CN104586759A - Non-alkaline ganciclovir injection and preparation method thereof - Google Patents
Non-alkaline ganciclovir injection and preparation method thereof Download PDFInfo
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- CN104586759A CN104586759A CN201510038721.6A CN201510038721A CN104586759A CN 104586759 A CN104586759 A CN 104586759A CN 201510038721 A CN201510038721 A CN 201510038721A CN 104586759 A CN104586759 A CN 104586759A
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Abstract
The invention relates to a non-alkaline ganciclovir injection and a preparation method thereof. The pH value of the product solution is 7.4+/-0.4. The injection is prepared from 2-5 parts of ganciclovir, 2-25 parts of sulfobutyl ether-beta-cyclodextrin, 50-200 parts of water for injection and a proper amount of other additives. The preparation method comprises the following steps: firstly, preparing a soluble compound solution of ganciclovir and sulfobutyl ether-beta-cyclodextrin; then adding a pH regulating agent (or not adding), dissolving, sterilizing and filtering to obtain concentrated injection, or further preparing a lyophilized powder injection. According to the preparation method, multiple effects can be achieved by using only one cyclodextrin inclusion material, i.e., the solubility of ganciclovir can be sufficiently increased, the ganciclovir can be more stable, stimulation caused by using sodium hydroxide and other strong alkali can be avoided, and the injection can be used as filler, a supporting agent even a protective agent when frozen and dried. Therefore, the safety can be improved, the formula and the process can be simplified, and the non-alkaline ganciclovir injection is beneficial to clinical application and advantageous to industrial production.
Description
[technical field]
The invention belongs to pharmaceutical technology sectors, particularly relate to a kind of Novel injection ganciclovir preparation and preparation method thereof, its zest is little, good patient compliance.
[background technology]
Ganciclovir, it is second filial generation anti-herpesvirus medicament, contestable suppresses DNA polymerase, and mix in the DNA of virus and host cell, thus suppress DNA synthesis, be one of resisting DNA virus medicine of at present most wide spectrum, be also the choice drug for the treatment of cytomegalovirus infection, be widely used in the treatment indication of multiple viral infection: (1) prevention may betide the cytomegalovirus disease of the organ transplant recipients of cytomegalovirus (CMV) infection risk.(2) cytomegaloviral retinitis that immunodeficiency patient (comprising HIV sufferers) occurs is treated.
Ganciclovir (Ganciclovir; GCV), its chemical name is 9-(1,3-dihydroxy-2-third oxygen methyl)-guanine; Molecular formula: C
9h
13n
5o
4; Molecular weight: 255.23.Crude drug character is white loose block or powder, has to draw moist, and omit/be slightly soluble in water (Ch.P.2005), Merck Index provides its concrete dissolubility, is 4.3mgmL
-1.
GCV goes on the market injection type at present based on lyophilized injectable powder, and its character is bulk or the powder of white or off-white color; Its specification is 50mg or 250mg, based on 250mg; Its general production procedure is: and drug solution preparing → fill partly jumps a queue → and lyophilization → tamponade rolls lid → visual inspection → packaging: and its basic prescription composition comprises:
| Composition | Effect |
| Ganciclovir | Principal agent |
| Sodium hydroxide | Solubilising (salify) property alkali |
| Mannitol, dextran | Filler/proppant/freeze drying protectant |
| Water for injection | Solvent |
But there is following problems in above-mentioned prescription: in drug solution preparing process, to be increased the dissolubility of ganciclovir by salify (ganciclovir sodium) owing to adding a large amount of sodium hydroxide, finally make the pH value of medicinal liquid up to 10.5 ~ 11.5, thus cause patient to produce the more serious zest such as pain, thus affect its clinical practice.
Maanshan Fengyuan Pharmaceutical Co., Ltd. authorizes in patent of invention CN101711746B (authorized announcement date on February 29th, 2012) in China and has invented a kind of new ganciclovir for injection lyophilized formulations and preparation method thereof, it is characterized in that adopting novel water solublity enclose material HP-β-CD (HP-β-CD) (to form clathrate by enclose principle, or claim molecular capsule) the dual principle of combining hydrogen oxidation sodium salify realizes the solubilising of ganciclovir, reduces the zest intensity (pH value is down to 9.5 from 11) that strong basicity causes to a certain extent.
But because the enclose (solubilising) of its HP-β-CD adopted to ganciclovir is limited in one's ability, be not enough to make ganciclovir solubilising to valid density under neutral solution condition, therefore still need to use sodium hydroxide, cause solution ph before its lyophilizing after solution and lyophilizing after product dilution still up to 9.5, still there is certain zest, exceed general provision and the safety range of normal injection agent pH value 4 ~ 9.If the enclose material-drug ratios provided according to it (i.e. master-enclosed molecule than) and the technology of preparing of correspondence thereof can not obtain clear solution lower than (pH value 7.4 ± 0.2) under the neutrallty condition of 30 DEG C, namely failing to dissolve completely under this condition of ganciclovir.
Sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) is the hydrophilic β-cdderivatives obtained with Isosorbide-5-Nitrae-butane sultone generation substitution reaction by β-CD.Modal is that substitution value is respectively SBE
4-β-CD and SBE
7-β-CD, the adjuvant that the latter is used as ejection preparation is gone on the market by the examination & approval of U.S. FDA, trade name
its safety and often than HP-β-CD, advantage is had more, the antifungal drug that Pfizer has gone on the market to the enclose solubilization of most drug
it is application
the concentrated type intravenous formulations that clathrate (molecular capsule) makes is formed with active component voriconazole (voriconazole).
[summary of the invention]
The present invention's formula composition aiming to provide a kind of ganciclovir injection of neutrality newly and preparation method thereof, to solve the defect of the patient's poor compliance caused due to system strong basicity in above-mentioned technology.
