CN106236732A - A kind of preparation method of everolimus soft capsule - Google Patents
A kind of preparation method of everolimus soft capsule Download PDFInfo
- Publication number
- CN106236732A CN106236732A CN201610769371.5A CN201610769371A CN106236732A CN 106236732 A CN106236732 A CN 106236732A CN 201610769371 A CN201610769371 A CN 201610769371A CN 106236732 A CN106236732 A CN 106236732A
- Authority
- CN
- China
- Prior art keywords
- parts
- everolimus
- soft capsule
- utricule
- acid
- 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.)
- Pending
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
Abstract
The present invention relates to the preparation method of a kind of everolimus soft capsule.Step: with gelatin, stearic acid, soybean protein, glycerol and pure water for utricule raw material, makes and obtains utricule；The content being uniformly mixed according to prescription；By content and utricule through pelleting, shape, wash ball, be dried, pick ball and subpackage step, prepare soft capsule.The everolimus soft capsule that the present invention prepares has good stability, the advantage that character is stable.The treatment tumor of the present invention, the drug regimen of immunosuppressant, reasonable mixture ratio, with rapid delivery of pharmaceuticals, described disease can be produced good curative effect.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to the preparation method of a kind of everolimus soft capsule.
Everolimus (Everolimus), chemical name: 40-O-(2-ethoxy)-rapamycin, molecular formula:
C53H83NO14, molecular weight: 958.2244.It is three kind new medicines for treating tumor, immunosuppressant, currently faces
Research before bed.
Background technology
Everolimus is mainly used to the rejection after preventing renal transplantation and heart transplant operation clinically.Its mechanism of action
Mainly include immunosuppressive action, antitumor action, antivirus action, vascular protection effect.Often other are immune with ciclosporin etc.
Inhibitor is used in combination to reduce toxicity.
Compared with sirolimus, the pharmacokinetics of everolimus is more superior.
Everolimus is developed at first by Novartis Co., Ltd of Switzerland (Novartis), has the dosage form such as tablet and dispersible tablet.Business
Name of an article Certican.Within 2003, list in Sweden first, captured European market in 2006 the most comprehensively.
Everolimus (Everolimus) is a kind of Macrocyclolactone lactone kind medicine, and structure belongs to rapamycin
(rapamycin) derivant, therefore it is also called 40-O-(2-ethoxy)-rapamycin, functionally it belongs to mTOR kinase inhibition
Agent, mechanism of action is mainly combined formation suppression complex, thus suppresses the kinase whose work of mTOR with intracellular protein FKBP-12
Property, reduce downstream effect thing S6 ribosomal protein kinases (S6K1) and eukaryotic elongation factor 4E associated proteins (4E-BP) of mTOR
Activity, disturb the growth of cancerous cell, differentiation and metabolism, play Graft Versus Tumor.Research display, everolimus has immunity to be pressed down
Make use, antitumor action, antivirus action, vascular protection effect etc..At present, everolimus is mainly used to prevention and has clinically
Light moderate immune repels the rejection of the renal transplantation of kidney transplant patients's appearance of risk, and for Sutent or rope
The advanced renal cell cancer patient that La Feini fails to respond to any medical treatment.Additionally, everolimus amounts to 6 indications (late period mammary gland the U.S. is the most granted
Cancer, endocrine tumors, renal cell carcinoma, renal angiomyolipoma and tuberous sclerosis).
Additionally, except renal cell carcinoma, everolimus is the most being carried out neuroendocrine tumor, lymphoma, other cancers
And the research of tuberous sclerosis, can share as unitary agent or with existing cancer treatment method.As research medicine
Thing, the safety of everolimus and effectiveness also do not completely set up at tumor area, be in now strict control and
The clinical experimental stage that monitoring is carried out.The design of these tests is to be more fully understood that the potential benefit of this compound and phase
The risk answered.Due to the uncertainty of clinical trial, can't guarantee now that everolimus can be as the medicine of tumor indication
Product commercial sale in the world.
[patent and the market analysis] everolimus compound and formulation patent thereof are expired in 2016, domestic declare a number relatively
Few, there is synthetic technology barrier in crude drug.Everolimus approved is used for advanced breast cancer, endocrine tumors, renal cell carcinoma, kidney
Angiomyolipoma and tuberous sclerosis etc..Follow-up also at other indications of continual exploitation, application prospect is widely.2010
Year, the sales volume of this medicine was 297.1 million dollars, and 2011 annual sales amounts are 492.4 million dollars.Sales volume increases very fast, it was predicted that
Prospect is preferable.
Summary of the invention
It is an object of the invention to: the preparation method of the everolimus soft capsule of a kind of good stability is provided, mainly passes through
Add stability component and realize above-mentioned purpose.
