CN114010590A

CN114010590A - Nucleoside antiviral drug gel and preparation method and application thereof

Info

Publication number: CN114010590A
Application number: CN202111407521.5A
Authority: CN
Inventors: 程义云; 胡婧婧; 洪家旭; 周旭娇
Original assignee: East China Normal University; Eye and ENT Hospital of Fudan University
Current assignee: East China Normal University; Eye and ENT Hospital of Fudan University
Priority date: 2021-11-24
Filing date: 2021-11-24
Publication date: 2022-02-08
Anticipated expiration: 2041-11-24
Also published as: CN114010590B

Abstract

The invention discloses a nucleoside antiviral drug gel, which comprises the following components: deoxyguanosine or a derivative thereof, a nucleoside antiviral drug, alkali metal ions, a pH regulator and water. The invention also discloses a preparation method of the nucleoside antiviral drug gel, which comprises the following steps: heating the deoxyguanosine or its derivative, nucleoside antiviral drug, alkali metal salt for providing alkali metal ions, and water for injection to dissolve, adding pH to adjust, autoclaving, and cooling to room temperature to form gel. The gel provided by the invention is obtained by the participation and assembly of nucleoside drugs, is a viscoelastic body, has higher fluidity at low frequency, shows the characteristics of the viscoelastic body in the presence of shear force, and can restore the deformation caused by the shear force. The invention also provides application of the medicine gel in treating eye, skin and mucosa tissue infection. The gel can resist blinking shear and has good application prospect in ophthalmic gel preparations.

Description

Nucleoside antiviral drug gel and preparation method and application thereof

Technical Field

The invention belongs to the technical field of biological medicines, and relates to nucleoside antiviral medicine gel and a preparation method and application thereof.

Background

Clinically, the viral keratitis is treated by locally dropping antiviral drugs, and preparations comprise eye drops, eye ointments and eye gels. Due to the physiological structure characteristics of eyes, the eye drops have extremely low bioavailability, only about 1 to 3 percent of medicaments can exert activity, the duration of the medicament effect is short, the administration is frequent, and medicament resistance, accumulated toxicity and the like are easily induced. Creams and gels have received much attention in ophthalmic dosage forms because of the increased local retention rate. However, the cream has poor transparency and refractive index, so that the field of vision is easily blurred, the use scene is limited, and inconvenience is brought to a patient. The current clinical ophthalmic gel preparation is mostly prepared by wrapping antiviral drugs by adopting a gel matrix, wherein the gel matrix comprises one or more of carbomer, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium hyaluronate or methylcellulose, and carbomer series is the most main gel matrix of the current clinical ophthalmic gel preparation. Although gel dosage forms have better clarity and refractive index than ointments, the following problems still exist with this type of gel matrix: 1) the drug is loaded in the gel through physical wrapping effect, and the release rate of the drug cannot be controlled; 2) the shape of the eye mask is similar to that of a semisolid, the eye mask is not easy to spread on the ocular surface, is easy to be sheared to eyelashes and outer eyelids by eyelids in the blinking process, does not have deformation recovery capability, and is stopped at the eyelashes and the outer eyelids due to the high viscosity and semisolid characteristics, so that the loss rate is high; and the high viscosity causes irritation to eyes, stimulates lacrimal secretion, and increases gel loss. 3) The carbomer gel matrix is sensitive to salt ions, the gel framework collapses under the environment of tears,

disclosure of Invention

In order to solve the defects of the prior art, the invention aims to provide a nucleoside antiviral drug gel and a preparation method thereof. The nucleoside antiviral drug gel provided by the invention has high bioavailability, can be efficiently retained on the ocular surface, and can delay the release of the drug.

The invention provides nucleoside antiviral drug gel, which consists of the following components: deoxyguanosine or a derivative thereof, a nucleoside antiviral drug, alkali metal ions, a pH regulator and water.

