CN109276556B - Calcitriol soft capsule - Google Patents

Calcitriol soft capsule Download PDF

Info

Publication number
CN109276556B
CN109276556B CN201811412695.9A CN201811412695A CN109276556B CN 109276556 B CN109276556 B CN 109276556B CN 201811412695 A CN201811412695 A CN 201811412695A CN 109276556 B CN109276556 B CN 109276556B
Authority
CN
China
Prior art keywords
calcitriol
soft capsule
parts
calcitriol soft
capsule according
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
Application number
CN201811412695.9A
Other languages
Chinese (zh)
Other versions
CN109276556A (en
Inventor
陈阳生
王明刚
孙桂玉
刘晓霞
杜昌余
王清亭
刘振玉
臧云龙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CP Pharmaceutical Qingdao Co Ltd
Original Assignee
CP Pharmaceutical Qingdao Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by CP Pharmaceutical Qingdao Co Ltd filed Critical CP Pharmaceutical Qingdao Co Ltd
Priority to CN201811412695.9A priority Critical patent/CN109276556B/en
Publication of CN109276556A publication Critical patent/CN109276556A/en
Application granted granted Critical
Publication of CN109276556B publication Critical patent/CN109276556B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a calcitriol soft capsule, and belongs to the field of pharmaceutical preparations. The invention provides a calcitriol soft capsule which consists of a content and a capsule shell, wherein the content comprises calcitriol, an antioxidant and a solvent, and the capsule shell comprises a gel, a plasticizer, a preservative, a colorant and water. The screened antioxidant formula comprises butyl anisole, dibutyl hydroxy toluene and propyl gallate, and the plasticizer formula comprises glycerol and stearic acid. Under the formula, the calcitriol can exist stably, and related substances are controlled within a reasonable range, so that a novel calcitriol soft capsule with stable quality is provided.