Technical scheme is:
The preparation method of a kind of everolimus soft capsule, comprises the steps:
1st step, makes utricule: by weight, with gelatin 15～25 parts, stearic acid 3～6 parts, soybean protein 2～3 parts, glycerol
10～25 parts is utricule raw material with pure water 10～15 parts, injects in glue pot by glycerol and pure water, and heated and stirred adds bright
Glue, stearic acid and soybean protein, continue the final vacuum deaeration that stirs, and makes and obtains utricule；
2nd step: preparation content: by weight, by soybean oil 30～90 parts, unsaturated fatty acid 4～9 parts, everolimus 1
～5 parts and glycerol 5～20 parts mix, cross colloid mill, the content being uniformly mixed；
3rd step: the content that the 2nd step is obtained and the 1st step obtain utricule through pelleting, shape, wash ball, be dried, pick ball and point
Dress step, prepares everolimus soft capsule.
In the 1st described step, the temperature of agitating heating is 60～70 DEG C.
In the 2nd described step, unsaturated fatty acid is selected from docosahexenoic acid, eicosapentaenoic acid, fish oil, Semen Lini
Oil, borage oil, alpha-linolenic acid, gamma-Linolenic acid, conjugated linoleic acid or Saw Palmetto P.E.
In the 2nd described step, the temperature 50 during mixing～70 DEG C, incorporation time 20～40min, the number of times crossing colloid mill is
1～3 time.
The everolimus soft capsule that the present invention prepares has good stability, the advantage that character is stable.
Detailed description of the invention
The content of the soft capsule of the present invention, in addition to the above-mentioned components, according to actual application needs, it is also possible to comprise it
Its additive component, described additive component can comprise other components of one or more applicable foods.These include
Antioxidant, emulsifying agent, preservative, sweeting agent, essence, pH adjusting agent etc..Additive component is mixed with compositions mixed
Weight percentage ranges shared by compound can be maximum 89wt%, such as 10～89wt%, more preferably 20～75wt%.
Antioxidant can use tocopherols such as alpha-tocopherol, alpha-tocopherol cetylate, alpha-tocopherol acetate,
Tert-butyl hydroxy toluene, butylhydroxy anisole, ascorbic acid, its salt and ester, such as sodium ascorbate, calcium ascorbate,
Vitamin C acyl phosphate ester, the fatty acid ester such as Vitamin C acyl stearate of ascorbic acid and Vitamin C acyl cetylate and ethoxy
Base quinoline.
The fatty acid ester such as Vitamin C acyl Petiolus Trachycarpi of the example of emulsifying agent especially lipophile dispersant, e.g. ascorbic acid
Acid esters, polyglyceryl fatty acid ester such as polyglycereol-3-polyricinoleate, fatty acid esters of sorbitan, especially anhydrosorbitol
Alcohol C10～C28 fatty acid ester.
As pH adjusting agent, can be included in the preparation compositions of the present invention to improve or reduce the preparation group of the present invention
The pH of compound.The pH of described preparation compositions can be lowered or improve, the effect perceived for sense organ, or is used for improving physics and chemistry
Characteristic, such as, increase the dissolubility of the compound of dissolving.PH adjusting agent may refer to acidulant or basifier.Such as, lactic acid, lemon
Lemon acid, malic acid, potassium hydroxide, calcium hydroxide and magnesium hydroxide.
Preservative, the non-limiting example that can be optionally included in the preservative in the preparation compositions of the present invention includes:
Acetic acid, citric acid, benzoic acid, sorbic acid, sulfur dioxide, Potassium Benzoate, potassium sorbate.
As essence, oils and fats essence and the powdered flavors such as one kind or two or more natural essence, compound essence are preferably used, but
It is not particularly limited.Such as, wintergreen oil, Oleum Cinnamomi, menthol oil, oleum menthae viridis, lime oil, Oleum lavandula angustifolia, Fructus Fragariae Ananssae oil, chinese cymbidium
Ketone.
As sweeting agent, preferably commonly use sweeting agent, such as, select at least from maltose alcohol, sucrose, glucose, glucosan
1 kind.
Embodiment 1
The preparation method of everolimus soft capsule, step:
1st step, makes utricule: by weight, with 15 parts of gelatin, stearic acid 3 parts, soybean protein 2 parts, glycerol 10 parts and pure water
10 parts is utricule raw material, injects in glue pot by glycerol and pure water, and 60 DEG C of heated and stirred add gelatin, stearic acid and Semen sojae atricolor
Albumen, continues the final vacuum deaeration that stirs, and makes and obtains utricule；
2nd step: preparation content: by weight, by soybean oil 85 parts, gamma-Linolenic acid 4 parts, everolimus 1 part and glycerol
20 parts mix at 50 DEG C, incorporation time 20min, cross colloid mill 3 times, the content being uniformly mixed；
3rd step: the content that the 2nd step is obtained and the 1st step obtain utricule through pelleting, shape, wash ball, be dried, pick ball and point
Dress step, prepares everolimus soft capsule.