The structural formula of the deoxyguanosine derivative is shown as the following formula (1):

wherein X and Y are hydrogen bond donor or acceptor groups selected from-OH and-CH₂OH、-CH₂CH₂One of OH and I;

the final molar concentration of the deoxyguanosine or the derivative thereof is 30 mM-85 mM or the final mass concentration thereof is 0.8% -2.3%; preferably, the final molar concentration is 50-60mM, corresponding to a final mass concentration of 1.4-1.68%.

The nucleoside antiviral drugs comprise ganciclovir, acyclovir, penciclovir or derivatives with the same therapeutic activity as the three drugs;

the mass concentration of the nucleoside antiviral drug is 0.01-0.5%; for ganciclovir, the mass concentration is preferably 0.15%; for acyclovir, the mass concentration is preferably 0.1%.

The alkali metal ions comprise potassium ions and sodium ions; the alkali metal ion is provided by a salt species comprising the alkali metal ion; preferably, it is potassium ion, derived from potassium chloride, and has a final molar concentration twice that of deoxyguanosine or a derivative thereof.

The ratio of the final molar concentration of the alkali metal ions to the deoxyguanosine or the derivative thereof is 1-2.5, preferably 2; wherein, the final mass fraction of potassium ions is 0.1 to 0.85 percent; for sodium ions, the final mass fraction is 0.065-0.5%

The pH regulator comprises sodium hydroxide, potassium hydroxide, phosphate buffer, boric acid buffer and the like, and needs to be consistent with alkali metal ions in a system when in use.

The pH regulator is used for regulating the pH value of the solution, and is added in a proper amount according to the amount of the solution and the pH value until the pH value of the solution is neutral; preferably, the pH is adjusted to 7.4.

The water is water for injection.

The invention also provides a preparation method of the nucleoside antiviral drug gel, which comprises the following steps: heating and dissolving the deoxyguanosine or its derivative, the nucleoside antiviral drug, the alkali metal salt for providing alkali metal ions and the water for injection, adding a pH regulator to adjust the pH to 7.4, carrying out autoclaving, and cooling to room temperature to form the gel.

The heating temperature is 80-90 ℃;

the autoclaving was carried out under normal autoclaving conditions (115 ℃, 30 minutes).

The invention also provides the nucleoside antiviral drug gel prepared by the preparation method.

The drug gel is characterized by viscous fluid at low frequency (namely the shear rate is less than 1.01/s), and the loss angle is 0.3-0.95; preferably, the loss angle is 0.4-0.9, and the material has better fluidity; the rubber is characterized by visco-elastic body under shearing force and has deformation recovery performance.

The medicine gel can be used for treating eye, skin and mucosa tissue infection.

The invention also provides application of the medicine gel in preparing medicines for treating eye, skin and mucosa tissue infection.

The medicine gel provided by the invention can resist blinking and shearing, and has a good application prospect in ophthalmic gel preparations.

In one embodiment, the deoxyguanosine, the nucleoside antiviral drug, a proper amount of potassium ions or sodium ions and water for injection are taken according to the formula amount, heated and dissolved (the temperature ranges from 80 ℃ to 90 ℃), and added with a pH regulator to regulate the pH to 7.4; sterilizing under hot pressure (115 deg.C, 15 min), packaging, and cooling to room temperature to obtain gel.

Compared with the prior art, the nucleoside antiviral drug gel has the excellent effects that:

1) the medicine is not loaded in the gel through physical wrapping, but is assembled into a gel framework through non-covalent action, so that the medicine release rate is more controllable;

2) the eye gel has the characteristics of viscous fluid at low frequency, has good fluidity and can be uniformly spread on the surface of an eyeball;

3) the eye twinkling eye gel is a viscoelastic body when the eye twinkling eye is sheared, can recover after deformation when the shearing force is removed, cannot be sheared from the conjunctival sac to the eyelids or eyelashes, and has high retention efficiency.

4) The preparation method of the nucleoside antiviral drug gel is simple to operate and suitable for large-scale production.