Description

Calcitriol soft capsule
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a calcitriol soft capsule.
Background
Calcitriol (Calcitriol, 1), chemical name 9, 10-secocholest-5Z, 7E, 10(19) -triene-1 α, 3 β, 25-triol. Calcitriol is one of the most important metabolic active products of vitamin D3 in human bodies, and can promote the absorption of calcium by intestinal tracts and regulate the calcification of bone. Calcitriol was first produced by roche, switzerland, marketed in 1978 under the trade designation "Rocaltrol", and was used for the treatment of postmenopausal osteoporosis, chronic renal dysfunction, postoperative hypothyroidism, idiopathic parathyroidism, pseudohypothyroidism, vitamin D-dependent rickets, hypophosphatemic vitamin D-resistant rickets, and the like. Calcitriol has been used clinically for osteoporosis in japan, new zealand, australia, italy, the uk for decades. Because calcitriol is an endogenous substance, the curative effect is definite, and the calcitriol is safe and stable, the calcitriol is the first choice medicine for osteoporosis.
The calcitriol has high physiological activity, the single administration dosage is very small, the general treatment dosage is only 0.25 mu g/day-1.0 mu g/day, compared with other oral solid dosage forms, the calcitriol is dissolved in a proper fat-soluble matrix to prepare a soft capsule, the uniform and accurate loading quantity can be ensured, the dosage error is small, and the dosage of a patient per time is stable, so that the curative effect is ensured, and the toxic and side effects are prevented.
The soft capsule dosage form is also called soft capsule, and is a capsule prepared by sealing a mixture of solution, suspension, emulsion or semisolid (paste, etc.) in a spherical or elliptical soft capsule shell, and has a shape of circle, ellipse, fish, tube, etc. The soft capsule has the advantages that the embedded content is completely isolated from external factors such as air and the like, so that the active ingredients in the content are prevented from being damaged by the external factors; the capsule can effectively maintain volatile and oxidizable components, the content or net content of each active component of a single capsule particle can be kept stable, the medicinal and health-care values of the content can be ensured, the peculiar smell of partial functional medicines or foods can be effectively masked, the sense rejection of consumers is reduced, the capsule belongs to an edible natural product, and the raw materials can be prepared or extracted from food-derived materials.
The soft capsule is a new dosage form developed after tablets and injections, the shell of the soft capsule is formed by pressing gelatin, and the capsule shell internally contains liquid medicine, which has slower effect than the injections, but has faster effect than the tablets, capsules and granules, has high bioavailability, is more convenient to carry than oral liquid, and can cover the bad smell of some medicines. The soft capsule has the advantages of accurate content, scientific process, convenient use, high bioavailability, quick response, high curative effect and the like which are not possessed by other formulations, so that the soft capsule is more and more favored by markets and patients.
Calcitriol is weak in stability and very sensitive to light and air, and although the calcitriol is encapsulated by a rubber sheet in a sealing manner, the calcitriol can isolate air to a certain extent and slow down the oxidation of effective substances, but the oxidation inactivation of the calcitriol in the storage process is still difficult to avoid. In order to further improve the stability of the calcitriol soft capsule, researchers continuously optimize and screen the formula of the calcitriol soft capsule. Nevertheless, there is still a lack of calcitriol soft capsules of stable quality.
Disclosure of Invention
The invention aims to provide a calcitriol soft capsule with stable quality.
In order to solve the technical problem, the technical scheme provided by the application is that the calcitriol soft capsule consists of a content and a capsule shell, wherein the content comprises calcitriol, an antioxidant and a solvent.
The capsule shell comprises gelling agent, plasticizer, preservative, colorant and water.
The antioxidant comprises butyl anisole, dibutyl hydroxy toluene and propyl gallate.
Preferably, the antioxidant comprises 0.5-1 part of butyl anisole, 0.3-0.6 part of dibutyl hydroxy toluene and 0.1-0.8 part of propyl gallate according to the parts by weight.
The solvent comprises soybean oil, caprylic/capric macrogol glyceride and polyglycol ether.
Preferably, the solvent comprises 50-100 parts by weight of soybean oil, 30-60 parts by weight of caprylic/capric polyethylene glycol glyceride and 40-80 parts by weight of polyethylene glycol ether.
The gelling agent comprises one or more of acacia, gelatin, carrageenan, xanthan gum, gellan gum and konjac gum.
The plasticizer comprises one or more of glycerol, sorbitol, polyethylene glycol 200, polyethylene glycol 400 and stearic acid.
Preferably, the plasticizer comprises glycerin and stearic acid.
The preservative comprises one or more of methyl paraben, ethyl paraben, phenethyl alcohol and chlorobutanol.
The colorant comprises one or more of carmine pigment, bright melanin, lemon yellow and iron oxide red.
The content comprises 0.1-0.5 part of calcitriol, 1-3 parts of antioxidant and 300 parts of solvent 150-.
The capsule shell comprises, by weight, 1000 parts of gelling agent 500-.
The invention has the beneficial effects that:
the invention designs a brand-new calcitriol soft capsule formula, researches on antioxidant and plasticizer, wherein the screened antioxidant formula comprises butyl anisole, dibutyl hydroxy toluene and propyl gallate, and the plasticizer formula comprises glycerol and stearic acid. Under the formula, the calcitriol can exist stably, and related substances are controlled within a reasonable range, so that a novel calcitriol soft capsule with stable quality is provided.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
EXAMPLE 1 Effect of antioxidants on calcitriol Soft Capsule stability study
Soybean oil, caprylic/capric polyethylene glycol glyceride and polyethylene glycol ether are selected as solvents, contents of calcitriol soft capsules are prepared according to the formula shown in table 1, soft capsules are prepared by using capsules containing 0.1 g/capsule of gelatin, 0.05 g/capsule of glycerin, 2000.05 g/capsule of polyethylene glycol, 0.0001 g/capsule of methyl paraben, 0.0001 g/capsule of ethyl paraben and 0.0002 g/capsule of lemon yellow, an acceleration test is carried out, and the detection is carried out by an HPLC method after 1 month, and the results are shown in table 1.
TABLE 1 Effect of antioxidants on calcitriol Soft Capsule stability study Experimental results
Figure GDA0002763789960000031
Figure GDA0002763789960000041
From the above results, it is found that when butyl anisole, tert-butylhydroquinone, dibutylhydroxytoluene and propyl gallate are used as antioxidants, calcitriol soft capsules are superior in stability, and therefore, the combination of these four antioxidants is used as a further optimization screen. The results are shown in Table 2.
TABLE 2 Effect of antioxidants on calcitriol Soft Capsule stability study Experimental results (II)
Figure GDA0002763789960000042
Figure GDA0002763789960000051
From the above results, it was found that the stability of calcitriol soft capsules was the best when butyl anisole, dibutyl hydroxytoluene and propyl gallate were selected as antioxidants.
EXAMPLE 2 study of the Effect of plasticizer on the stability of calcitriol Soft capsules
Soybean oil, caprylic/capric polyethylene glycol glyceride and polyethylene glycol ether were selected as solvents, butyl anisole, dibutyl hydroxy toluene and propyl gallate were selected as antioxidants, contents of calcitriol soft capsules were prepared according to the formulation of Table 1, soft capsules were prepared with capsule shells containing 0.1 g/capsule of gelatin, 0.1 g/capsule of antioxidant, 0.0001 g/capsule of methyl paraben, 0.0001 g/capsule of ethyl paraben and 0.0002 g/capsule of lemon yellow, accelerated tests were performed, and the results were determined by HPLC after 1 month as shown in Table 3.
TABLE 3 results of experimental study on the effect of plasticizer on calcitriol soft capsule stability
Figure GDA0002763789960000052
Figure GDA0002763789960000061
From the above results, it was found that the stability of the calcitriol soft capsule was the best when glycerin and stearic acid were selected as plasticizers.
EXAMPLE 3 preparation of calcitriol Soft capsules
Calcitriol soft capsules were prepared according to the formulation of table 4, using soybean oil, caprylic capric acid macrogol glyceride and macrogol ether as solvents, butyl anisole, dibutyl hydroxytoluene and propyl gallate as antioxidants, glycerol and stearic acid as plasticizers.
TABLE 4 calcitriol Soft Capsule formulation
Figure GDA0002763789960000062
Figure GDA0002763789960000071
EXAMPLE 4 calcitriol Soft Capsule influencing factor test
The calcitriol soft capsule of preparation example 1 was placed under high temperature (40 ℃), light (4500 ± 500Lx) and low temperature (-18 ℃) conditions, and samples were taken at 5 th and 10 th days, and the results of the stability test were examined for each index, and are shown in table 5.
TABLE 5 calcitriol Soft Capsule Effect factor test results
Figure GDA0002763789960000072
Figure GDA0002763789960000081
According to the results, the results of the calcitriol soft capsule influence factor test meet the requirements.
Example 5 calcitriol Soft Capsule acceleration test
The calcitriol soft capsules prepared in preparation examples 1 to 3 were placed at 40 ℃ and RH 75%, and sampled at 0 th, 1 th, 2 th and 3 rd months, respectively, to test each examination index of the stability test. The results are shown in Table 6.
TABLE 6 results of calcitriol soft capsule acceleration test
Figure GDA0002763789960000082
According to the results, the results of the accelerated test of the calcitriol soft capsule meet the requirements.
Example 6 calcitriol Soft Capsule Room temperature Long-term sample Retention test
The calcitriol soft capsules prepared in preparation examples 1 to 3 are placed at room temperature, samples are taken at 0 th month and 3 rd month respectively, and various investigation indexes of a stability test are detected. The results are shown in Table 7.
TABLE 7 results of the calcitriol soft capsule long-term sample retention at room temperature
Figure GDA0002763789960000083
Figure GDA0002763789960000091
According to the results, the results of the room-temperature long-term sample retention test of the calcitriol soft capsule meet the requirements.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.