Embodiment 2
The preparation method of everolimus soft capsule, step:
1st step, makes utricule: by weight, with 25 parts of gelatin, stearic acid 6 parts, soybean protein 3 parts, glycerol 25 parts and pure water
15 parts is utricule raw material, injects in glue pot by glycerol and pure water, and 70 DEG C of heated and stirred add gelatin, stearic acid and Semen sojae atricolor
Albumen, continues the final vacuum deaeration that stirs, and makes and obtains utricule；
2nd step: preparation content: by weight, by soybean oil 85 parts, gamma-Linolenic acid 4 parts, everolimus 1 part and glycerol
20 parts mix at 50 DEG C, incorporation time 20min, cross colloid mill 3 times, the content being uniformly mixed；
3rd step: the content that the 2nd step is obtained and the 1st step obtain utricule through pelleting, shape, wash ball, be dried, pick ball and point
Dress step, prepares everolimus soft capsule.
Embodiment 3
The preparation method of everolimus soft capsule, step:
1st step, makes utricule: by weight, with 20 parts of gelatin, stearic acid 5 parts, soybean protein 3 parts, glycerol 20 parts and pure water
12 parts is utricule raw material, injects in glue pot by glycerol and pure water, and 65 DEG C of heated and stirred add gelatin, stearic acid and Semen sojae atricolor
Albumen, continues the final vacuum deaeration that stirs, and makes and obtains utricule；
2nd step: preparation content: by weight, by soybean oil 90 parts, gamma-Linolenic acid 4 parts, everolimus 1 part and glycerol
15 parts mix at 50 DEG C, incorporation time 20min, cross colloid mill 3 times, the content being uniformly mixed；
3rd step: the content that the 2nd step is obtained and the 1st step obtain utricule through pelleting, shape, wash ball, be dried, pick ball and point
Dress step, prepares everolimus soft capsule.
Embodiment 4
The preparation method of everolimus soft capsule, step:
1st step, makes utricule: by weight, with 20 parts of gelatin, stearic acid 5 parts, soybean protein 3 parts, glycerol 20 parts and pure water
12 parts is utricule raw material, injects in glue pot by glycerol and pure water, and 65 DEG C of heated and stirred add gelatin, stearic acid and Semen sojae atricolor
Albumen, continues the final vacuum deaeration that stirs, and makes and obtains utricule；
2nd step: preparation content: by weight, by soybean oil 90 parts, gamma-Linolenic acid 4 parts, everolimus 1 part and glycerol
15 parts mix at 50 DEG C, incorporation time 20min, cross colloid mill 3 times, the content being uniformly mixed；
3rd step: the content that the 2nd step is obtained and the 1st step obtain utricule through pelleting, shape, wash ball, be dried, pick ball and point
Dress step, prepares everolimus soft capsule.
Claims (4)
1. the preparation method of an everolimus soft capsule, it is characterised in that comprise the steps:
1st step, makes utricule: by weight, with gelatin 15～25 parts, stearic acid 0～6 parts, soybean protein 0～3 parts, glycerol
10～25 parts is utricule raw material with pure water 10～15 parts, injects in glue pot by glycerol and pure water, and heated and stirred adds bright
Glue, stearic acid and soybean protein, continue the final vacuum deaeration that stirs, and makes and obtains utricule；
2nd step: by weight, by soybean oil 30～90 parts, unsaturated fatty acid 4～9 parts, everolimus 1～5 parts and glycerol
5～20 parts mix, and cross colloid mill, the content being uniformly mixed；
3rd step: the content that the 2nd step is obtained and the 1st step obtain utricule through pelleting, shape, wash ball, be dried, pick ball and point
Dress step, prepares everolimus soft capsule.
The preparation method of everolimus soft capsule the most according to claim 1, it is characterised in that: in the 1st described step, stir
The temperature mixing heating is 60～70 DEG C.
The preparation method of everolimus soft capsule the most according to claim 1, it is characterised in that: in the 2nd described step, no
Satisfied fatty acid selected from docosahexenoic acid, eicosapentaenoic acid, fish oil, Semen Lini oil, borage oil, alpha-linolenic acid, γ-
Linolenic acid, conjugated linoleic acid or Saw Palmetto P.E.