Drawings

FIG. 1 is a graph of ganciclovir gel at different ratios of potassium ion concentration according to example 1 of the present invention (the values in the graph are the molar ratio of potassium ion to 2' -deoxyguanosine);

FIG. 2 shows ganciclovir gel (in mM) in example 2 according to the invention in different formulation ratios;

FIG. 3 is a graph of the stability of ganciclovir gel (in mM) in different formulation ratios according to example 2 of the invention;

FIG. 4 shows acyclovir gels (in mM) in various formulation ratios according to example 3 of the present invention;

FIG. 5 shows the stability of acyclovir gels (in mM) according to example 3;

FIG. 6 is ganciclovir gel and acyclovir gel with different drug concentrations in example 4 of the invention;

FIG. 7 is a fluid plot of novel ganciclovir gel and clinical ganciclovir gel according to example 5 of the present invention;

FIG. 8 is a plot of the angular frequency sweep of novel ganciclovir gel and clinical ganciclovir gel according to example 6 of the present invention;

FIG. 9 is a strain sweep curve of novel ganciclovir gel and clinical ganciclovir gel of example 7 of the invention;

FIG. 10 is a graph of loss tangent values for novel ganciclovir gel and clinical ganciclovir gel of example 7 of the invention;

FIG. 11 is the behavior of ganciclovir gel in example 8 of the invention and clinical reference ganciclovir gel on the surface of an artificial eye model;

FIG. 12 is a graph of the tear fluid resistance of ganciclovir gel of example 9 of the invention and a clinical reference ganciclovir gel;

figure 13 is a release profile of ganciclovir gel from clinical reference ganciclovir gel in example 10 of the invention;

FIG. 14 shows the concentrations of ganciclovir gel in the conjunctiva and cornea of mice in example 11 of the invention and clinical reference ganciclovir gel;

FIG. 15 is a graph of the death curves of viral keratitis mice treated with ganciclovir gel in example 12 of the invention with clinical reference ganciclovir gel;

FIG. 16 is a graph showing corneal haze scores of mice with viral keratitis treated with ganciclovir gel and clinical reference ganciclovir gel in example 12 of the invention; n.s. shows that the therapeutic effect of the clinical reference gel was not significantly different from that of PBS, and that the therapeutic effect of ganciclovir gel in example 11 was significantly different from that of the clinical reference gel and PBS.

FIG. 17 is the ratio of the corneal lesion area of mice with viral keratitis treated with ganciclovir gel to the clinical reference ganciclovir gel in example 12 of the invention. N.s. shows that the therapeutic effect of the clinical reference gel was not significantly different from that of PBS, and that the difference between the therapeutic effect of the ganciclovir gel of example 12 and that of the clinical reference gel and that of PBS was extremely significant.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

Example 1

A ganciclovir gel, which comprises the following formula:

14.26mg of 2 '-deoxyguanosine, 1.5 mg of ganciclovir, 0.35 ml of water and 0.5 ml of KCl mother liquor, wherein the concentration of the KCl mother liquor is respectively 25mM, 50mM, 75mM, 100mM, 150mM, 200mM, 250mM, 300mM and 400mM, 0.15 ml of water is additionally added, the mixture is uniformly mixed, the mixture is heated at 90 ℃ for 3 minutes to obtain a clear solution, and the clear solution is cooled to room temperature to obtain gels, the molar ratios of potassium ions to 2' -deoxyguanosine are respectively 0.25, 0.5, 0.75, 1, 1.5, 2, 3 and 4, and the obtained gels are shown in a graph 1. The molar ratio of potassium ions is 1-2.5, and the gel has stability and good transparency.

Example 2

Ganciclovir gels were prepared according to the following formulations, respectively:

2.85mg, 5.7mg, 8.56mg, 11.41mg, 14.26mg, 17.11mg, 19.96mg, 22.82mg, and 25.67mg of 2 ' -deoxyguanosine were each fixed at twice the molar concentration of 2 ' -deoxyguanosine, 1mL of a mixed system was prepared with the concentrations of 2 ' -deoxyguanosine being 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, and 90mM, and the content of ganciclovir being fixed at 1.5 mg, and the mixed system was shaken for 1 minute, heated to 90 ℃, dissolved into a transparent solution, and then cooled to room temperature, and the obtained gel was as shown in FIG. 2, and after standing for three months, as shown in FIG. 3. The gel state at the initial stage of comprehensive preparation and after three months can be obtained, and when the concentration of the auxiliary material dG is between 40 and 80mM, a novel ganciclovir gel which is relatively transparent, and has good visibility and stability can be obtained.

