CN115252572A - Alfacalcidol soft capsule and preparation method thereof - Google Patents
Alfacalcidol soft capsule and preparation method thereof Download PDFInfo
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- CN115252572A CN115252572A CN202211046888.3A CN202211046888A CN115252572A CN 115252572 A CN115252572 A CN 115252572A CN 202211046888 A CN202211046888 A CN 202211046888A CN 115252572 A CN115252572 A CN 115252572A
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- soft capsule
- alfacalcidol
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- 239000007901 soft capsule Substances 0.000 title claims abstract description 145
- 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 description 86
- 229960002535 alfacalcidol Drugs 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229920001577 copolymer Polymers 0.000 claims abstract description 19
- 108010010803 Gelatin Proteins 0.000 claims abstract description 14
- 239000008273 gelatin Substances 0.000 claims abstract description 14
- 229920000159 gelatin Polymers 0.000 claims abstract description 14
- 235000019322 gelatine Nutrition 0.000 claims abstract description 14
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001413 amino acids Chemical class 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims abstract description 7
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 4
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 4
- 239000003755 preservative agent Substances 0.000 claims abstract description 3
- 230000002335 preservative effect Effects 0.000 claims abstract description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 3
- 239000008158 vegetable oil Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 43
- 238000002156 mixing Methods 0.000 claims description 31
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 14
- 239000008159 sesame oil Substances 0.000 claims description 13
- 235000011803 sesame oil Nutrition 0.000 claims description 13
- 235000010388 propyl gallate Nutrition 0.000 claims description 11
- 239000000473 propyl gallate Substances 0.000 claims description 11
- 229940075579 propyl gallate Drugs 0.000 claims description 11
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000007493 shaping process Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- 235000019483 Peanut oil Nutrition 0.000 claims description 5
- 239000000312 peanut oil Substances 0.000 claims description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 claims description 4
- 108010039918 Polylysine Proteins 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 claims description 2
- PDIFJEAXAUQCGA-UHFFFAOYSA-N 4-hydroxybenzoic acid;propanoic acid Chemical compound CCC(O)=O.OC(=O)C1=CC=C(O)C=C1 PDIFJEAXAUQCGA-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 claims description 2
- 239000011627 DL-alpha-tocopherol Substances 0.000 claims description 2
- 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 description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 2
- BBQAATXCGGCSCO-UHFFFAOYSA-N acetic acid;4-hydroxybenzoic acid Chemical compound CC(O)=O.OC(=O)C1=CC=C(O)C=C1 BBQAATXCGGCSCO-UHFFFAOYSA-N 0.000 claims description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 229920000724 poly(L-arginine) polymer Polymers 0.000 claims description 2
- 108010011110 polyarginine Proteins 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 239000003549 soybean oil Substances 0.000 claims description 2
- 235000012424 soybean oil Nutrition 0.000 claims description 2
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims description 2
- 235000019281 tert-butylhydroquinone Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 2
- 238000001179 sorption measurement Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 41
- 239000004615 ingredient Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- -1 hydrogen ions Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229930003316 Vitamin D Natural products 0.000 description 3
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
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- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 235000019166 vitamin D Nutrition 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- 150000003710 vitamin D derivatives Chemical class 0.000 description 3
- 229940046008 vitamin d Drugs 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
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- 208000013038 Hypocalcemia Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- 239000008186 active pharmaceutical agent Substances 0.000 description 1
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- 210000002805 bone matrix Anatomy 0.000 description 1
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- 230000000705 hypocalcaemia Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 210000000936 intestine Anatomy 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
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Images
Classifications
-
- 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
-
- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
Abstract
The invention relates to a stable alfacalcidol soft capsule preparation and a preparation method thereof. The soft capsule content comprises alfacalcidol, vegetable oil, glycolide-lactide copolymer, preservative and antioxidant, and the soft capsule shell comprises gelatin, glycerol, amino acid polymer and water. According to the invention, the negatively charged glycolide-lactide copolymer is added into the content and the positively charged amino acid polymer is added into the capsule shell, so that the adsorption effect of the capsule shell on alfacalcidol in the soft capsule content is remarkably reduced, and the overall stability of the preparation is improved.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to alfacalcidol soft capsules and a preparation method thereof.