Claims (11)

1. The calcitriol soft capsule is characterized by consisting of contents and a capsule shell, wherein the contents comprise calcitriol, an antioxidant and a solvent, the capsule shell comprises a gelling agent, a plasticizer, a preservative, a colorant and water, and the antioxidant comprises butyl anisole, dibutyl hydroxy toluene and propyl gallate.
2. Calcitriol soft capsule according to claim 1, characterized in that the solvent comprises soybean oil, caprylic capric macrogol glyceride and polyethylene glycol ether.
3. The calcitriol soft capsule according to claim 2, wherein the antioxidant comprises, in parts by weight, butyl anisole 0.5-1 parts, dibutyl hydroxytoluene 0.3-0.6 parts, and propyl gallate 0.1-0.8 parts.
4. The calcitriol soft capsule according to claim 2, wherein the solvent comprises 50-100 parts by weight of soybean oil, 30-60 parts by weight of caprylic capric polyglycol glyceride and 40-80 parts by weight of polyethylene glycol ether.
5. The calcitriol soft capsule according to claim 1, wherein the gelling agent comprises one or more of acacia gum, gelatin, carrageenan, xanthan gum, gellan gum and konjac gum.
6. The calcitriol soft capsule according to claim 1, characterized in that the plasticizer comprises one or more of glycerol, sorbitol, polyethylene glycol 200, polyethylene glycol 400 and stearic acid.
7. Calcitriol soft capsule according to claim 6, characterized in that the plasticizer comprises glycerol and stearic acid.
8. Calcitriol soft capsule according to claim 1, characterized in that the preservative is selected from one or more of methyl paraben, ethyl paraben, phenylethyl alcohol and chlorobutanol.
9. Calcitriol soft capsule according to claim 1, characterized in that the colorant is selected from one or more of carmine, brilliant melanin, lemon yellow and iron oxide red.
10. The calcitriol soft capsule according to claim 1, wherein the content comprises 0.1-0.5 parts of calcitriol, 1-3 parts of antioxidant and 300 parts of solvent 150-.
11. The calcitriol soft capsule according to claim 1, wherein the capsule shell comprises, by weight, 500-1000 parts of gelling agent, 500-500 parts of plasticizer, 0.1-0.5 part of preservative, 0.5-2 parts of colorant and 1000 parts of water.
CN201811412695.9A 2018-11-26 2018-11-26 Calcitriol soft capsule Active CN109276556B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811412695.9A CN109276556B (en) 2018-11-26 2018-11-26 Calcitriol soft capsule