The preparation method of everolimus soft capsule the most according to claim 1, it is characterised in that: in the 2nd described step, mixed
Temperature 50 during conjunction～70 DEG C, incorporation time 20～40min, the number of times crossing colloid mill is 1～3 time.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610769371.5A CN106236732A (en) | 2016-08-31 | 2016-08-31 | A kind of preparation method of everolimus soft capsule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610769371.5A CN106236732A (en) | 2016-08-31 | 2016-08-31 | A kind of preparation method of everolimus soft capsule |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106236732A true CN106236732A (en) | 2016-12-21 |
Family
ID=58080470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610769371.5A Pending CN106236732A (en) | 2016-08-31 | 2016-08-31 | A kind of preparation method of everolimus soft capsule |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106236732A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1919194A (en) * | 2006-08-17 | 2007-02-28 | 刘瑜玲 | Liquid composition of sirolimus |
| CN101416953A (en) * | 2007-10-23 | 2009-04-29 | 江苏信孚药业有限公司 | Tacrolimus soft capsules and preparation method thereof |
| CN102770129A (en) * | 2009-10-30 | 2012-11-07 | 阿里亚德医药股份有限公司 | Methods and compositions for treating cance |
| CN105476011A (en) * | 2015-12-27 | 2016-04-13 | 刘家容 | Preparing method of lycopene soft capsule |
-
2016
- 2016-08-31 CN CN201610769371.5A patent/CN106236732A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1919194A (en) * | 2006-08-17 | 2007-02-28 | 刘瑜玲 | Liquid composition of sirolimus |
| CN101416953A (en) * | 2007-10-23 | 2009-04-29 | 江苏信孚药业有限公司 | Tacrolimus soft capsules and preparation method thereof |
| CN102770129A (en) * | 2009-10-30 | 2012-11-07 | 阿里亚德医药股份有限公司 | Methods and compositions for treating cance |
| CN105476011A (en) * | 2015-12-27 | 2016-04-13 | 刘家容 | Preparing method of lycopene soft capsule |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101716878B1 (en) | Pharmaceutical Capsule Composite Formulation of Dutasteride and Tadalafill Comprising Glycerol Fatty Acid Ester Derivative or Propylene Glycol Fatty Acid Ester Derivative And Method For Preparation thereof | |
| CN109475492A (en) | Treatment of solid tumor method | |
| RU2015144285A (en) | COMPOSITION BASED ON ACETATE ABIATERON | |
| CN104224711B (en) | Paclitaxel submicron emulsion taking steroid compound as intermediate vector | |
| TW201707685A (en) | A pharmaceutical composition for reducing local fat and uses thereof | |
| Zheng et al. | Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo | |
| CN107308111A (en) | One kind contains in olive oil/long chain fat emulsion injection and preparation method thereof | |
| JP2018515484A (en) | Cabazitaxel fat emulsion injection, preparation method thereof and use thereof | |
| TW201204350A (en) | Non-aqueous taxane pro-emulsion formulations and methods of making and using the same | |
| Wang et al. | In vitro and in vivo evaluation of drug-eluting microspheres designed for transarterial chemoembolization therapy | |
| CN105434331B (en) | A kind of self-emulsifying Co-Q10 finish and its preparation method and application | |
| JP6521274B2 (en) | Pharmaceutical composition for oral administration comprising taxane | |
| CA3148455A1 (en) | Solubilizate with curcumin and optionally at least one other active substance | |
| Fu et al. | Chemo-immune synergetic therapy of esophageal carcinoma: trastuzumab modified, cisplatin and fluorouracil co-delivered lipid–polymer hybrid nanoparticles | |
| JP2019513812A (en) | Chemotherapy improvement | |
| WO2022160970A1 (en) | Concentrated solution of insoluble drug not containing ethanol, and micellar solution prepared therefrom | |
| Yu et al. | Polymeric nanoparticles encapsulating α-mangostin inhibit the growth and metastasis in colorectal cancer | |
| Shikanov et al. | Efficacy of poly (sebacic acid‐co‐ricinoleic acid) biodegradable delivery system for intratumoral delivery of paclitaxel | |
| CN106236732A (en) | A kind of preparation method of everolimus soft capsule | |
| CN102940630A (en) | Medicinal composition containing temsirolimus and preparation method of medicinal composition | |
| Song et al. | characterization and in vivo evaluation of novel lipid–chlorambucil nanospheres prepared using a mixture of emulsifiers for parenteral administration | |
| CN101632635A (en) | Antitumor emulsion and preparation method thereof | |
| CN107648307B (en) | Composition, preparation method and application thereof | |
| WO2021003890A1 (en) | Method for preparing tetrodotoxin esterified product | |
| JP2017214335A (en) | Coenzyme q10 composition and soft capsule that is filled with the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20161221 |
|
| WD01 | Invention patent application deemed withdrawn after publication |