The invention provides a kind of ganciclovir for injection preparation of non-salt form, its prescription advantages of simple more, technique is more simple and easy to do.Prescription comprises: ganciclovir 2 ~ 5 parts, SBE-β-CD2 ~ 25 part, water for injection 50 ~ 200 parts, and other additives are as appropriate in pH adjusting agent.Technique comprises the steps (A+B or A+C):
A: the SBE-β-CD taking proportional quantity, adds water for injection, be stirred to and dissolve completely, stirs 2 ~ 12h under adding the injection stage ganciclovir constant temperature of proportional quantity, adds appropriate sodium hydrogen phosphate adjust pH 7.4 ± 0.2, obtain equilibrium system solution A after fully dissolving.
B: after above-mentioned balance solution being placed in refrigerator (6 ± 2) DEG C reequilibrate 2 ~ 8h, aseptic filtration, obtains concentrated injection, quality inspection, packaging.
C: also can by after direct for balance solution A aseptic filtration, freeze drying process lyophilizing routinely, obtains freeze-dried powder.
Ganciclovir for injection preparation of the present invention and preparation method thereof has following beneficial effect:
1), in injection Formulation, under the prerequisite ensureing product quality, except effective ingredient, adjuvant is selected more few better, and pH value is more less close to 7.4 zests, and safety is higher, and patient's compliance is better.The present invention only uses a kind of adjuvant of sulfobutyl ether-beta-cyclodextrin in drug solution preparing process, does not need the highly basic such as hydro-oxidation sodium just can make more than ganciclovir solubilising to valid density.
2) lactose in existing commercialized product prescription, dextran, mannitol are excipient (generally making filler/proppant/freeze drying protectant); only adopt SBE-β-CD adjuvant stronger than HP-beta-schardinger dextrin-solubilising power just to play figuration and the dual function increasing dissolubility in the present invention, prescription and technique are more simplified.
[detailed description of the invention]
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Take injection stage SBE respectively
7-β-CD 10g, water for injection adds to 100ml, stir at 25 DEG C and make it dissolve, and inject a grade ganciclovir 2g, after stirring 4h, add sodium hydrogen phosphate adjust pH 7.4 ± 0.2 under constant temperature, through 0.22 μm of microporous filter membrane aseptic filtration, lyophilization, to obtain final product.
Embodiment 2
Take injection stage SBE respectively
4-β-CD 25g, water for injection adds to 100ml, stir at 20 DEG C and make it dissolve, and inject a grade ganciclovir 3g, stir 8h under constant temperature, through 0.22 μm of microporous filter membrane aseptic filtration, lyophilization, to obtain final product.
Embodiment 3
Take injection stage SBE respectively
7-β-CD 10g, water for injection adds to 100ml, stir at 25 DEG C and make it dissolve, and inject a grade ganciclovir 2g, after stirring 4h under constant temperature, add 7.4 ± 0.2, the 0.22 μm of microporous filter membrane aseptic filtration of sodium hydrogen phosphate adjust pH, lyophilization, to obtain final product.
Embodiment 4
Take injection stage SBE respectively
4-β-CD 30g, water for injection adds to 100ml, stir at 30 DEG C and make it dissolve, inject a grade ganciclovir 2g, after stirring 8h under constant temperature, add sodium hydrogen phosphate adjust pH 7.4 ± 0.2, leave standstill 4h at (6 ± 2) DEG C, 0.22 μm of microporous filter membrane aseptic filtration, obtains (concentrated injection).
Embodiment 5
Take injection stage SBE respectively
7-β-CD 20g, water for injection adds to 100ml, stir at 30 DEG C and make it dissolve, and injects a grade ganciclovir 3g, stirs 6h under constant temperature, and leave standstill 6h at (6 ± 2) DEG C, through 0.22 μm of microporous filter membrane aseptic filtration, lyophilization, to obtain final product.
Claims (4)
1. a ganciclovir for injection preparation, it is characterized in that, after dissolving, its pH value is equal or close to body fluid (5.8 ~ 8.2), its prescription comprises ganciclovir 2 ~ 5 parts, sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) 2 ~ 25 parts, water for injection 0 ~ 200 part, other additives 0 ~ 20 part.
2. SBE-β-CD according to claim 1 comprises the specification of variant substitution value, as SBE
4-β-CD or SBE
7-β-CD.
3. injection according to claim 1 comprises liquid concentrated injection, also comprises solid-state lyophilized injectable powder.
4. injection preparation process according to claim 1 is as follows: the soluble complex solution first preparing ganciclovir and SBE-β-CD, add pH adjusting agent (or not adding), aseptic filtration after dissolving, obtains concentrated injection, or can be prepared into freeze-dried powder further.
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|---|---|---|---|
| CN201510038721.6A CN104586759A (en) | 2015-01-21 | 2015-01-21 | Non-alkaline ganciclovir injection and preparation method thereof |
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|---|---|---|---|
| CN201510038721.6A CN104586759A (en) | 2015-01-21 | 2015-01-21 | Non-alkaline ganciclovir injection and preparation method thereof |
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| CN104586759A true CN104586759A (en) | 2015-05-06 |
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105169407A (en) * | 2015-10-15 | 2015-12-23 | 重庆大学 | Sulfobutyl ether-beta-cyclodextrin inclusion compound of trimethoprim and powder injection preparation thereof |
-
2015
- 2015-01-21 CN CN201510038721.6A patent/CN104586759A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105169407A (en) * | 2015-10-15 | 2015-12-23 | 重庆大学 | Sulfobutyl ether-beta-cyclodextrin inclusion compound of trimethoprim and powder injection preparation thereof |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150506 |