CN111214453B - Alfacalcidol soft capsule and preparation method thereof - Google Patents
Alfacalcidol soft capsule and preparation method thereof Download PDFInfo
- Publication number
- CN111214453B CN111214453B CN202010153122.XA CN202010153122A CN111214453B CN 111214453 B CN111214453 B CN 111214453B CN 202010153122 A CN202010153122 A CN 202010153122A CN 111214453 B CN111214453 B CN 111214453B
- Authority
- CN
- China
- Prior art keywords
- capsule
- alfacalcidol
- parts
- gelatin
- mass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960002535 alfacalcidol Drugs 0.000 title claims abstract description 107
- 239000007901 soft capsule Substances 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 title claims abstract 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 111
- 239000002775 capsule Substances 0.000 claims abstract description 105
- 108010010803 Gelatin Proteins 0.000 claims abstract description 74
- 239000008273 gelatin Substances 0.000 claims abstract description 74
- 229920000159 gelatin Polymers 0.000 claims abstract description 74
- 235000019322 gelatine Nutrition 0.000 claims abstract description 74
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 74
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 48
- 229920001661 Chitosan Polymers 0.000 claims abstract description 48
- 239000000661 sodium alginate Substances 0.000 claims abstract description 48
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 48
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 48
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 42
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims abstract description 38
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims abstract description 38
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims abstract description 38
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims abstract description 37
- 235000011187 glycerol Nutrition 0.000 claims abstract description 37
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 30
- 108010061711 Gliadin Proteins 0.000 claims abstract description 28
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims abstract description 27
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims abstract description 27
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims abstract description 27
- 239000007788 liquid Substances 0.000 claims abstract description 25
- 229940045110 chitosan Drugs 0.000 claims abstract description 24
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims abstract description 20
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- ARIWANIATODDMH-AWEZNQCLSA-N 1-lauroyl-sn-glycerol Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)CO ARIWANIATODDMH-AWEZNQCLSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 11
- 229960005150 glycerol Drugs 0.000 claims description 11
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000004806 packaging method and process Methods 0.000 claims description 10
- 239000006187 pill Substances 0.000 claims description 10
- 238000007493 shaping process Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 8
- 229940070765 laurate Drugs 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 239000003814 drug Substances 0.000 abstract description 9
- 229940057917 medium chain triglycerides Drugs 0.000 abstract description 3
- OFHCOWSQAMBJIW-AOSUDXALSA-N (1r,3s,5e)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-6-methylheptan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1/C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AOSUDXALSA-N 0.000 description 93
- 230000000052 comparative effect Effects 0.000 description 21
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 235000017060 Arachis glabrata Nutrition 0.000 description 3
- 244000105624 Arachis hypogaea Species 0.000 description 3
- 235000010777 Arachis hypogaea Nutrition 0.000 description 3
- 235000018262 Arachis monticola Nutrition 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 235000020232 peanut Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- 108090000445 Parathyroid hormone Proteins 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 239000000199 parathyroid hormone Substances 0.000 description 2
- 229960001319 parathyroid hormone Drugs 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 240000001592 Amaranthus caudatus Species 0.000 description 1
- 235000009328 Amaranthus caudatus Nutrition 0.000 description 1
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000003712 Complement factor B Human genes 0.000 description 1
- 108090000056 Complement factor B Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000004178 amaranth Substances 0.000 description 1
- 235000012735 amaranth Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000002805 bone matrix Anatomy 0.000 description 1
- 150000001668 calcitriol derivatives Chemical class 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000007791 dehumidification Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 208000025061 parathyroid hyperplasia Diseases 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to alfacalcidol soft capsules and a preparation method thereof. Is prepared from capsule shell liquid and capsule content; wherein the capsule contents comprise: alfacalcidol, medium-chain triglycerides, ascorbyl palmitate, gliadin, polyethylene glycol, phospholipids, monoglyceryl laurate; the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan. The preparation method is simple, and the prepared alfacalcidol soft capsule has good stability and bioavailability, and is suitable for popularization and application.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to alfacalcidol soft capsules and a preparation method thereof.