Example 3

Acyclovir gel is prepared according to the following formula:

2.85mg, 5.7mg, 8.56mg, 11.41mg, 14.26mg, 17.11mg, 19.96mg, 22.82mg, 25.67mg and 28.52mg of 2 ' -deoxyguanosine were added at twice the molar concentration of 2 ' -deoxyguanosine, respectively, and 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM and 100mM of 2 ' -deoxyguanosine was added at 1.0 mg of acyclovir, and a 1mL mixed system was prepared, followed by shaking for 1 minute, heating to 90 ℃, dissolving the solution into a clear solution, cooling to room temperature, and leaving the gel as shown in FIG. 4, and leaving it to stand for three months as shown in FIG. 5:

the gel state can be obtained at the initial stage of comprehensive preparation and after three months, and the novel acyclovir gel with good transparency, visibility and stability can be obtained when the concentration of the auxiliary material dG is between 40 and 70 mM.

Example 4

Respectively preparing novel ganciclovir gels with the mass concentration of 0.2%, 0.3%, 0.4%, 0.5% and 0.6% and acyclovir gels with the mass concentration of 0.4%, 0.5%, 0.6% and 0.7%. As shown in fig. 6, when the drug concentration exceeds 0.4%, ganciclovir gel precipitates, and when the drug concentration exceeds 0.5%, acyclovir gel precipitates, and it can be seen that the gel can maintain good visibility within 0.5% of the drug mass concentration.

However, the concentration is only the drug concentration when the dG auxiliary material is used alone, and the concentration of the drug can be increased by adding other commonly used ophthalmic drug auxiliary materials when necessary, and meanwhile, good visibility is kept.

Example 5

1mL of novel ganciclovir gels (named as novel ganciclovir gels 1-3) with auxiliary materials of 40mM, 60mM and 80mM of dG concentration are prepared respectively, and clinical reference preparations (clinical ganciclovir gels containing the same medicine concentration and beneficial to Hubei Keyi) are taken to test respective rheological properties.

Sample size 1mL, gap 400 μm, shear rate set to 0.01-1000S^-1The complex viscosity and the shear stress of the ganciclovir gel are detected by scanning the flow mode of the ganciclovir gel, and a fluidics type curve of the ganciclovir gel is obtained, as shown in figure 7. The figure shows that the novel ganciclovir gel has a plateau area similar to Newtonian fluid in a low-frequency area, the viscosity of the gel does not change along with the shear rate, and the gel has no yield stress, which indicates that the gel has good casting and spreading performance at low frequency. And clinical referenceThe gel had a significant yield stress, 5.8Pa in this experiment, was rigid at low stress, had no flow, and exhibited bingham fluid characteristics.

Example 6

The three formulations of novel ganciclovir gel samples obtained in example 5 of the invention and clinical ganciclovir gel samples are taken to be 1mL respectively, the gap is 400 μm, the strain rate is fixed to be 0.1%, the angular frequency is set to be 0.1-100rad/s, and the angular frequency scanning is carried out, and the obtained result is shown in figure 8. Ganciclovir gels of three different formulations all exhibit typical viscoelastic fluid characteristics, exhibit viscous fluid behavior at low frequencies, and are matched with flow scan curves thereof, which shows that the ganciclovir gels have good casting and spreading properties at low frequencies, exhibit elastomeric behavior at high frequencies, and therefore can recover elastic deformation after high-frequency shear force is removed, and the fluidics properties make the ganciclovir gels suitable for ocular physiological structures, can be spread on the ocular surface, and can resist blink shear. And the storage modulus of the clinical gel ganciclovir gel is obviously higher than the loss modulus, and the clinical gel ganciclovir gel shows typical semisolid characteristics, so the clinical gel ganciclovir gel does not have automatic casting and spreading performance, cannot be uniformly spread on the ocular surface, and has no viscoelastic fluid characteristics.