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811412695.9A CN109276556B (en) 2018-11-26 2018-11-26 Calcitriol soft capsule

Publications (2)

Publication Number Publication Date
CN109276556A CN109276556A (en) 2019-01-29
CN109276556B true CN109276556B (en) 2021-02-19

Family

ID=65172657

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811412695.9A Active CN109276556B (en) 2018-11-26 2018-11-26 Calcitriol soft capsule

Country Status (1)

Country Link
CN (1) CN109276556B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114948894A (en) * 2022-05-07 2022-08-30 正大制药（青岛）有限公司 Soft capsule with calcitriol component and preparation method thereof
CN116585284B (en) * 2023-06-13 2024-03-19 常州市武进人民医院(常州市第八人民医院) Calcitriol soft capsule, preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007916A1 (en) * 2001-07-17 2003-01-30 Teva Pharmaceutical Industries Ltd. Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate
CN103784419A (en) * 2012-10-31 2014-05-14 成都国弘医药有限公司 Softgel containing calcitriol and preparation method
CN105362249A (en) * 2014-08-07 2016-03-02 西藏通泰医药有限公司 Calcitriol capsule type drop and preparation method thereof
CN106265586A (en) * 2015-05-26 2017-01-04 郑州泰丰制药有限公司 A kind of preparation method of calcitriol soft capsule preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007916A1 (en) * 2001-07-17 2003-01-30 Teva Pharmaceutical Industries Ltd. Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate
CN103784419A (en) * 2012-10-31 2014-05-14 成都国弘医药有限公司 Softgel containing calcitriol and preparation method
CN105362249A (en) * 2014-08-07 2016-03-02 西藏通泰医药有限公司 Calcitriol capsule type drop and preparation method thereof
CN106265586A (en) * 2015-05-26 2017-01-04 郑州泰丰制药有限公司 A kind of preparation method of calcitriol soft capsule preparation

Also Published As

Publication number Publication date
CN109276556A (en) 2019-01-29

Similar Documents

Publication Publication Date Title
US20080305163A1 (en) Butylphthalide soft gel capsule and its preparation procedure
EP4035657A1 (en) Drug composition containing abiraterone acetate, and preparation method therefor and application thereof
CN109276556B (en) Calcitriol soft capsule
CN108697668A (en) Medical component and application thereof for reducing local fat
CN109745330B (en) Preparation of vitamin D by oleanolic acid and ursolic acid3Use of drugs with metabolic enzyme activity
ES2864153T3 (en) New crystal form of dapagliflozin and method of preparation and use of the same
CN100594894C (en) New formulation for retinoid-containing soft gelatin capsules
CN110755401B (en) Curcumin piperine preparation, preparation method and application thereof
CN109481414B (en) Adeladol soft capsule
JP2001527573A (en) Carotenoid preparation
CN105687207A (en) Ointment for treating dermatitis and eczema and preparation method thereof
CN101439083A (en) Chinese medicine soft capsules for clearing wind heat and clearing nasal passage, as well as preparation method and quality control method
CN113559112B (en) Preparation method and application of NMN-containing composition
CN111214453B (en) Alfacalcidol soft capsule and preparation method thereof
CN110934847A (en) Preparation method of eldecalcitol soft capsule
CN103054830B (en) Soft capsule for treating nerve diseases
CN107875134A (en) paricalcitol liquid hard capsule and preparation method thereof
CN112121006A (en) Vitamin ADE composition for injection livestock and preparation method thereof
CN109316454B (en) Calcitriol preparation
CN109260209B (en) Calcitriol soft capsule and preparation method thereof
CN111529488A (en) Progesterone self-emulsifying composition and application thereof
CN111544406A (en) Parricalcitol oral preparation
JPH054925A (en) Soft capsule preparation of alpha calcidiol
CN106619560B (en) Polyene phosphatidyl choline capsule and preparation process thereof
CN109091482A (en) A kind of paste for papular urticaria

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