Background
Alfacalcidol (Alfacalcidol) is a calcitriol analogue and is hydroxylated in the liver only to become active 1 alpha, 25- (0H)2D 3. Can increase the reabsorption of calcium by small intestine and renal tubule, inhibit parathyroid hyperplasia, reduce the synthesis and release of parathyroid hormone, and inhibit bone absorption; increase the synthesis of transforming growth factor-B (TGF-B) and insulin-like growth factor-I (1GF-I), promote the synthesis of collagen and bone matrix protein; regulating muscle calcium metabolism, promoting muscle cell differentiation, enhancing muscle strength, increasing nerve and muscle coordination, and reducing fall tendency. Alfacalcidol has the functions of regulating the balance of calcium and phosphorus in human body, increasing the absorption of calcium and phosphorus in intestinal tract, reducing the parathyroid hormone level in blood plasma, and improving menopause and osteoporosis caused by using hormone medicines in women. It is suitable for treating osteoporosis, rickets and osteomalacia caused by various reasons.
It is shown by research that alfacalcidol has a short half-life in human body after oral administration, needs to be administered for many times within 24 hours in order to maintain stable blood concentration, and has poor compliance. The capsule can cover up the unpleasant odor of the medicine and is easy to swallow; can improve the stability and bioavailability of the medicine; can also release the medicine in fixed time and fixed position, can make up the defects of other solid dosage forms, and has wide application.
The soft capsule is composed of a content and a capsule shell, wherein the capsule shell is generally composed of a matrix, a plasticizer, a preservative, an opacifier, a pigment and a solvent, the matrix is generally gelatin, the plasticizer is glycerol, sorbitol and the like, the preservative is methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, potassium sorbate and the like, the opacifier is titanium dioxide, the pigment is quinine, red iron oxide, manganese dioxide, black iron oxide, amaranth and the like, and the solvent is water. The composition of the contents is generally a drug and a solvent. The capsule has the advantages of good appearance, good stability, and good compliance, and is moisture-proof, oxidation-proof, and light-proof.
However, alfacalcidol has poor stability, and although the stability of alfacalcidol can be improved to a certain extent after the alfacalcidol is prepared into soft capsules, the existing soft capsules of alfacalcidol have still not ideal stability, and have the defects of poor stability and low bioavailability.
For example, in the prior art, chinese patent application CN 103110606a discloses an alfacalcidol soft capsule and a preparation method thereof. The content of the alfacalcidol soft capsule consists of the following components in parts by weight: an oily matrix, an antioxidant, alfacalcidol; the oily base is a medium chain triglyceride. The alfacalcidol soft capsule prepared by the method has good stability, but the bioavailability is unknown.
Therefore, there is a need for further research and improvement on alfacalcidol soft capsule preparations to obtain a technology with poor stability and good bioavailability.
Disclosure of Invention
In order to overcome the technical problems, the invention provides an alfacalcidol soft capsule, which is simple in preparation method, and the prepared alfacalcidol soft capsule has good stability and bioavailability and is suitable for popularization and application.
In order to achieve the above purpose, the technical scheme provided by the invention is as follows:
an alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein the capsule contents comprise: alfacalcidol, medium-chain triglycerides, ascorbyl palmitate, gliadin, polyethylene glycol, phospholipids, monoglyceryl laurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.2-0.5% of the mass of the gelatin; preferably 0.4%;
the total mass of the sodium alginate and the chitosan is 5-10% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1-2: 1.
The using amount of the glycerol is 20-50% of the mass of the gelatin, and the preferable using amount is 30%;
the mass ratio of the water to the gelatin is 1-2:1, preferably 1: 1;
preferably, the capsule content comprises, in parts by weight: 0.0001-0.005 part of alfacalcidol, 1200 parts of medium-chain triglyceride, 0.1-5 parts of ascorbyl palmitate, 50-100 parts of gliadin, 10-50 parts of polyethylene glycol, 5-20 parts of phospholipid and 1-10 parts of glycerol monolaurate;
preferably, the capsule content comprises, in parts by weight: 0.0005-0.001 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.5-2 parts of ascorbyl palmitate, 60-80 parts of gliadin, 10-30 parts of polyethylene glycol, 3-6 parts of phospholipid and 2-5 parts of glycerol monolaurate;
preferably, the molecular weight M of the polyethylene glycol is 400-; preferably, M is 800;
preferably, the mass ratio of the phospholipid to the glycerol monolaurate is 2-5: 1;
the invention also aims to provide a preparation method of the alfacalcidol soft capsule, which comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring to obtain capsule contents;
(3) dissolving gelatin in hot water, and adding glycerol, ethylparaben, sodium alginate and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules, shaping in cold air, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Preferably, in the step (2), the rotation speed of the stirring is 2000-3000 rpm;
preferably, in the step (3), the temperature of the hot water is 60-80 ℃;
preferably, in the step (4), the cold air has a qualitative temperature of 18-25 ℃ and a humidity of 40-50%.