Background
Alfacalcidol is an active metabolite of vitamin D and plays an important role in regulating calcium balance and skeletal metabolism. Alfacalcidol can be activated by 25-hydroxylase in the liver and exerts vitamin D effects in the whole body and osteoblasts. It exerts a unique pleiotropic effect in the intestine, bone, parathyroid, muscle and brain. Alfacalcidol can increase the calcium recovery of small intestine and renal tubule, inhibit parathyroid hyperplasia, reduce parathyroid hormone synthesis and release, and inhibit bone absorption; can also increase the synthesis of transforming growth factor and insulin-like growth factor, and promote the synthesis of collagen and bone matrix protein; in addition, the medicine can also regulate muscle calcium metabolism, promote muscle cell differentiation, enhance muscle strength, increase neuromuscular coordination and reduce falling tendency. Based on these pharmacological mechanisms, alfacalcidol is now mainly used for improving symptoms caused by abnormal vitamin D metabolism (such as hypocalcemia, convulsion, bone pain and bone damage), and also for osteoporosis.
Alfacalcidol is a potent drug substance, has a low daily oral dose for adults, and can be made into soft capsules for administration. Patent CN104800187A describes a method for preparing alfacalcidol soft capsules, which relates to a method for preparing soft capsules after uniformly mixing alfacalcidol with glycerol, polyethylene glycol, penetration enhancer, thickener and the like, and aims to improve the stability and bioavailability of medicines. Patent CN109568287A describes a preparation method of alfacalcidol soft capsules, which relates to a method for preparing soft capsules by uniformly mixing alfacalcidol with an oily matrix, an antioxidant and the like, and aims to improve the stability of the soft capsules.
Although the method can realize the preparation of the alfacalcidol soft capsule, the method fails to indicate how to prevent the transfer of alfacalcidol from the content of the soft capsule to the shell of the soft capsule. In fact, due to the nature of soft capsule formulations, the transfer of drug to the capsule shell in soft capsules can cause drug leakage and accelerate drug degradation. After alfacalcidol migrates from the content to the capsule shell, the degradation or loss of the active ingredients is more easily caused, and the content of the active ingredients is reduced.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of overcoming the technical defect of the existing alfacalcidol soft capsule, namely overcoming the problem that alfacalcidol migrates from the content of the soft capsule to the capsule shell of the soft capsule, and aims to provide an alfacalcidol soft capsule which is more stable in whole and a preparation method thereof.
In order to solve the technical problems, the invention provides the following technical scheme:
an alfacalcidol soft capsule comprises soft capsule content and a soft capsule shell,
the content of the soft capsule is prepared from the following components in parts by weight:
the soft capsule shell is prepared from the following components in parts by weight:
the applicant finds that when the soft capsule content contains glycolide-lactide copolymer capable of dissociating hydrogen ions and the soft capsule shell contains amino acid polymer capable of adsorbing hydrogen ions, the migration amount of alfacalcidol from the soft capsule content to the soft capsule shell is remarkably reduced, and higher chemical stability is shown in a high-humidity accelerated stability experiment. The applicant speculates that the reason may be that the glycolide-lactide copolymer serving as the hydrogen ion donor and the amino acid polymer serving as the hydrogen ion acceptor form a glycolide-lactide copolymer layer on the inner side of the soft capsule shell due to the action of electrostatic attraction at the junction of the soft capsule content and the soft capsule shell, so that the adsorption action and the migration action of alfacalcidol to the soft capsule shell are retarded, and the better overall stability is represented.
