrystalline cellulose PH112, mixing, adding sodium stearyl fumarate, mixing, tabletting at a tabletting pressure of 6.0-10.0 KN, with a specification of 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Example 2
2) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, microcrystalline cellulose PH113 accounting for 50 percent of the weight, sodium carboxymethyl starch and menthol uniformly, granulating by a dry method, finishing granules by a 1mm screen, adding the rest microcrystalline cellulose PH113, mixing uniformly, adding magnesium stearate, mixing uniformly, tabletting, and tabletting pressure being 6.0-100KN, 100mg sapropterin hydrochloride (C) 9 H 15 N 5 O 3 2HCl gauge).
Example 3
1) Prescription of prescription
2) Preparation process
Mixing prescription amount of sapropterin hydrochloride, maltitol, hydroxyethylcellulose, micropowder silica gel of 30% weight, croscarmellose sodium and vanillin uniformly, granulating by dry method, finishing granules by using a 1mm screen, adding the rest micropowder silica gel, mixing uniformly, adding zinc stearate, mixing uniformly, tabletting, and tabletting pressure of 6.0-10.0 KN, wherein each tablet contains 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Example 4
1) Prescription of prescription
2) Preparation process
Mixing prescription amount of sapropterin hydrochloride, maltitol, hydroxyethylcellulose, 40% weight of spray-dried lactose, low-substituted hydroxypropyl cellulose and menthol uniformly, granulating by dry method, using 1mm screen to obtain granules, adding residual spray-dried lactose, mixing uniformly, adding sodium stearyl fumarate, mixing uniformly, tabletting pressure is 6.0-10.0 KN, and tablet size is 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Example 5
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, 40% microcrystalline cellulose PH112, guar gum and ethyl vanillin, granulating by dry method, sieving with 1mm sieve, adding residual microcrystalline cellulose PH112, mixing, adding sodium stearyl fumarate, mixing, tabletting at a tabletting pressure of 6.0-10.0 KN, with a specification of 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Example 6
1) Prescription of prescription
2) Preparation process
Mixing prescription amount of sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, 40% weight of microcrystalline cellulose UF702, guar gum and ethyl vanillin uniformly, granulating by dry method, using 1mm screen to obtain granules, adding the rest microcrystalline cellulose UF702, mixing uniformly, adding sodium stearyl fumarate, mixing uniformly, tabletting pressure of 6.0-10.0 KN, and tablet containing 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Example 7
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, 40% pregelatinized starch, guar gum, and ethyl incenseThe grass aldehyde is evenly mixed, granulated by a dry method, granulated by a screen mesh of 1mm, evenly mixed with the rest pregelatinized starch, evenly mixed with sodium stearyl fumarate, pressed into tablets, the pressing pressure is 6.0-10.0 KN, and the specification is that each tablet contains 100mg of sapropterin hydrochloride (in C 9 H 15 N 5 O 3 2HCl gauge).
