CN102342911A

CN102342911A - Ganciclovir eye drops and preparation method thereof

Info

Publication number: CN102342911A
Application number: CN2011103027604A
Authority: CN
Inventors: 黄迎春; 张卉
Original assignee: Nanjing H&d Pharmaceutical Technology Co ltd
Current assignee: Nanjing H&d Pharmaceutical Technology Co ltd
Priority date: 2011-10-09
Filing date: 2011-10-09
Publication date: 2012-02-08

Abstract

The invention aims to provide a ganciclovir antiviral new drug for eyes with high efficiency, low toxicity, strong selectivity and good stability and a preparation method thereof. The content of ganciclovir, a main drug of the invention, is 0.1 wt%. The auxiliary agent is cosolvent, isotonic regulator, pH regulator, antiseptic, and water for injection. Compared with the prior art, the invention has the following advantages: a boric acid buffer solution, namely a mixed solution of boric acid and borax, is adopted, and the buffer solution has strong buffering capacity and is highly soluble in water. Poloxamer is selected as the cosolvent, and multiple data show that the application of poloxamer improves the inherent quality of the medicine, increases the stability of the preparation, reduces the stimulation of the anti-inflammatory analgesic to eyes, has no hemolytic effect compared with tween-80, does not interfere the bacteriostatic action of the preservative, and has very obvious effect of reducing the stimulation of the medicine to eyes.

Description

Eye Drops of Ganciclovir and preparation method thereof

Technical field

The present invention relates to a kind of Eye Drops of Ganciclovir matching method and brand-new preparation technology, belong to medical technical field.

Background technology

Viral keratitis is caused by the infection of herpetoviridae herpes simplex virus type 1; It is the healthy common multiple disease of the human eye of serious harm; High without healing person's blind rate, nearly there is 5,000,000 patients every year in China because of infective virus property keratitis blinding or vision decline.Existing antiviral medicament for the eyes such as idoxuridine, cytosine arabinoside and ancitabine etc. are easy to generate drug resistance or significantly untoward reaction.0.1% aciclovir eye drop and 3.0% eye ointment of Hubei medical industry academy development have curative effect preferably in clinical treatment list bleb keratitis, and since nineteen eighty-three was identified operation, nearly annual clinical use amount was all more than 1.5 hundred million.Single Archie Lip river Wei also has weak point, and its water solublity is relatively poor, and dissolubility only 0.13% in 25 ℃ water, and 0.1% eye drop of being prepared is prone to crystallization in cold season, and influence is used.3.0% eye ointment dosage is bigger than normal, increases adverse reaction rate.Secondly, the same with other ucleosides antiviral drugs, the Archie Lip river Wei ophthalmic preparation long period uses repeatedly and viral drug resistance strain also can occur.Therefore, clinical ophthalmology is badly in need of a kind of efficient, low toxicity, new anti-virus ophthalmic preparation that selectivity is strong.

Ganciclovir (Ganciclovir), in June, 1988, in Britain's approval listing, intravenous injection was used for treatment and epidemic prevention defective patient, organ transplantation person's cytomegalovirus infection first.

Summary of the invention

The objective of the invention is to overcome the deficiency of technical background, provide that a kind of efficient, low toxicity, selectivity are strong, the new antiviral drug ganciclovir eye medication of good stability and preparation method thereof.

Technology bill provided by the invention is: the medication of ganciclovir eye, it comprises ganciclovir pharmaceutically useful auxiliary agent and antiviral effective dose and that be dispersed in said auxiliary agent.

In instance of the present invention, the medication of ganciclovir eye is an eye drop.

The pH value of above-mentioned eye drop is 5.0～8.0, preferred pH value 7.0～8.0, and ganciclovir content is 0.1wt%.Said auxiliary agent is cosolvent, isoosmotic adjusting agent, pH regulator agent, antiseptic, water for injection.Wherein pH adjustment agent preferred boric acid salt buffer is right; Its content of the preferred poloxamer of cosolvent is 5wt%; Antiseptic is that its content of preferred benzalkonium bromide is 0.2wt%; Isoosmotic adjusting agent is that its content of sodium chloride is 0.25wt%.Its preparation method is: cosolvent as for adding injection water low temperature swelling in the retort, will be dissolved completely that ganciclovir adds in the above-mentioned cosolvent again, add other regulators again.Add to the full amount of water for injection, the 0.22um mocromembrane filters, and in the aseptic condition packing, seals.

The present invention compared with prior art has the following advantages: eye drop dosage of the present invention is few, and systemic side effects is few, directly in ocular absorption, can be absorbed the arrival lesions position fast, brings into play therapeutical effect rapidly.Adopting borate buffer is the mixed solution of boric acid and Borax, and this buffer has very strong buffer capacity, and is solvable at the water camber.Cosolvent is selected poloxamer for use; The application that all shows poloxamer in pharmacology, pharmacodynamics, clinical verification is for the inherent quality that improves medicine; Increase stability of formulation; Reduce anti-inflammatory analgesic to stimulating eyes; Compare no haemolysis in tween 80; Do not disturb the bacteriostasis of antiseptic, reduce medicine very significantly stimulating eyes property effect.

Dissolubility and the pH value of ganciclovir in water has very big relation, and increases with the rising of temperature.Ophthalmic preparation has strict requirement to pH value, must be controlled between 5.0～8.0, could reduce the zest of ophthalmic.Be made into the ganciclovir solution of different pH value through preferred various buffer agent, experiment shows:, preserve at 4 ℃ and do not separate out crystallization in one month being made into pH value in 7.0～8.0 0.1% Eye Drops of Ganciclovir with phosphate-buffered.Separate out crystallization in cold season for avoiding eye drop; Select that hypotoxicity, zest are little for use, the poloxamer of good hydrophilic property is as cosolvent; The poloxamer of preferred variable concentrations adds in the 1.0% ganciclovir solution of pH value 7.0～8.0; Through placing one month at 4～5 ℃; The concentration of poloxamer is that 5% solution is not separated out crystallization, and the consumption of poloxamer is excessive, the production operation difficulty; And the interference analysis Determination on content, so the optium concentration of cosolvent poloxamer is 5%.Poloxamer with 5%; PH value is that 7.0～8.0 borate buffering is right; Antibacterial is 5% benzalkonium bromide; Isoosmotic adjusting agent is a sodium chloride; Process 0.1% Eye Drops of Ganciclovir thus; Through the storage 4 years down of light stability test, hot accelerated stability test and room temperature condition, with zero the time relatively, all no abnormal variation of pH value, clarity, assay, determination of foreign matter, health examination.With 0.1% and 0.2% Eye Drops of Ganciclovir single and 10 days multiple dosings of continuous use, the result shows the eye drop nonirritant to this eye drop to the big ear rabbit of Japan.Preparation flow figure sees Fig. 1

Description of drawings

Fig. 1 Eye Drops of Ganciclovir prepared flow chart

0 day content chromatogram of Fig. 2 Eye Drops of Ganciclovir influence factor

Fig. 3 Eye Drops of Ganciclovir reference substance content chromatogram

0 day related substance chromatogram of Fig. 4 Eye Drops of Ganciclovir influence factor

Fig. 5 Eye Drops of Ganciclovir influences the plain 0 day own control related substance chromatogram of shadow

The specific embodiment

Following embodiment only is to describe in detail the present invention, rather than restriction the present invention.

Embodiment 1: the adjuvant compatibility is investigated

1: ganciclovir 0.1g, water for injection 100ml

2: ganciclovir 0.1g, tween 80 0.1g, water for injection 100ml

3: ganciclovir 0.1g, poloxamer 10g, water for injection 100ml

4: ganciclovir 0.1g, mannitol 5g, water for injection 100ml

5: ganciclovir 0.1g, sodium chloride 0.9g, water for injection 100ml

6: ganciclovir 0.1g, borate buffer system, water for injection 100ml

7: ganciclovir 0.1g, phosphate buffer, water for injection 100ml

8: ganciclovir 0.1g, 5% benzalkonium bromide 1.5g, water for injection 100ml

9: ganciclovir 0.1g, 5% benzalkonium bromide 0.2%, water for injection 100ml

To survey pH value after the above-mentioned prescription outfit completion, tabulation as follows

Table 1

Visible from table, remove the borate buffer system and pH value all do not had very big influence with all the other adjuvants of phosphate buffer, but phosphate buffer during factors influencing in the pH value variation greatly, so buffer system preferred boric acid salt buffer system.

Embodiment 2:

Operating procedure:

1. take by weighing ganciclovir and add water 150ml, add tween 80 0.2g, stir and make dissolving;

2. take by weighing mannitol 10g and add above-mentioned solution, stir and make it dissolving;

3. take by weighing boric acid, Borax to above solution, after the stirring and dissolving, add benzalkonium bromide;

4. add the injection water, be settled to 200ml, shake up;

5. filtering with microporous membrane degerming, encapsulation.

Embodiment 3:

Operating procedure:

1. take by weighing poloxamer 10g, add the 100ml cold-water solution;

2. take by weighing ganciclovir 0.2g, add injection water 50ml dissolving;

3. mix above two kinds of solution, add phosphate buffer;

4. in above-mentioned solution, add mannitol, benzalkonium bromide again, stir and make it to dissolve mixing;

5. add the injection water, be settled to 200ml, shake up;

6. filtering with microporous membrane degerming, encapsulation.

Embodiment 4:

Operating procedure:

Mannitol in embodiment 3 technologies is changed to sodium chloride, operates with method.

Embodiment 5:

Operating procedure:

Embodiment 3 technology mesoboric acid salt buffers are right to changing phosphate-buffered into, and the mannitol consumption reduces to 3g simultaneously, operates with method.

Embodiment 6:

Operating procedure:

1. take by weighing poloxamer 10g, add 100ml cold water swelling;

2. accurately take by weighing ganciclovir 0.2g, add 50ml water for injection, add 2 sodium hydroxide and make dissolving fully;

3. mix above solution stirring evenly after, add the borate buffering again to, mannitol, benzalkonium bromide, stirring and dissolving mix homogeneously;

4. add the injection water, be settled to 200ml, shake up;

5. filtering with microporous membrane degerming, encapsulation.

Embodiment 7:

Operating procedure:

1. accurately take by weighing ganciclovir 0.2g, add injection water 150ml and stir, drip 2 sodium hydroxide and make it complete molten;

2. essence takes by weighing boric acid, Borax, sodium chloride and adds above-mentioned solution;

3. take by weighing benzalkonium bromide and add 1,2 solution;

Take by weighing poloxamer at last and add above solution, swelling is complete;

4. add the injection water and be settled to 200ml;

5. filtering with microporous membrane degerming, encapsulation.

Embodiment 8:

Operating procedure:

Embodiment 7 technology mesoboric acid salt buffers are right to changing sodium acetate buffer into, operate with method.

Embodiment 9:

Operating procedure:

Sodium acetate buffer in embodiment 8 technologies is right to changing phosphate-buffered into, operate with method.

Embodiment 10:

The screening experiment of ganciclovir 0.1% eye drop buffer agent pH value

Same buffering sees the following form to the influence of different pH value to 0.1% Eye Drops of Ganciclovir

Table 2

Embodiment 11:

The test of 0.1% Eye Drops of Ganciclovir cosolvent concentration screening

Under the identical pH value, the cosolvent of variable concentrations sees the following form to the influence of 0.1% Eye Drops of Ganciclovir

Claims

1. ganciclovir eye medication, it comprises pharmaceutically useful auxiliary agent and is distributed in the ganciclovir that has the antiviral effective dose in the auxiliary agent, it is characterized in that: the medication of said eye is an eye drop, and the pH scope that normal eyes can tolerate is 5.0～9.0, pH did not have uncomfortable sensation at 6～8 o'clock.The content of ganciclovir is 0.1wt%, and the content of cosolvent poloxamer is 5wt%.

2. 1 described medication as requested is characterized in that: said auxiliary agent also comprises isoosmotic adjusting agent, pH regulator agent, antiseptic and water for injection.

3. 2 described medications as requested is characterized in that: isoosmotic adjusting agent is a sodium chloride, and its content is 0.25wt%; The pH regulator agent is that the borate buffering is right; Antiseptic is a benzalkonium bromide, its content 0.2wt%.

4. according to claim 1 or 2 or 3 described medications, it is characterized in that: pH value is 6～8.

5. claim 1 or 1 or 2 or the method for preparing of 3 said medications, its preparation process is:

(1) accurately takes by weighing the poloxamer that accounts for eye drop 5wt% and add about 60% water for injection swelling;

(2) take by weighing the ganciclovir that accounts for eye drop 0.1wt% in addition, taking by weighing residue adjuvant boric acid and boric acid again, to regulate pH value be 7～8, and sodium chloride is regulated osmotic pressure 280～320mOsm/L, adds that to inject water about 30%, stirs;

(3) mixed solution that will contain principal agent joins swelling completely in the poloxamer solution, and water for injection is full dose in addition, stirs;

(4) the pin activated carbon of the 0.05-0.2% of the above-mentioned overall solution volume of adding stirred 10-30 minute, and solution is adopted the carbon removal of titanium rod filtration under diminished pressure, and twice 0.22 microporous filter membrane fine straining of reuse get Eye Drops of Ganciclovir;

(5) adding the antiseptic benzalkonium bromide that accounts for eye drop 0.2wt% at last stirs;

(6) get Eye Drops of Ganciclovir and measure pH value, content, after the filtrating passed examination,, press the labelled amount embedding in eye-drop liquid bottle according to the loading amount of cubage fill solution.