Compared with the prior art, the invention has the technical advantages that:
(1) the alfacalcidol soft capsule provided by the invention has the technical advantages of good stability and bioavailability, and is suitable for popularization and application;
(2) the medium-chain triglyceride can effectively disperse alfacalcidol, and the phospholipid, the monoglyceryl laurate and the polyethylene glycol can effectively improve the stability of capsule contents, so that the capsule contents can be prepared into a microemulsion and then put into a soft capsule, and the bioavailability can be greatly improved;
(3) the gliadin used in the invention has better protection on alfacalcidol, and after the soft capsule is taken, the gliadin can be controlled to have good release property, so that effective blood concentration can be effectively achieved.
Detailed Description
Example 1
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.8 part of ascorbyl palmitate, 80 parts of gliadin, 30 parts of polyethylene glycol, 20 parts of phospholipid and 10 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 800;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2500rpm to obtain capsule contents;
(3) dissolving gelatin in 70 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 20 ℃ and the humidity of 45%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Example 2
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0001 part of alfacalcidol, 500 parts of medium-chain triglyceride, 0.5 part of ascorbyl palmitate, 50 parts of gliadin, 10 parts of polyethylene glycol, 5 parts of phospholipid and 1 part of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.2 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 5% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1: 1; the using amount of the glycerol is 20% of the mass of the gelatin; the mass ratio of the water to the gelatin is 2: 1;
the molecular weight M of the polyethylene glycol is 400;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2000rpm to obtain capsule contents;
(3) dissolving gelatin in 60 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 18 ℃ and the humidity of 40%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Example 3
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.005 part of alfacalcidol, 1200 parts of medium-chain triglyceride, 2 parts of ascorbyl palmitate, 100 parts of gliadin, 50 parts of polyethylene glycol, 6 parts of phospholipid and 2 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.5 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 10% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 2: 1; the using amount of the glycerol is 50% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 2000;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 3000rpm to obtain capsule contents;
(3) dissolving gelatin in 80 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 25 ℃ and the humidity of 50%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Example 4
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.001 part of alfacalcidol, 800 parts of medium-chain triglyceride, 5 parts of ascorbyl palmitate, 60 parts of gliadin, 10 parts of polyethylene glycol, 6 parts of phospholipid and 3 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan; the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 6 percent of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1:1
The using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 1000;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2000rpm to obtain capsule contents;
(3) dissolving gelatin in 80 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 25 ℃ and the humidity of 50%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Comparative example 1
Compared with example 1, the difference is that gliadin is replaced by peanut protein.
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.8 part of ascorbyl palmitate, 80 parts of peanut protein, 30 parts of polyethylene glycol, 20 parts of phospholipid and 10 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 800;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, peanut protein, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2500rpm to obtain capsule contents;
(3) dissolving gelatin in 70 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 20 ℃ and the humidity of 45%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Comparative example 2
The difference compared to example 1 is that monolauric acid monoglyceride was used in place of the phospholipid.
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.8 part of ascorbyl palmitate, 80 parts of gliadin, 30 parts of polyethylene glycol and 30 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 800;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol and monoglycerol laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2500rpm to obtain capsule contents;
(3) dissolving gelatin in 70 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 20 ℃ and the humidity of 45%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Comparative example 3
The difference compared to example 1 is that the monolauric acid monoglyceride was replaced with a phospholipid.
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.8 part of ascorbyl palmitate, 80 parts of gliadin, 30 parts of polyethylene glycol and 30 parts of phospholipid;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 800;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol and phospholipid to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2500rpm to obtain capsule contents;
(3) dissolving gelatin in 70 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 20 ℃ and the humidity of 45%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Comparative example 4
The difference compared to example 1 is the replacement of medium chain triglycerides with corn germ oil.