Example 8
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, microcrystalline cellulose PH112 accounting for 85% of the weight, guar gum and ethyl vanillin uniformly, granulating by a dry method, finishing granules by using a 1mm screen, adding the rest microcrystalline cellulose PH112, mixing uniformly, adding sodium stearyl fumarate, mixing uniformly, tabletting, wherein the tabletting pressure is 6.0-10.0 KN, and the specification is that each tablet contains 100mg sapropterin hydrochloride (in C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 1
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, 40% microcrystalline cellulose PH112, guar gum and ethyl vanillin, granulating by dry method, sieving with 1mm screen, adding residual microcrystalline cellulose PH112, mixing, adding sodium stearyl fumarate, mixing, tabletting at a pressure of 6.0-10.0 KN, and granulating with a tablet pressure of 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 2
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, hydroxyethylcellulose, 40% microcrystalline cellulose PH112, guar gum and ethyl vanillin, granulating by dry method, sieving with 1mm sieve, adding residual microcrystalline cellulose PH112, mixing, adding sodium stearyl fumarate, mixing, tabletting at a pressure of 6.0-10.0 KN, and granulating to obtain tablet containing sapropterin hydrochloride 100mg (with C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 3
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, povidone, 40% microcrystalline cellulose PH112, guar gum and ethyl vanillin, granulating by dry method, sieving with 1mm sieve, adding residual microcrystalline cellulose PH112, mixing, adding sodium stearyl fumarate, mixing, tabletting at a pressure of 6.0-10.0 KN, and granulating with a tablet pressure of 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 4
1) Prescription of prescription
2) Preparation process
Mixing sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, microcrystalline cellulose PH112, guar gum and ethyl vanillin uniformly, granulating by dry method, sieving with 1mm sieve, adding sodium stearyl fumarate, mixing uniformly, tabletting under a tabletting pressure of 6.0-10.0 KN, wherein each tablet contains 100mg sapropterin hydrochloride (with C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 5
1) Prescription of prescription
2) Preparation process
The preparation method comprises the steps of respectively sieving sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, microcrystalline cellulose PH112, guar gum and ethyl vanillin with a 30-mesh sieve, placing the mixture into a mixer for mixing for 30min, adding sodium stearyl fumarate which is sieved with a 60-mesh sieve into the mixture for mixing uniformly, directly tabletting the powder, wherein the tabletting pressure is 6.0-10.0 KN, and the specification is 100mg sapropterin hydrochloride (C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 6
1) Prescription of prescription
2) Preparation process
The sapropterin hydrochloride, maltitol, hydroxyethyl methylcellulose, microcrystalline cellulose PH112, guar gum and ethyl vanillin with the prescription dose are respectively sieved by a 30-mesh sieve and are placed in a high-efficiency wet mixing granulation modeMixing in a machine to obtain a mixture; adding purified water into the mixture to prepare a soft material, granulating, drying in a fluidized bed by blowing, granulating, adding sodium stearyl fumarate, mixing uniformly, tabletting at a tabletting pressure of 6.0-10.0 KN, wherein each tablet contains 100mg of sapropterin hydrochloride (in C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 7
1) Prescription of prescription
2) Preparation process
The preparation method comprises the steps of uniformly mixing the prescription amount of sapropterin hydrochloride, anhydrous dicalcium phosphate, 40% of mannitol, povidone, ascorbic acid and general riboflavin, granulating by a dry method, using a 1mm screen for finishing granules, adding the rest mannitol for uniformly mixing, adding sodium stearyl fumarate for uniformly mixing, tabletting, wherein the tabletting pressure is 6.0-10.0 KN, and the specification is that each tablet contains 100mg sapropterin hydrochloride (in terms of C 9 H 15 N 5 O 3 2HCl gauge).
Comparative example 8
1) Prescription of prescription
2) Preparation process
Placing the sapropterin hydrochloride with the prescription amount into a mixer, and mixing for 10min at 25 r/min; then adding mannitol into a mixer, and mixing for 10min; adding anhydrous calcium hydrophosphate and povidone into a mixer, and mixing for 10min; adding ascorbic acid and riboflavin, and mixing for 3min; filtering sodium stearyl fumarate, sieving with 25 mesh sieve, adding into a mixer, mixing for 5min, tabletting under 6.0-10.0 KNEach tablet of the formulation contains 100mg of sapropterin hydrochloride (C 9 H 15 N 5 O 3 2HCl gauge).
