CN111214453B - Alfacalcidol soft capsule and preparation method thereof - Google Patents

Alfacalcidol soft capsule and preparation method thereof Download PDF

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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
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capsule
alfacalcidol
parts
gelatin
mass
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CN111214453A (en
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高建胜
孙维广
刘琴玲
黄志云
黎志坚
梁贝尔
苏草茵
邝安安
钟小天
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Guangzhou Baiyunshan Xingqun Pharmaceutical Co ltd
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    • 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

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

Alfacalcidol soft capsule and preparation method thereof
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
Figure BDA0002403135540000111
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.
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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

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* Cited by examiner, † Cited by third party
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

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