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of corn germ oil, 0.8 part of ascorbyl palmitate, 80 parts of gliadin, 30 parts of polyethylene glycol, 20 parts of phospholipid and 10 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.2-0.5% of the mass of the gelatin; preferably 0.4%;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 800;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) mixing corn germ oil with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring at 2500rpm to obtain capsule contents;
(3) dissolving gelatin in 70 deg.C hot water, adding glycerol, ethylparaben, sodium alginate, and chitosan to obtain capsule shell solution;
(4) preparing the capsule content and the capsule shell liquid into soft capsules by using a full-automatic soft capsule machine, shaping in cold air at the temperature of 20 ℃ and the humidity of 45%, washing pills, drying and packaging to obtain the alfacalcidol soft capsules.
Comparative example 5
The difference from example 1 is that the molecular weight of polyethylene glycol is different.
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.8 part of ascorbyl palmitate, 80 parts of gliadin, 30 parts of polyethylene glycol, 20 parts of phospholipid and 10 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 3000;
the preparation method of the alfacalcidol soft capsule comprises the same steps as example 1.
Comparative example 6
Compared with example 1, the difference is the preparation method.
An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content;
wherein, according to the weight portion, the capsule content includes: 0.0005 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.8 part of ascorbyl palmitate, 80 parts of gliadin, 30 parts of polyethylene glycol, 20 parts of phospholipid and 10 parts of glycerol monolaurate;
the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the dosage of the ethylparaben is 0.4 percent of the mass of the gelatin;
the total mass of the sodium alginate and the chitosan is 7% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1.5: 1; the using amount of the glycerol is 30% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1: 1;
the molecular weight M of the polyethylene glycol is 800;
the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) dispersing alfacalcidol in medium-chain triglyceride, adding ascorbyl palmitate, gliadin, phospholipid, glycerol monolaurate and polyethylene glycol, stirring at 2500rpm, and making into emulsion to obtain capsule content;
(2) dissolving gelatin in hot water of 70 ℃, and adding glycerol, ethylparaben, sodium alginate and chitosan to prepare the capsule shell solution;
(3) encapsulating the capsule content in a skin membrane formed by extending the capsule shell liquid, and performing rotary dehumidification and drying at 35 ℃ to obtain the alfacalcidol soft capsule.
Examples of effects
1. Stability test
Test drugs: alfacalcidol soft capsules prepared in examples 1-4 and comparative examples 1-6.
The test method comprises the following steps: the dissolution of alfacalcidol in the test samples was measured within 16 hours according to the method for determining the release rate (see first method XD in the appendix, second part of the Chinese pharmacopoeia, 2000, version), using the dissolution rate method (first method XC in the appendix, second part of the Chinese pharmacopoeia, 2000, version) for 0 month, 3 months and 6 months (at 25 ℃ and 60% relative humidity), as shown in Table 1.
Table 1 dissolution data
Therefore, the alfacalcidol soft capsule provided by the invention has a good slow release effect and good stability within 6 months. Meanwhile, the specific components of the alfacalcidol soft capsule have great influence on the stability and the release effect of the alfacalcidol soft capsule.
2. Accelerated stability test
Test drugs: alfacalcidol soft capsules prepared in examples 1-4 and comparative examples 1-6.
The test method comprises the following steps: the content was measured by HPLC after sampling at 0, 7, 14, 21 and 28 days at 4500lx illumination intensity. Conditions of HPLC: a chromatographic column: ODS-C18 column, octadecylsilane chemically bonded silica is used as filler; mobile phase: acetonitrile-water (75: 25); detection wavelength: 265 nm; flow rate: 1.0 mL/min; sample introduction amount: 50 μ L. The theoretical plate number should not be 5000 as low as the alfacalcidol peak, and the degree of separation between the alfacalcidol peak and the trans-alfacalcidol peak should be greater than 1.0. The content is calculated by adopting an external standard method. The results of the assay (percentage of measured to indicated amounts) are given in table 2 below.
TABLE 2 accelerated stability test content measurement results (%)
| Test group | Day 0 | 7 days | 14 days | 21 days | 28 days |
| Example 1 | 100.0 | 99.3 | 97.1 | 95.8 | 90.4 |
| Example 2 | 99.9 | 99.1 | 97.4 | 94.5 | 89.9 |
| Example 3 | 100.0 | 99.3 | 96.9 | 94.2 | 90.1 |
| Example 4 | 100.1 | 99.1 | 97.2 | 93.5 | 89.9 |
| Comparative example 1 | 100.0 | 97.2 | 94.5 | 89.2 | 80.3 |
| Comparative example 2 | 100.1 | 96.3 | 90.6 | 85.4 | 72.1 |
| Comparative example 3 | 100.0 | 94.7 | 87.2 | 81.2 | 69.5 |
| Comparative example 4 | 99.9 | 92.6 | 83.3 | 75.4 | 62.1 |
| Comparative example 5 | 100.0 | 97.9 | 92.5 | 83.2 | 78.3 |
| Comparative example 6 | 99.9 | 98.2 | 93.6 | 85.6 | 80.9 |
Therefore, the alfacalcidol soft capsule provided by the invention has better stability. Meanwhile, the specific components of the alfacalcidol soft capsule have a great influence on the stability of the alfacalcidol soft capsule.