As a preferable scheme of the invention, the vegetable oil is one or more of soybean oil, corn oil, peanut oil and sesame oil.
As a preferable scheme of the invention, the glycolide-lactide copolymer is one or more of glycolide-lactide copolymer (5050) and glycolide-lactide copolymer (7525).
As a preferable scheme of the invention, the preservative is one or more of p-hydroxybenzoate, p-hydroxybenzoate acetate, p-hydroxybenzoate propionate, p-hydroxybenzoate and benzoic acid.
In a preferred embodiment of the present invention, the antioxidant is one or more selected from ascorbyl palmitate, all-rac-alpha-tocopherol, 2, 6-di-tert-butyl-4-methylphenol, tert-butylhydroquinone, butyl hydroxy anisol and propyl gallate.
As a preferable scheme of the invention, the amino acid polymer is one or more of epsilon-polylysine (polymerized by 25-30L-lysine groups) and polyarginine (polymerized by 5-30L-arginine groups).
As a more preferable scheme of the invention, the content of the soft capsule is prepared from the following components in parts by weight:
the soft capsule shell is prepared from the following components in parts by weight:
as the most preferable scheme of the invention, the content of the soft capsule is prepared from the following components in parts by weight:
the soft capsule shell is prepared from the following components in parts by weight:
as a preferred technical scheme, the preparation method of the alfacalcidol soft capsule comprises the following steps:
(1) Mixing total amount of glycolide-lactide copolymer (5050), p-hydroxy-phenyl propionate, propyl gallate and half amount of oleum Sesami, stirring, and dissolving to obtain solution I;
(2) Mixing the whole amount of alfacalcidol and a small amount of sesame oil, and stirring for dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding the rest oleum Sesami, and stirring to obtain soft capsule content solution;
(4) Mixing the total amount of nonapolyarginine, glycerol and water, stirring uniformly, heating to 60 ℃, adding the total amount of gelatin, slowly stirring uniformly, and vacuumizing for 30 minutes to obtain a soft capsule shell solution;
(5) Pressing into soft capsule with a soft capsule machine, drying and shaping to obtain alfacalcidol soft capsule.
The invention has the beneficial effects that: the applicant finds that when the soft capsule content contains glycolide-lactide copolymer capable of dissociating hydrogen ions and the soft capsule shell contains amino acid polymer capable of adsorbing hydrogen ions, the amount of the drug migrating from the soft capsule content to the soft capsule shell of alfacalcidol is remarkably reduced, and higher chemical stability is shown in an oxygen-enriched accelerated stability experiment.
Drawings
Fig. 1 is a schematic diagram of the chemical structure of alfacalcidol of the present invention.
Detailed Description
The present invention will now be described in further detail with reference to the accompanying drawings. The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
Example 1: alfacalcidol soft capsule
As shown in fig. 1, the alfacalcidol soft capsule described in this example is prepared according to the following formula:
the content of the soft capsule is prepared from the following components in parts by weight in the following table 1:
TABLE 1 table of the ingredients of the contents of the soft capsules
| Alfacalcidol | 0.25 part of |
| Sesame oil | 95000 parts of |
| Glycolide-lactide copolymer (5050) | 5000 portions of |
| P-hydroxy-phenyl propionate | 30 portions of |
| Propyl gallate | 50 portions of |
The soft capsule shell is prepared from the following components in parts by weight in the following table 2:
TABLE 2 ingredient table of soft capsule shell
| Gelatin | 100 portions of |
| Glycerol | 30 portions of |
| Nonapolyarginine | 25 portions of |
| Water (I) | 90 portions of |
The preparation method of the alfacalcidol soft capsule described in this embodiment includes the following steps:
(1) Mixing full amount of glycolide-lactide copolymer (5050), p-hydroxy-phenyl-propionate, propyl gallate and half amount of oleum Sesami, stirring and dissolving to obtain solution I;
(2) Mixing the whole amount of alfa ossol and a small amount of sesame oil, and stirring for dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding the rest oleum Sesami, and stirring to obtain soft capsule content solution;
(4) Mixing the total amount of nonapolyarginine, glycerol and water, stirring uniformly, heating to 60 ℃, adding the total amount of gelatin, slowly stirring uniformly, and vacuumizing for 30 minutes to obtain a soft capsule shell solution;
(5) Making into soft capsule with soft capsule machine, drying, and shaping.