Example 7

Three novel ganciclovir gel formulations obtained in the embodiment 5 of the invention are taken, wherein the formulation is 1mL, the gap is 400 μm, the angular frequency is fixed to be 1Hz, the strain rate is set to be 0.01-500%, strain scanning is carried out, and the obtained result is shown in figure 9. The novel ganciclovir gels with three different formulas have good strain resistance, and can resist strain of 220%, 250% and 535% respectively when the content of the auxiliary material dG is 40mM, 60mM and 80mM, while clinical ganciclovir gel can resist strain of only 25%.

Meanwhile, the loss tangent value of the novel ganciclovir gel is between 0.95 and 0.4, which is obviously higher than that of clinical ganciclovir gel (lower than 0.1), and the novel ganciclovir gel has stronger flowing performance, as shown in figure 10.

Example 8

Evaluation of artificial eye model for shear force resistance:

150 mg of the ganciclovir gel prepared in the invention and the clinical ganciclovir reference gel with the auxiliary material dG concentration of 50mM are respectively taken and dripped on an artificial eye model, and the spreading condition is observed. As shown in fig. 11a, the ganciclovir gel of the invention can be uniformly spread on the surface of the artificial eye model, while the clinical ganciclovir gel does not have any spreading behavior and shows solid-like property. In addition, the simulated blinking shear imparts some shear force to the gel, as shown in fig. 11b, the ganciclovir gel can recover to deform to the original position after the shear force is withdrawn, while the clinical ganciclovir gel cannot recover to deform after the shear force is withdrawn, so that loss occurs under the action of the shear force.

The viscosities of ganciclovir gels prepared in example 5 of the invention are 3.1pa.s, 36.8pa.s and 132.5pa.s, respectively, and the viscosity of clinical reference gel is about 578.8 pa.s. Therefore, in the present invention, the effect of the unique viscoelastic rheological behavior of the gel is utilized, rather than increasing the viscosity to increase the retention rate.

Example 9

Resistance to tears:

100 mg of the ganciclovir gel with dG concentration of 60mM prepared in example 5 and a reference preparation (clinical ganciclovir gel with the same drug concentration, Hubei Keyi) are respectively put in a small dish, 1ml of artificial tears are added dropwise, the soaking is carried out for 1 minute, the liquid is removed, and the weight is weighed. As shown in fig. 12, clinical ganciclovir gel showed significant degradation loss, while the ganciclovir gel proposed in the present invention showed no significant loss.

Example 10

In vitro release performance evaluation:

ganciclovir gel (0.15% ganciclovir content) was prepared at 60mM 2 '-deoxyguanosine concentration by 17.1 mg 2' -deoxyguanosine, 0.5 mL potassium chloride solution (200mM), 1.5 mg ganciclovir, and 0.5 mL water.

150 mg of the ganciclovir gel and a reference preparation (clinical ganciclovir gel containing the same drug concentration, Hubei Keyi) are respectively taken into a small tube, 300 microliter of artificial tears are externally added, the artificial tears are released at 37 ℃, 50 microliter of artificial tears are respectively sampled at 1 hour, 3 hours, 6 hours and 9 hours, and fresh artificial tears with the same volume are simultaneously supplemented. The released ganciclovir is detected by adopting a high performance liquid chromatography, the accumulated release amount is calculated, the release curve of the obtained ganciclovir is shown in figure 13, the novel ganciclovir gel only releases about 60 percent of the drug within 9 hours, and the drug of the clinical ganciclovir gel is completely released within 6 hours.