3. Bioavailability of
8 beagle dogs (all male) were orally administered with alfacalcidol soft capsules prepared in examples 1 and 3 of the present invention and comparative examples 1 to 6 (at 25 ℃ C. and 60% relative humidity for 12 months), at a dose of 10.0. mu.g/dog (based on alfacalcidol), with an interval of 7 days. After drug administration, blood samples were taken at various times and the maximum alfacalcidol blood concentration (C) was performedmax) And bioavailability (AUC)0→48) And (4) calculating. The collection time points were 0h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 32h, 48h, and the resulting averages were calculated as shown in table 3 below.
TABLE 3 comparison of bioavailability
| Test group | Cmax(ng/ml) | AUC0→48(ng·h/ml) |
| Example 1 | 1.68±0.45 | 19.2±3.21 |
| Example 3 | 1.71±0.67 | 18.8±1.73 |
| Comparative example 1 | 0.76±0.19 | 9.78±0.98 |
| Comparative example 2 | 1.29±0.34 | 11.3±3.75 |
| Comparative example 3 | 1.14±0.11 | 13.7±0.62 |
| Comparative example 4 | 1.46±0.22 | 10.9±2.89 |
| Comparative example 5 | 0.83±0.06 | 8.86±3.01 |
| Comparative example 6 | 0.98±0.37 | 9.45±2.96 |
Therefore, the alfacalcidol soft capsule provided by the invention has the advantages that the alfacalcidol blood concentration is higher, the bioavailability is higher, and meanwhile, the specific components of the alfacalcidol soft capsule have larger influence on the bioavailability.
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (7)
1. An alfacalcidol soft capsule is prepared from capsule shell solution and capsule content; wherein, according to the weight portion, the capsule content includes: 0.0001-0.005 part of alfacalcidol, 1200 parts of medium-chain triglyceride, 0.1-5 parts of ascorbyl palmitate, 50-100 parts of gliadin, 10-50 parts of polyethylene glycol, 5-20 parts of phospholipid and 1-10 parts of glycerol monolaurate; the capsule shell liquid comprises the following components: gelatin, glycerol, water, ethylparaben, sodium alginate and chitosan;
the molecular weight M =400-2000 of the polyethylene glycol;
the dosage of the ethylparaben is 0.2-0.5% of the mass of the gelatin; the total mass of the sodium alginate and the chitosan is 5-10% of the mass of the gelatin, and the mass ratio of the sodium alginate to the chitosan is 1-2: 1; the using amount of the glycerol is 20-50% of the mass of the gelatin; the mass ratio of the water to the gelatin is 1-2: 1.
2. The alfacalcidol soft capsule of claim 1, wherein the capsule contents comprise, in parts by weight: 0.0005-0.001 part of alfacalcidol, 1000 parts of medium-chain triglyceride, 0.5-2 parts of ascorbyl palmitate, 60-80 parts of gliadin, 10-30 parts of polyethylene glycol, 5-6 parts of phospholipid and 2-5 parts of glycerol monolaurate.
3. The alfacalcidol soft capsule according to claim 1, wherein the molecular weight of the polyethylene glycol M = 800.
4. The alfacalcidol soft capsule according to claim 1, wherein the amount of ethylparaben is 0.4% by mass of gelatin.
5. The alfacalcidol soft capsule according to claim 1, wherein the mass ratio of phospholipid to monoglycerol laurate is 2-5: 1.
6. Process for the preparation of alfacalcidol soft capsules according to any one of claims 1 to 5, comprising the following steps:
(1) mixing medium-chain triglyceride with ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid and monoglyceride laurate to obtain a mixture 1;
(2) adding alfacalcidol into the mixture 1 under the protection of nitrogen, and stirring to obtain capsule contents;
(3) dissolving gelatin in hot water, and adding glycerol, ethylparaben, sodium alginate and chitosan to obtain capsule shell solution; the temperature of the hot water is 60-80 ℃;
(4) preparing the capsule content and the capsule shell liquid into soft capsules, shaping in cold air, washing pills, drying and packaging to obtain the alfacalcidol soft capsules; the cold air setting temperature is 18-25 deg.C, and the humidity is 40-50%.