Example 2: alfacalcidol soft capsule
As shown in fig. 1, the alfacalcidol soft capsule of the present embodiment is prepared according to the following formula:
the soft capsule content is prepared from the following components in parts by weight according to the following table 3:
TABLE 3 table of the ingredients of the contents of the soft capsules
| Alfacalcidol | 0.5 portion |
| Sesame oil | 90000 shares of |
| Glycolide-lactide copolymer (5050) | 10000 portions of |
| P-hydroxy-phenyl propionate | 30 portions of |
| Propyl gallate | 50 portions of |
The soft capsule shell is prepared from the following components in parts by weight in the following table 4:
TABLE 4 ingredient table of soft capsule shell
| Gelatin | 100 portions of |
| Glycerol | 30 portions of |
| Nonapolyarginine | 30 portions of |
| Water (W) | 90 portions of |
The process for preparing alfacalcidol soft capsules described in this example was the same as that described in example 1.
Example 3: alfacalcidol soft capsule
As shown in fig. 1, the alfacalcidol soft capsule described in this example is prepared according to the following formula:
the soft capsule content is prepared from the following components in parts by weight in the following table 5:
TABLE 5 table of the ingredients of the contents of the soft capsules
The soft capsule shell is prepared from the following components in parts by weight in the following table 6:
TABLE 6 ingredient table of soft capsule shell
| Gelatin | 100 portions of |
| Glycerol | 30 portions of |
| Epsilon-polylysine | 30 portions of |
| Water (I) | 110 portions of |
The preparation method of the alfacalcidol soft capsule described in this embodiment includes the following steps:
(1) Mixing the total amount of glycolide-lactide copolymer (7525), p-hydroxy-benzene propionate, all-racemic-alpha-tocopherol and half amount of peanut oil, stirring and dissolving to obtain solution I;
(2) Mixing the total amount of alfacalcidol and a small amount of peanut oil, stirring and dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding rest peanut oil, and stirring to obtain soft capsule content solution;
(4) Mixing the total amount of epsilon-polylysine, glycerol and water, uniformly stirring, heating to 60 ℃, adding the total amount of gelatin, slowly and uniformly stirring, and vacuumizing for 30 minutes to obtain a soft capsule shell solution;
(5) Making into soft capsule with soft capsule machine, drying, and shaping.
Comparative example 1: alfacalcidol soft capsule
The alfacalcidol soft capsules in the comparative example were prepared according to the following formula:
the soft capsule content is prepared from the following components in parts by weight according to the following table 7:
TABLE 7 table of the ingredients of the contents of the soft capsules
The soft capsule shell is prepared from the following components in parts by weight in the following table 8:
TABLE 8 ingredient table of soft capsule shell
| Gelatin | 100 portions of |
| Glycerol | 30 portions of |
| Water (W) | 90 portions of |
The preparation method of the alfacalcidol soft capsule in the comparative example comprises the following steps:
(1) Mixing full amount of p-hydroxy-phenyl propionate, propyl gallate and half amount of oleum Sesami, stirring and dissolving to obtain solution I;
(2) Mixing the whole amount of alfacalcidol and a small amount of sesame oil, and stirring for dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding the rest oleum Sesami, and stirring to obtain soft capsule content solution;
(4) Mixing glycerol with water, stirring, heating to 60 deg.C, adding gelatin, slowly stirring, and vacuumizing for 30 min to obtain soft capsule shell solution;
(5) Making into soft capsule with soft capsule machine, drying, and shaping.