Verification embodiment
Experimental example 1: determination of hardness, content uniformity and mouthfeel of the tablets obtained in the examples
Measurement of hardness: the ideal chewable tablet has proper lower hardness limit and upper hardness limit, the lower hardness limit can provide certain compression resistance for the tablet to smoothly produce, package and transport, and the hardness requirement of the fourth part of Chinese pharmacopoeia on common tablets can be generally referred to, namely, the hardness is above 50N, and the tensile strength is better than 1.5-3.0 MPa; the upper hardness limit should ensure that the tablet has proper chewiness to avoid damage to teeth and lower jaw during chewing, and the test method should simulate actual chewing process as much as possible, such as saliva wetting, simulated tooth chewing, etc., and CDE suggests that the chewable tablet should have a lower hardness value (e.g., < 120N). The measuring method comprises the following steps: the tablet is soaked in a small amount (for example, 1 ml) of simulated saliva (the composition of the simulated saliva refers to the technical guidelines for the quality attribute study of chewable tablets disclosed by CDE) for a short time (for example, less than or equal to 30 seconds), then hardness is measured, 10 tablets are continuously measured at a time under the specified conditions by adopting a proper tablet hardness tester, and the average hardness and the hardness value of each tablet are recorded.
Determination of content uniformity: the content uniformity inspection method according to the fourth general rule 0941 of Chinese pharmacopoeia is used for detecting that the standard is A+2.2S is less than or equal to 15.
The mouthfeel testing method comprises the following steps: by 10 teenagers aged 12-16 years old, the evaluation personnel can correctly taste the chewable tablets with different fineness and different hardness, the application effect of the chewable tablets is evaluated by three aspects of smoothness, fineness and hardness of the surface of the chewable tablets, and the taste effect is that the surface of the chewable tablets is smooth, the taste is fine and smooth, no gritty, the softness and hardness are moderate, and the chewable tablets have certain sweetness. The non-chewable tablets prepared in comparative examples 7 to 8 were not subjected to taste testing.
Table 1 the measurement results of examples 1 to 8 and comparative examples 1 to 8
As can be seen from Table 1, the hardness, content uniformity and taste of the tablets obtained in examples 1 to 7 all meet the standards; in example 8, a slightly excessive filler was initially added, the mixing of the components was poor, the obtained tablet had a slightly gritty feel, while in comparative example 4, the filler was added all at once, the uniformity of mixing of the components was worse, and the obtained tablet had a stronger gritty feel; in comparative example 5, the powder direct compression preparation method is adopted, the uniformity of the mixed powder is poor, and the prepared tablet has poor taste and rough taste; in comparative example 6, the granules were granulated by wet granulation, the granules were pressed together and were sticky and soft in strips, the resulting tablets were too hard and had a rough mouthfeel; comparative example 8 also used the powder direct compression method, and the uniformity of the mixed powder was poor.
Experimental example 2: determination and comparison of dissolution behavior of the resulting formulations
The tablets (6 tablets) obtained in each example and comparative example were sampled and tested for elution amount at 5, 15 and 30 minutes at a rotation speed of 50 rpm by taking a solution of SDS acetate at pH4.5+0.3% as a elution medium, referring to a test apparatus for the second method of the dissolution rate measurement method in the fourth section 0931 of the Chinese pharmacopoeia 2020.
TABLE 2 dissolution measurement results for examples 1 to 8 and comparative examples 1 to 8
As can be seen from Table 2, each of examples 1 to 8 and comparative examples 1 to 5 can achieve a dissolution of more than 85% in 30 minutes; in comparative example 6, the wet granulation process was adopted, and the dissolution effect of the obtained tablet was reduced due to the phenomenon of extrusion, adhesion, etc. of granules occurring when preparing granules; comparative example 7, because dicalcium phosphate anhydrous is used as a binder and mannitol is used as a filler, the dissolution of the resulting tablet is still poor, although the preparation method of the present invention is used; in comparative example 8, the formulation was different from that of comparative example 7 in terms of preparation method, and dissolution of the obtained tablet was worse.
Experimental example 3: stability investigation of the resulting formulations
At a temperature of 40+/-2 ℃; the sample was left for 6 months under conditions of a relative humidity of 75.+ -. 5% (acceleration), and samples were taken at the end of the 0 th, 3 rd and 6 th months, and the relative substances (total impurities,%) were measured.
