CN104606682A - Ganciclovir eye preparation and preparation method thereof - Google Patents

Abstract

The invention relates to novel ganciclovir (GCV) eye drops or eye gel and a preparation method thereof. The pH (potential of hydrogen) value of a product solution is 6-8. The eye drops or the eye gel comprises 0.1-5% of GCV, 5-30% of sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD), 50-99% of injection water and 0-20% of other additives. The preparation process comprises the following steps: firstly, preparing a soluble compound solution of GCV and SBE-beta-CD, adding (or not adding) a macromolecular thickener (a viscosity modifier) solution containing a pH regulator, an isotonic regulator and a bacteriostat, mixing, performing sterilization, and filtering to obtain the eye drops or the eye gel. The use of SBE-beta-CD can not only improve the dissolubility of GCV but also improve the stability and the permeable cornea absorption of GCV, so that the bioavailability of GCV and the safety of a preparation are improved. Compared with a preparation in the market, the eye drops or the eye gel is relatively safe, stable and efficient.

Description

A kind of ganciclovir ophthalmic preparation and preparation method thereof

[technical field]

The invention belongs to pharmaceutical technology sectors, be specifically related to a kind of eye drop of ganciclovir, gel for eye use and preparation method thereof.

[background technology]

The herpes simplex keratitis (HSK) that herpes simplex virus I-type (HSV-1) causes is the modal viral infection of eye, after eye or other position of whole body are subject to repeated infection, Virus transport is up to trigeminal ganglion, hide in sensory neuron or directly hide in cornea, when the immune state of body changes, or stimulate lower often recurrence by the reason such as psychic trauma, endocrine disturbance, make cornea form cicatrix, thus cause inpairment of vision or blinding.

Ganciclovir (Ganciclovir; GCV), its chemistry 9-(1,3-dihydroxy-2-third oxygen methyl)-guanine by name; 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), it is 4.3mgmL that Merck Index provides its concrete dissolubility ¹(25 DEG C).Since nineteen ninety, GCV is as new selective anti-herpesvirus medicine, it is another efficient, that low toxicity, selectivity the are strong viral chemotherapeutics agent occurred after acyclovir, its 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, all have stronger activity to the multiple herpesvirus of human body.

In ocular disease treatment, local eye dripping (eye drop) is the most general, widely accepted route of administration.But what nictation, various reflection caused sheds tears, by row's directed stream, medicine can be removed from eyeball surface fast flush; In addition, the anatomy of cornea, physiologic characteristic, and the rapid absorption of medicine has also been blocked in barrier action, therefore the bioavailability of eye drop is lower, and drug effect remains short, and administration is frequent, and dosage is also wayward.When medicine indissoluble, bioavailability reduces further.

Domestic be used for the treatment of HSK Eye Drops of Ganciclovir and ganciclovir ophthalmic gel respectively at 2004 and listing in 2005, due to the restriction of GCV dissolubility, the concentration of GCV is low to moderate 1.0mgmL respectively ¹and 1.5mgg ¹, and for storing, transport and the temperature that uses all must higher than 10 DEG C, otherwise will crystallization, for safety brings larger hidden danger.

[summary of the invention]

The object of this invention is to provide rational formula of a kind of ophthalmic preparation of safe, efficient, stable ganciclovir and preparation method thereof, be used for the treatment of the ocular viral such as HSK for clinical ophthalmology and catch a kind of new elegant formulations is provided.How to increase the dissolubility of principal agent GCV and keep its stability, ensure its low irritant, high bioavailability becomes the key issue that the present invention will solve.

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.SBE-β-CD is added in prescription, after forming solubility clathrate with GCV, the apparent solubility of GCV can be made to improve more than ten times on the one hand, make it also be unlikely under refrigerated conditions to separate out drug crystallization, on the other hand, the stability of GCV can be improved, increase GCV corneal permeability.There are no irritative response in the test of rabbit Draize Ocular irritation.

Meanwhile, alternative adds the excellent high polymer adjuvant of appropriate biocompatibility, as HA-Na, poloxamer188, hydroxypropyl emthylcellulose etc., by increase viscosity extend GCV in the holdup time of eye thus improve bioavailability.

The present invention is by appropriate design prescription, and successfully solve above-mentioned key issue, prescription is as follows:

Prescription	Content (w/w)
		Ganciclovir (GCV)	0.1％～5％
SBE-β-CD (cosolvent)	5％～35％
		Antibacterial	0～2％
Thickening agent	0～5％
		PH value regulator	0～2％
Water for injection	50％～99％

Wherein, thickening agent used is: one or more the mixture in HA-Na (hyaluronate sodium), carbopol, polyvinyl alcohol, hyaluronic acid sodium, sodium alginate, chitosan, methylcellulose (MC), hydroxypropyl emthylcellulose (HPMC), poloxamer188 etc.; Described cosolvent is the SBE-β-CD of various possibility substitution value; Described antibacterial is: one or more the mixture in phenylmercuric nitrate, thimerosal, benzalkonium chloride, chlorobutanol, oxybenzene esters (parabens), sorbic acid, hibitane etc.; Described pH value regulator is: sodium hydrogen phosphate or sodium borate; The pH of said preparation is 6 ~ 8.

The preparation method of this novel ganciclovir ophthalmic preparation is:

A: the thickening agent taking recipe quantity, is sprinkled in water for injection, and fully swelling, dissolving, adds the antibacterial of recipe quantity, pH value regulator, be stirred to dissolve, obtain A agent; Also thickening agent, pH adjusting agent can not be added.

B: be dissolved in another water for injection by the SBE-β-CD of recipe quantity, adds GCV after dissolving completely again, dissolves and fully balances, obtaining B agent.

C: finally slowly add in A agent by B agent, 0.45 μm of filtering with microporous membrane, supplements excess water via filter membrane, aseptic filtration, and quality inspection is packed, and obtains gel for eye.

Ganciclovir for injection preparation of the present invention and preparation method thereof has following beneficial effect:

The novel GCV ophthalmic preparation that the present invention obtains adopts SBE-β-CD to make cosolvent, a difficult problem for easy crystallization under efficiently solving GCV low solubility, low corneal permeability, low bioavailability, low temperature; Also alternative adds the adhering high polymer adjuvant of good biological and makes flowable gel, improves the GCV ophthalmic time of staying, reduces administration number of times, improves bioavailability.Compare the preparation that goes on the market safer, stable, efficient.

[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

A: take 0.2gHA-Na, is sprinkled in 50mL water for injection, and fully swelling, dissolving, adds the benzalkonium bromide of 0.1g, and sodium borate adjusts pH to 7.4, obtains A agent.

B: by the SBE of 15.0g ₄-β-CD is dissolved in another 50mL water for injection, adds 2.0g GCV again after dissolving completely, dissolves and fully balances 6h, obtain B agent at (6 ± 2) DEG C.

C: finally slowly add in A agent by B agent, 0.45 μm of filtering with microporous membrane, aseptic filtration, quality inspection is packed, and obtains eye liquid or semi-solid preparation.

Embodiment 2

By the SBE of 25.0g ₇-β-CD is dissolved in 100mL water for injection, adds the thimerosal of 2.5g GCV, 0.1g after dissolving completely again, and (6 ± 2) DEG C lower magnetic force stirring and dissolving also fully balances 8h, 0.45 μm of filtering with microporous membrane, aseptic filtration, and quality inspection is packed, and to obtain final product.

Embodiment 3

A: take 0.15gHA-Na, is sprinkled in 50mL water for injection, and fully swelling, dissolving, adds the benzalkonium bromide of 0.1g, and pH to 7 ~ 7.4 adjusted by sodium hydrogen phosphate, obtain A agent.

B: by the SBE of 20.0g ₇-β-CD is dissolved in another 50mL water for injection, adds 2.5g GCV again after dissolving completely, dissolves and fully balances 8h, obtain B agent at (6 ± 2) DEG C.

C: finally slowly add in A agent by B agent, 0.45 μm of filtering with microporous membrane, aseptic filtration, quality inspection is packed, and obtains ophthalmic preparation.

Embodiment 4

A: take 0.1g HPMC, is sprinkled in 50mL water for injection, and fully swelling, dissolving, adds the benzalkonium bromide of 0.05g, obtain A agent.

B: by the SBE of 15.0g ₇-β-CD is dissolved in another 50mL water for injection, adds 3.0g GCV again after dissolving completely, dissolves and fully balances 6h, obtain B agent at (6 ± 2) DEG C.

C: finally slowly add in A agent by B agent, 0.45 μm of filtering with microporous membrane, aseptic filtration, quality inspection is packed, and to obtain final product.

Claims (4)

1. a ganciclovir ophthalmic preparation, it is characterized in that, its pH value is equal or close to tear (6.0 ~ 8.0), its prescription comprises ganciclovir 0.1% ~ 5%, sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) 5% ~ 30%, injection 50 ~ 99%, other additives 0 ~ 20%.

2. SBE-β-CD according to claim 1 comprises the specification of various different degree of substitution, as SBE ₄-β-CD, SBE ₇-β-CD, etc.

3. ophthalmic preparation according to claim 1 comprises liquid, the semi-solid ophthalmic preparations such as eye drop, collyrium, gel for eye.

4. ophthalmic preparation preparation process according to claim 1 is as follows: the soluble complex solution first preparing ganciclovir and SBE-β-CD, add (or not adding) pH adjusting agent, isoosmotic adjusting agent, additives that thickening agent is equiprobable, necessary again, aseptic filtration after dissolving, obtains liquid eye drop or gel for eye.