Comparative example 2: alfacalcidol soft capsule
The alfacalcidol soft capsule in the comparative example is prepared according to the following formula:
the soft capsule content is prepared from the following components in parts by weight as shown in the following table 9:
TABLE 9 ingredient table of soft capsule contents
| Alfacalcidol | 0.25 part |
| Sesame oil | 95000 parts of |
| P-hydroxy-phenyl propionate | 30 portions of |
| Propyl gallate | 50 portions of |
The soft capsule shell is prepared from the following components in parts by weight as shown in the following table 10:
TABLE 10 ingredient table of soft capsule shell
| Gelatin | 100 portions of |
| Glycerol | 30 portions of |
| Nonapolyarginine | 25 portions of |
| Water (W) | 90 portions of |
The preparation method of the alfacalcidol soft capsule in the comparative example comprises the following steps:
(1) Mixing full amount of p-hydroxy-phenyl propionate, propyl gallate and half amount of oleum Sesami, stirring and dissolving to obtain solution I;
(2) Mixing the whole amount of alfacalcidol and a small amount of sesame oil, and stirring for dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding the rest oleum Sesami, and stirring to obtain soft capsule content solution;
(4) Mixing the total amount of nonapolyarginine, glycerol and water, stirring uniformly, heating to 60 ℃, adding the total amount of gelatin, slowly stirring uniformly, and vacuumizing for 30 minutes to obtain a soft capsule shell solution;
(5) Making into soft capsule with soft capsule machine, drying, and shaping.
Comparative example 3: alfacalcidol soft capsule
The alfacalcidol soft capsules in the comparative example were prepared according to the following formula:
the soft capsule content is prepared from the following components in parts by weight as shown in the following table 11:
TABLE 11 ingredient table of soft capsule contents
The soft capsule shell is prepared from the following components in parts by weight as shown in the following table 12:
TABLE 12 tables of the ingredients of the Soft Capsule shells
| Gelatin | 100 portions of |
| Glycerol | 30 portions of |
| Water (I) | 90 portions of |
The preparation method of the alfacalcidol soft capsule in the comparative example comprises the following steps:
(1) Mixing full amount of glycolide-lactide copolymer (5050), p-hydroxy-phenyl-propionate, propyl gallate and half amount of oleum Sesami, stirring and dissolving to obtain solution I;
(2) Mixing the whole amount of alfa ossol and a small amount of sesame oil, and stirring for dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding the rest oleum Sesami, and stirring to obtain soft capsule content solution;
(4) Mixing glycerol with water, stirring, heating to 60 deg.C, adding gelatin, slowly stirring, and vacuumizing for 30 min to obtain soft capsule shell solution;
(5) Making into soft capsule with soft capsule machine, drying, and shaping.
Experimental example 1: substance migration test
1.1 test sample: samples 1-3 are alfacalcidol soft capsules prepared in examples 1-3 of the present invention; reference 1-3 are alfacalcidol soft capsules prepared in reference examples 1-3; control 4 was alfacalcidol soft capsules prepared according to the recipe and process described in example 1 in CN 104800187.
1.2 test methods: samples were taken at room temperature at 65% relative humidity for 24 months at 0, 6, 12, 18 and 24 months respectively (n = 60). Longitudinally cutting the samples by using a scalpel respectively, and extruding the contents in the samples; the sample was perfused with 1mL of fresh sesame oil by pipette through the dissected site, squeezed out, and repeated about 20 times until alfacalcidol could not be detected by high performance liquid chromatography in the squeezed sesame oil. And shearing the capsule shell of the soft capsule of each sample by using ophthalmic scissors, filling the cut capsule shell into a sample bottle, adding 15mL of 50% methanol aqueous solution, stirring for 12 hours, and extracting alfacalcidol in the capsule shell. Filtering the extract by a microporous filter membrane, quantitatively determining alfacalcidol by using a high performance liquid chromatograph, and calculating the percentage of the content of alfacalcidol in the capsule shell in each labeled alfacalcidol soft capsule medicine.