7. The method for preparing alfacalcidol soft capsules as claimed in claim 6, wherein in step (2), the rotation speed of the stirring is 2000-3000 rpm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010153122.XA CN111214453B (en) | 2020-03-06 | 2020-03-06 | Alfacalcidol soft capsule and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010153122.XA CN111214453B (en) | 2020-03-06 | 2020-03-06 | Alfacalcidol soft capsule and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111214453A CN111214453A (en) | 2020-06-02 |
| CN111214453B true CN111214453B (en) | 2021-04-13 |
Family
ID=70808503
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010153122.XA Active CN111214453B (en) | 2020-03-06 | 2020-03-06 | Alfacalcidol soft capsule and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111214453B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113546062B (en) * | 2021-08-05 | 2022-11-01 | 上海健康医学院 | A kind of vitamin D soft capsule and preparation method thereof |
| CN118252813B (en) * | 2024-05-30 | 2024-09-06 | 青松医药集团股份有限公司 | Alfacalcidol soft capsule and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810336A (en) * | 2010-04-30 | 2010-08-25 | 广东仙乐制药有限公司 | Chewable soft capsules and method for preparing same |
| CN109568287A (en) * | 2019-01-16 | 2019-04-05 | 广州白云山星群(药业)股份有限公司 | Alfacalcidol soft capsule and preparation method thereof |
-
2020
- 2020-03-06 CN CN202010153122.XA patent/CN111214453B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810336A (en) * | 2010-04-30 | 2010-08-25 | 广东仙乐制药有限公司 | Chewable soft capsules and method for preparing same |
| CN109568287A (en) * | 2019-01-16 | 2019-04-05 | 广州白云山星群(药业)股份有限公司 | Alfacalcidol soft capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111214453A (en) | 2020-06-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1091368C (en) | Pharmaceutical composition comprising coenzyme Q10 | |
| CN111214453B (en) | Alfacalcidol soft capsule and preparation method thereof | |
| US8263119B2 (en) | Capsule formulations containing lanthanum compounds | |
| CN109745330B (en) | Application of oleanolic acid and ursolic acid in the preparation of drugs for regulating the activity of vitamin D3 metabolizing enzymes | |
| CN109276556B (en) | Calcitriol soft capsule | |
| CN101366697A (en) | Novel nano-lipid carrier for injection embodying paclitaxel series substances and preparation method thereof | |
| CN101028274A (en) | Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method | |
| CN110934847A (en) | Preparation method of eldecalcitol soft capsule | |
| CN1857676A (en) | Zedoary oil microcapsule preparation and its preparing process | |
| CN101084934A (en) | Liquid capsule of lucidum spore oil and preparation method | |
| CN106278907B (en) | A kind of Syprine Hydrochloride compound | |
| CN107362151A (en) | A kind of calcitriol liquid hard capsule and preparation method thereof, application | |
| CN102488650A (en) | Adenosine cyclophosphate pharmaceutical composition and preparation method thereof | |
| CN101890026B (en) | Water-soluble vitamin D2 calcium levulinate injection pharmaceutical composition | |
| CN103096876A (en) | New formulations of 14-epi-analogues of vitamin D | |
| CN109260209B (en) | Calcitriol soft capsule and preparation method thereof | |
| CN114404362A (en) | Oral composition of gambogic acid and its application in the preparation of tumor therapeutic drugs | |
| US20240122851A1 (en) | Vitamin d formulations | |
| CN104800187A (en) | Soft alfacalcidol capsule and preparation method thereof | |
| CN1868520A (en) | Compound Barbados aloe soft-capsule prepn. and its preparing method | |
| CN109224059A (en) | compound preparation and preparation method thereof | |
| CN116617274B (en) | Wall-broken ganoderma lucidum spore powder solid dispersion, and preparation method and application thereof | |
| EP4059490B1 (en) | Process for manufacturing vitamin d formulations | |
| CN112494452B (en) | Silibinin capsule and preparation method thereof | |
| CN109260224B (en) | Parricalcitol soft capsule and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |