CN106511265A - Oral solution containing itraconazole and preparation process of oral solution - Google Patents
Oral solution containing itraconazole and preparation process of oral solution Download PDFInfo
- Publication number
- CN106511265A CN106511265A CN201611007893.8A CN201611007893A CN106511265A CN 106511265 A CN106511265 A CN 106511265A CN 201611007893 A CN201611007893 A CN 201611007893A CN 106511265 A CN106511265 A CN 106511265A
- Authority
- CN
- China
- Prior art keywords
- itraconazole
- soluplus
- liquid
- oral solution
- solid dispersion
- 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
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Classifications
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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
- A61K9/08—Solutions
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Abstract
The invention discloses a preparation process of an oral solution containing itraconazole. The oral solution contains solid dispersion prepared by adopting itraconazole-Soluplus<*>(polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer), and other pharmaceutically acceptable auxiliary materials, and is prepared by adopting the solid dispersion technology, the bioavailability of the oral solution containing itraconazole can be effectively improved, the oral solution can be used for treating various fungal infections, and the process is simple and convenient, and suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of raising Itraconazole dissolubility in the solution and
The preparation method of its oral liquid.
Background technology
Entitled 4- [4- [4- [4- [[cis-2- (the 2,4 dichloro benzene base) -2- (1H-1,2,4- triazole -1- of Itraconazole chemistry
Ylmethyl) -1,3- dioxolanes -4- bases] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2- [(1RS) -1- methyl-propyls] -
1,2,4- triazole -3- ketone, English name is Itraconazole, is triazole type broad-spectrum antifungal medicine.In vitro study is
Show, its mechanism of action is that height selects interference fungal cytochrome P450 active, suppresses Cytochrome P450 dependency Ergota
The synthesis of sterol (important component part of fungal cell membrane), makes fungal cell's membrane damage, so as to cause cell death, to superficial
Funguses and the determined curative effect of deep mycosiies.The lipotropy of Itraconazole so as to which the dissolubility in water is poor, affects which biological
Availability, has a strong impact on therapeutic effect, and then hinders clinical practice.
Itraconazole is the antifungal type medicine that JANSSEN companies develop first, trade name SPORANOX® 1992 9
The moon lists capsule in the U.S. first, and specification is 100mg, and it is hard gelatin capsule that original grinds non-active ingredient in prescription composition, hydroxypropyl first
Cellulose, Polyethylene Glycol（PEG）20,000, titanium dioxide, FD＆C Blue No. 1, FD＆C Blue No. 2, D＆C, Red
No. 22 and D＆C Red No. 28, sugar ball includes sucrose, corn starch and purified water.Mouth is listed in the U.S. within 2 months 1997
Liquid is taken, and specification is 10mg/mL, injection is listed in the U.S. within 1999, and specification is 10mg/mL, is listed in Japan and other countries in addition,
Listing dosage form includes oral liquid, injection, piller, granule, capsule, dispersible tablet.Clinically it is used for treating the immunity of fungal infection
Hypofunction and nonimmunologic function immunocompromised patients.The itraconazole of Xi'an Yang Sen is listed for 2015 at home, and specification is
100mg, trade name itraconazole®.Domestic Chengdu Brilliant Pharmaceutical Co., Ltd. lists capsule in 2015 at home, and specification is
100mg, trade name easily open health®。
Itraconazole is practically insoluble in water, and bioavailability is relatively low, affects therapeutic effect.102362855 A of patent CN and
A kind of Itraconazole isomer oral liquid is disclosed in 102670490 A of CN, by the use of cyclodextrin or its derivant as increasing
Solvent, reaches the effect for improving Itraconazole dissolubility and bioavailability, but technique described in 102362855 A of CN is more
Complexity, and the chemical reagent such as concentrated hydrochloric acid are used in preparation process, it is unfavorable for industrialized production；102670490 A medium ring of CN is pasted
Smart scope is 30 ~ 60g/150mL, and large usage quantity is relatively costly.
The content of the invention
It is an object of the invention to provide the oral solution that a kind of process is simple, dissolubility are high, bioavailability is high.This
Invention relate to a kind of using graft copolymer Soluplus®Solid dispersion is prepared into Itraconazole, it is molten in raising preparation
The method of solution property.It is characterized in that containing Itraconazole-Soluplus®Made by solid dispersion, in addition with preservative, rectify
Taste agent and pH adjusting agent.Crude drug Itraconazole was crushed into 200 mesh sieves first, by Soluplus®It is placed in oil bath and treats which is complete
Itraconazole, stirring and dissolving is added to pour in culture dish after melting, ice bath is vacuum dried to being fully cured, and is crushed, and crosses 80 mesh
Sieve, obtains Itraconazole-Soluplus®Solid dispersion, wherein Itraconazole and Soluplus®Weight ratio be 1：1-1：
10, preferably 1：4-1：6；Oil bath temperature is 110-150 DEG C, preferably 130 DEG C；After adding Itraconazole, mixing time is 10-
50min, preferred 30min.By Itraconazole-Soluplus®Solid dispersion is dissolved as liquid I, and preservative is dissolved as liquid II, its
Middle preservative is parabenses, benzoic acid, one or more in sorbic acid, preferred benzoic acid and sorbic acid.Will
Liquid II and correctivess add liquid I, stir, and adjust pH, and constant volume, wherein correctivess are aspartame, acesulfame potassium, minty note
One or more in essence, Mentholum, saccharin sodium, stevioside, vanilla, cherry essence, preferred saccharin sodium and cherry essence,
PH adjusting agent is sodium hydroxide or hydrochloric acid.