1.3 test conditions: high Performance Liquid Chromatography (HPLC) is adopted, a chromatographic column is Diamonsil C18 (150 mm multiplied by 4.6 mm), a mobile phase is water-acetonitrile-methanol, isocratic elution is carried out, the sample injection amount is 100 mu L, and the detection wavelength is 265nm.
1.4 test results: see table 13.
TABLE 13 The content of alfacalcidol in the capsule shell of the soft capsules in each sample was calculated as a percentage of the theoretical drug content of each alfacalcidol soft capsule (mean,%)
| 0 month | 6 months old | 12 months old | 18 months old | 24 months old | |
| Sample 1 | 0.01 | 0.02 | 0.02 | 0.03 | 0.04 |
| Sample 2 | 0.02 | 0.02 | 0.04 | 0.06 | 0.06 |
| Sample 3 | 0.01 | 0.07 | 0.13 | 0.18 | 0.22 |
| Reference 1 | 0.02 | 0.87 | 2.03 | 2.94 | 3.77 |
| Control 2 | 0.01 | 1.22 | 2.03 | 2.51 | 3.04 |
| Control 3 | 0.01 | 1.59 | 2.47 | 3.38 | 4.17 |
| Control 4 | 0.01 | 1.70 | 2.75 | 3.22 | 3.38 |
The results of this test demonstrate that the mass transport of samples 1, 2 and 3 prepared with the adjuvants and processes described herein is significantly less than the mass transport of the four controls under the same conditions. More alfacalcidol in the four controls migrated into the capsule shell.
Experimental example 2: oxygen enrichment accelerated stability experiment
2.1 test sample: samples 1-3 are alfacalcidol soft capsules prepared in examples 1-3 of the present invention; reference 1-3 are alfacalcidol soft capsules prepared in reference examples 1-3; control 4 was alfacalcidol soft capsules prepared according to the recipe and process described in example 1 in CN 104800187.
2.2 test methods: the air in the glass desiccator containing the sample was completely replaced with oxygen (sealed with vacuum grease and parafilm sealing film) at room temperature and 65% relative humidity, and the sample was left for 12 months and sampled at 0, 3, 6, 9 and 12 months (n = 60), respectively. The content of the alfacalcidol soft capsules was measured according to the method for measuring the content of alfacalcidol soft capsules on page 696 of the Chinese pharmacopoeia 2020 (second part).
2.3 test conditions: and (4) avoiding light. The measurement is carried out according to high performance liquid chromatography (general rule 0512) in China pharmacopoeia (second part) 2020. Chromatographic conditions are as follows: silica gel is used as a filling agent; petroleum ether (60-90 ℃) -ethyl acetate-tetrahydrofuran (2; the detection wavelength was 265nm. The number of theoretical plates is not less than 2500 calculated by alfacalcidol peak. The determination method comprises the following steps: 60 samples were taken, precisely weighed, the contents poured out, and the capsule shells were washed with ether. The ether was volatilized and precisely weighed to determine the average weight of the contents per granule. Mixing the contents uniformly, precisely weighing an appropriate amount, adding a mobile phase for dissolving, and quantitatively diluting to prepare a solution containing 1 mu g of alfacalcidol in 1mL, taking the solution as a test solution, precisely weighing 20 mu L of solution, injecting the solution into a liquid chromatograph, and recording a chromatogram; taking another appropriate amount of alfacalcidol reference substance, precisely stabilizing, adding mobile phase for dissolving, quantitatively diluting to obtain solution containing 1 μ g per 1mL, and determining by the same method. Calculating according to the peak area by an external standard method to obtain the product.
1.4 test results: see table 14.
TABLE 14 percentage of alfacalcidol content in the indicated amounts (average,%)
The test results show that the alfacalcidol content of samples 1, 2 and 3 prepared with the adjuvants and processes described herein is significantly higher than the alfacalcidol content of the four controls under the same conditions. This test demonstrates that the overall stability of the samples prepared with the adjuvants and processes described herein is higher.
Claims (9)
1. An alfacalcidol soft capsule comprises a soft capsule content and a soft capsule shell, and is characterized in that:
the content of the soft capsule is prepared from the following components in parts by weight:
the soft capsule shell is prepared from the following components in parts by weight:
2. alfacalcidol soft capsules according to claim 1, characterized in that: the vegetable oil is one or more of soybean oil, corn oil, peanut oil and sesame oil.
3. Alfacalcidol soft capsules according to claim 1, characterized in that: the glycolide-lactide copolymer is one or more of glycolide-lactide copolymer (5050) and glycolide-lactide copolymer (7525).
4. Alfacalcidol soft capsules according to claim 1, characterized in that: the preservative is one or more of p-hydroxybenzoate, p-hydroxybenzoate acetate, p-hydroxybenzoate propionate, p-hydroxybenzoate and benzoic acid.
5. Alfacalcidol soft capsules according to claim 1, characterized in that: the antioxidant is one or more of ascorbyl palmitate, all-rac-alpha-tocopherol, 2, 6-di-tert-butyl-4-methylphenol, tert-butyl hydroquinone, butyl hydroxy anisol and propyl gallate.
6. Alfacalcidol soft capsules according to claim 1, characterized in that: the amino acid polymer is one or more of epsilon-polylysine (polymerized by 25-30L-lysine groups) and polyarginine (polymerized by 5-30L-arginine groups).
7. Alfacalcidol soft capsules according to any of claims 1 to 6, characterized in that:
the content of the soft capsule is prepared from the following components in parts by weight:
the soft capsule shell is prepared from the following components in parts by weight:
8. alfacalcidol soft capsules according to claim 7, characterized in that:
the content of the soft capsule is prepared from the following components in parts by weight:
the soft capsule shell is prepared from the following components in parts by weight:
9. a process for the preparation of alfacalcidol soft capsules according to claim 8, characterized by comprising the following steps:
(1) Mixing total amount of glycolide-lactide copolymer (5050), p-hydroxy-phenyl propionate, propyl gallate and half amount of oleum Sesami, stirring, and dissolving to obtain solution I;
(2) Mixing the whole amount of alfacalcidol and a small amount of sesame oil, and stirring for dissolving to obtain a solution II;
(3) Mixing solution I and solution II, stirring, adding the rest oleum Sesami, and stirring to obtain soft capsule content solution;
(4) Mixing the whole nonapolyarginine, glycerol and water, stirring uniformly, heating to 60 ℃, adding the whole gelatin, slowly stirring uniformly, and vacuumizing for 30 minutes to obtain a soft capsule shell solution;
(5) Pressing into soft capsule with a soft capsule machine, drying and shaping to obtain alfacalcidol soft capsule.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100173002A1 (en) * | 2006-06-05 | 2010-07-08 | Jin Yulai | Microcapsules with improved shells |
| CN110996925A (en) * | 2017-08-02 | 2020-04-10 | 南洋理工大学 | Floatable pharmaceutical microcapsule compositions |
| CN111773197A (en) * | 2020-06-30 | 2020-10-16 | 正大制药（青岛）有限公司 | Novel alfacalcidol soft capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100173002A1 (en) * | 2006-06-05 | 2010-07-08 | Jin Yulai | Microcapsules with improved shells |
| CN110996925A (en) * | 2017-08-02 | 2020-04-10 | 南洋理工大学 | Floatable pharmaceutical microcapsule compositions |
| CN111773197A (en) * | 2020-06-30 | 2020-10-16 | 正大制药（青岛）有限公司 | Novel alfacalcidol soft capsule and preparation method thereof |
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