TABLE 3 stability measurement results for examples 1-8 and comparative examples 1-8
As can be seen from Table 3, the tablets obtained in the examples have better stability and less change of the related substances when left under accelerated conditions for 6 months; the preparation method comprises the steps that hydroxyethylmethylcellulose is not added in a preparation of a comparative example 1, maltitol is not added in a preparation of a comparative example 2, povidone is used for replacing maltitol and hydroxyethylmethylcellulose in a comparative example 3, and the obtained tablet cannot form a colloidal film for protecting the tablet after water absorption of auxiliary materials in a long-term preparation standing process, so that relevant substances of the tablet are remarkably increased; in comparative examples 4, 5 and 6, although maltitol and hydroxyethylcellulose were contained, the maltitol and hydroxyethylcellulose were dispersed by other auxiliary materials due to the different mixing order, and the active substances could not be effectively coated, and the stability of the obtained tablets was poor; comparative example 7 and comparative example 8 used the same formulation, and the preparation process was different, and the stability of the obtained tablets was poor.
Claims (10)
1. The sapropterin hydrochloride tablet is characterized by comprising sapropterin hydrochloride, maltitol, hydroxyethylcellulose and other pharmaceutically acceptable auxiliary materials.
2. The tablet according to claim 1, wherein the weight ratio of sapropterin hydrochloride to maltitol to hydroxyethylcellulose is 1:0.04-0.25.
3. The tablet according to claim 1, wherein the weight ratio of maltitol to hydroxyethylcellulose in the tablet is 1:1 to 3.
4. The tablet of claim 1, wherein the tablet is a chewable tablet.
5. The tablet of claim 1, wherein the other pharmaceutically acceptable excipients in the tablet are fillers, disintegrants, fragrances and lubricants.
6. The tablet of claim 5, wherein the filler is microcrystalline cellulose, spray-dried lactose, or colloidal silica.
7. The tablet of claim 5, wherein the disintegrant is sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, guar gum, or croscarmellose sodium.
8. The tablet of claim 5, wherein the tablet comprises the following components in weight percent:
9. a method for preparing a tablet according to claim 1, wherein the tablet is prepared by mixing sapropterin hydrochloride with maltitol and hydroxyethylcellulose, adding a part of filler by weight, mixing uniformly, granulating by dry method, adding the rest of filler, disintegrating agent and aromatic agent, mixing uniformly, adding lubricant, mixing uniformly, and tabletting.
10. The method according to claim 9, wherein the filler is present in an amount of 30 to 50% by weight based on the total weight of the filler.
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Citations (5)
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| CN101132776A (en) * | 2004-11-17 | 2008-02-27 | 生物马林药物股份有限公司 | Stable tablet formulation of tetrahydrobiopterin |
| WO2012127431A1 (en) * | 2011-03-24 | 2012-09-27 | Rubicon Research Private Limited | Stabilized compositions of tetrahydrobiopterin |
| US20130108694A1 (en) * | 2011-11-02 | 2013-05-02 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
| CN103458900A (en) * | 2011-03-01 | 2013-12-18 | 鲁必康研究私人有限公司 | Stable compositions of tetrahydrobiopterin |
| WO2021061065A1 (en) * | 2019-09-23 | 2021-04-01 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient |
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2023
- 2023-09-30 CN CN202311276216.6A patent/CN117205164A/en active Pending
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| CN101132776A (en) * | 2004-11-17 | 2008-02-27 | 生物马林药物股份有限公司 | Stable tablet formulation of tetrahydrobiopterin |
| CN103458900A (en) * | 2011-03-01 | 2013-12-18 | 鲁必康研究私人有限公司 | Stable compositions of tetrahydrobiopterin |
| WO2012127431A1 (en) * | 2011-03-24 | 2012-09-27 | Rubicon Research Private Limited | Stabilized compositions of tetrahydrobiopterin |
| US20130108694A1 (en) * | 2011-11-02 | 2013-05-02 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
| WO2021061065A1 (en) * | 2019-09-23 | 2021-04-01 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient |
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