Specific embodiment
Following examples further describe beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, do not limit this
The scope of invention, while those of ordinary skill in the art are also contained according to the obvious change made of the invention and modification
Within the scope of the invention.
（One）The preparation of oral liquid
Embodiment 1
Preparation technology
Itraconazole was crushed into 200 mesh sieves, by recipe quantity Soluplus®It is placed in 110 DEG C of oil baths, adds after which melts completely
Enter Itraconazole, stirring 10min dissolvings are poured in culture dish, and ice bath is vacuum dried to being fully cured, and is crushed, and crosses 80 mesh sieves,
Obtain Itraconazole-Soluplus®Solid dispersion；By Itraconazole-Soluplus®During solid dispersion adds a certain amount of water
It is dissolved as liquid I；Preservative is dissolved as into liquid II；Liquid II and correctivess are being added into liquid I, is being stirred, is adjusted pH, constant volume
100mL。
Embodiment 2
Preparation technology
Itraconazole was crushed into 200 mesh sieves, by recipe quantity Soluplus®It is placed in 150 DEG C of oil baths, adds after which melts completely
Enter Itraconazole, stirring 50min dissolvings are poured in culture dish, and ice bath is vacuum dried to being fully cured, and is crushed, and crosses 80 mesh sieves,
Obtain Itraconazole-Soluplus®Solid dispersion；By Itraconazole-Soluplus®During solid dispersion adds a certain amount of water
It is dissolved as liquid I；Preservative is dissolved as into liquid II；Liquid II and correctivess are being added into liquid I, is being stirred, is adjusted pH, constant volume
100mL。
Embodiment 3
Preparation technology
Itraconazole was crushed into 200 mesh sieves, by recipe quantity Soluplus®It is placed in 110 DEG C of oil baths, adds after which melts completely
Enter Itraconazole, stirring 10min dissolvings are poured in culture dish, and ice bath is vacuum dried to being fully cured, and is crushed, and crosses 80 mesh sieves,
Obtain Itraconazole-Soluplus®Solid dispersion；By Itraconazole-Soluplus®During solid dispersion adds a certain amount of water
It is dissolved as liquid I；Preservative is dissolved as into liquid II；Liquid II and correctivess are being added into liquid I, is being stirred, is adjusted pH, constant volume
100mL。
Embodiment 4
Preparation technology
Itraconazole was crushed into 200 mesh sieves, by recipe quantity Soluplus®It is placed in 150 DEG C of oil baths, adds after which melts completely
Enter Itraconazole, stirring 50min dissolvings are poured in culture dish, and ice bath is vacuum dried to being fully cured, and is crushed, and crosses 80 mesh sieves,
Obtain Itraconazole-Soluplus®Solid dispersion；By Itraconazole-Soluplus®During solid dispersion adds a certain amount of water
It is dissolved as liquid I；Preservative is dissolved as into liquid II；Liquid II and correctivess are being added into liquid I, is being stirred, is adjusted pH, constant volume
100mL。
Embodiment 5
Preparation technology
Itraconazole was crushed into 200 mesh sieves, by recipe quantity Soluplus®It is placed in 130 DEG C of oil baths, adds after which melts completely
Enter Itraconazole, stirring 30min dissolvings are poured in culture dish, and ice bath is vacuum dried to being fully cured, and is crushed, and crosses 80 mesh sieves,
Obtain Itraconazole-Soluplus®Solid dispersion；By Itraconazole-Soluplus®During solid dispersion adds a certain amount of water
It is dissolved as liquid I；Preservative is dissolved as into liquid II；Liquid II and correctivess are being added into liquid I, is being stirred, is adjusted pH, constant volume
100mL。
Comparative example
Preparation technology
Itraconazole is added and in a certain amount of water, is dissolved as liquid I；Preservative is dissolved as into liquid II；Liquid II and correctivess are being added
Liquid I, stirs, and adjusts pH, constant volume 100mL.
（Two）Criteria of quality evaluation
Each oral administration solution 10mL is taken, is centrifuged（4000rpm）10min, takes supernatant and is diluted to suitable concentration, using ultraviolet spectrometry
Absorbance at photometer measuring method detection 255nm, calculates principal agent concentration in sample according to standard curve.
By the comparison of comparative example and embodiment 1 ~ 5, by Itraconazole using the side directly dissolved in water
Formula, is unfavorable for the dissolving of medicine, by Itraconazole and Soluplus®Dissolubility after being prepared into solid dispersion in water has very
Big improvement, method are easy, it is easy to accomplish big to produce.
Embodiment described above is only to absolutely prove the present invention and the preferred embodiment lifted, the protection model of the present invention
Enclose not limited to this.Equivalent substitute or conversion that those skilled in the art are made on the basis of the present invention, in the present invention
Protection domain within.Protection scope of the present invention is defined by claims.
Claims (8)
1. a kind of preparation technology of Itraconazole oral solution, it is characterised in that：Containing Itraconazole-Soluplus®Made by
Solid dispersion, in addition with preservative, correctivess and pH adjusting agent.
2. according to claim 1：Itraconazole and Soluplus®Weight ratio be 1：1-1：10, preferably 1:4-1:6.
3. according to claim 1：Itraconazole-Soluplus®The preparation method of solid dispersion is by recipe quantity
Soluplus®It is placed in oil bath, after which melts completely, adds Itraconazole, stirring and dissolving to pour in culture dish, ice bath is to complete
All solidstate, vacuum drying are crushed, and cross 80 mesh sieves.
4. according to claim 3, it is characterised in that：Oil bath temperature is 110-150 DEG C, preferably 130 DEG C.
5. according to claim 3, it is characterised in that：After adding Itraconazole, mixing time is 10-50min, preferably
30min。
6. according to claim 1, it is characterised in that：In adding preservative parabenses, benzoic acid, sorbic acid
One or more, preferred benzoic acid, sorbic acid.
7. according to claim 1, it is characterised in that：Add correctivess aspartame, acesulfame potassium, Mint Essence, Mentholum,
One or more in saccharin sodium, stevioside, vanilla, cherry essence, preferred saccharin sodium and cherry essence.
8. according to claim 1, its preparation process is：
（1）By recipe quantity Soluplus®It is placed in oil bath, after which melts completely, adds Itraconazole, stirring and dissolving to pour training into
In foster ware, ice bath is vacuum dried to being fully cured, and is crushed, and is crossed 80 mesh sieves, is obtained Itraconazole-Soluplus®Solid disperses
Body；
（2）By Itraconazole-Soluplus®Solid dispersion is added to the water and is dissolved as liquid I；
（3）Preservative is dissolved as into liquid II；
（4）Liquid II and correctivess are being added into liquid I, is being stirred, is adjusted pH, constant volume.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611007893.8A CN106511265A (en) | 2016-11-16 | 2016-11-16 | Oral solution containing itraconazole and preparation process of oral solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611007893.8A CN106511265A (en) | 2016-11-16 | 2016-11-16 | Oral solution containing itraconazole and preparation process of oral solution |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106511265A true CN106511265A (en) | 2017-03-22 |
Family
ID=58352007
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611007893.8A Pending CN106511265A (en) | 2016-11-16 | 2016-11-16 | Oral solution containing itraconazole and preparation process of oral solution |
Country Status (1)
| Country | Link |
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| CN (1) | CN106511265A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285746A (en) * | 1997-12-31 | 2001-02-28 | 中外制药株式会社 | Method and composition of an oral preparation of itraconazole |
| WO2007047253A2 (en) * | 2005-10-11 | 2007-04-26 | Eastman Chemical Company | Pharmaceutical formulations of cyclodextrins and antifungal azole compounds |
| CN102188365A (en) * | 2011-05-11 | 2011-09-21 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
| CN102458373A (en) * | 2009-05-27 | 2012-05-16 | 株式会社三养生物制药 | Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same |
| CN103230363A (en) * | 2013-03-29 | 2013-08-07 | 湖北凤凰白云山药业有限公司 | Antifungal oral solution |
| CN105126110A (en) * | 2015-07-29 | 2015-12-09 | 中山大学 | Solid dispersion of itraconazole and preparation method and application of solid dispersion |
-
2016
- 2016-11-16 CN CN201611007893.8A patent/CN106511265A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285746A (en) * | 1997-12-31 | 2001-02-28 | 中外制药株式会社 | Method and composition of an oral preparation of itraconazole |
| WO2007047253A2 (en) * | 2005-10-11 | 2007-04-26 | Eastman Chemical Company | Pharmaceutical formulations of cyclodextrins and antifungal azole compounds |
| CN102458373A (en) * | 2009-05-27 | 2012-05-16 | 株式会社三养生物制药 | Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same |
| CN102188365A (en) * | 2011-05-11 | 2011-09-21 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
| CN103230363A (en) * | 2013-03-29 | 2013-08-07 | 湖北凤凰白云山药业有限公司 | Antifungal oral solution |
| CN105126110A (en) * | 2015-07-29 | 2015-12-09 | 中山大学 | Solid dispersion of itraconazole and preparation method and application of solid dispersion |
Non-Patent Citations (2)
| Title |
|---|
| 刘平等: "《中医药科学研究思路与方法》", 31 October 2006, 上海中医药大学出版社 * |
| 郭慧玲等: "《药剂学》", 28 February 2014, 中山大学出版社 * |
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Application publication date: 20170322 |