EXAMPLE 11 measurement of drug content in ocular surface tissue following a single administration of Ganciclovir gel in Balb/c mice

Experimental animals: balb/c mice, 8, weighing 18-20g, 6-8 weeks old, were from Sipur-Bikai laboratory animals Inc., Shanghai.

Test materials: novel ganciclovir gel 2 prepared in example 1 of the invention and a clinical reference formulation (clinical ganciclovir gel with the same drug concentration, Hubei Keyi).

The experimental method comprises the following steps: balb/c mice were divided into 2 groups of 4 mice each, 5. mu.l of ganciclovir gel and reference preparation prepared in example 1 of the invention were added to the left eyes of rabbits of each group, mice were sacrificed at 2h, 4h, 8h, and 24h, respectively, the cornea and conjunctiva were removed, and the ganciclovir content therein was analyzed by HPLC.

The experimental results are as follows: as shown in fig. 14, the ganciclovir gel in example 1 of the invention has higher drug retention rate, and the ganciclovir concentrations detected in corneal tissue and conjunctival tissue after 24h are 13.81ug/mL and 5.91ug/mL respectively, while clinical ganciclovir gel only detects 3.31ug/mL and 2.54ug/mL after 24 h.

Example 12 evaluation of the therapeutic Effect of herpes simplex viral keratitis

Experimental animals: balb/c mice, 15, weighing 18-20g, 6-8 weeks old, were from Sipur-Bikai laboratory animals Inc., Shanghai.

Test materials: novel ganciclovir gel 2 prepared in example 1 of the invention, a reference formulation (clinical ganciclovir gel with the same drug concentration, Hubei koyi), PBS.

The experimental method comprises the following steps: balb/c mice were divided into 3 groups of 5 mice each, and infected with herpes simplex virus (HSV-1) to induce the formation of viral keratitis simplex (HSK). Treatment was then carried out by adding 5. mu.l of ganciclovir gel prepared in example 1 of the invention, reference formulation (clinical ganciclovir gel with the same drug concentration, Hubei Keyi), PBS, respectively, to each eye. The solution is added dropwise once every other day, and the dropwise addition is accumulated for 5 times. Observing the survival condition of the mouse during the period, and counting a survival curve; and meanwhile, observing the infection condition of the cornea, scoring, taking a picture through a microscope, and counting the turbid area of the cornea.

The experimental results are as follows: as shown in fig. 15, the mice infected with herpes simplex virus had higher mortality, the survival rate of the mice treated with the clinical reference gel was lower than 40%, and there was no improvement compared to the HSK pathology control group, while the survival rate of the mice treated with the ganciclovir gel proposed in the present invention was up to 70% or more, which was significantly improved.

As shown in fig. 16, the corneal opacity of the mice treated with the clinical reference gel was not significantly different from that of the pathological control group, and the score was 3 points or more, whereas the mean value of the corneal opacity score was about 1.5 points after the treatment with the ganciclovir gel proposed in the present invention, and the corneal opacity was significantly improved.

As shown in fig. 17, the area of corneal lesion in mice treated with clinical reference gel was about 35%, which is equivalent to that of pathological control group, while the area of corneal lesion in mice treated with ganciclovir gel proposed in the present invention was only about 12%, which is significantly improved.

The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, which is set forth in the following claims.

Claims

1. The nucleoside antiviral drug gel is characterized by comprising the following components: deoxyguanosine or a derivative thereof, a nucleoside antiviral drug, alkali metal ions, a pH regulator and water.

2. The nucleoside antiviral drug gel of claim 1, wherein said deoxyguanosine derivative has the formula (1):

wherein X and Y are hydrogen bond donor or acceptor groups selected from-OH and-CH₂OH、-CH₂CH₂OH and I.

3. The nucleoside antiviral pharmaceutical gel of claim 1, wherein said nucleoside antiviral drugs comprise ganciclovir, acyclovir, penciclovir and derivatives thereof having the same therapeutic activity; the alkali metal ions comprise potassium ions and sodium ions; the alkali metal ion is provided by a salt species comprising the alkali metal ion.

4. The nucleoside antiviral pharmaceutical gel of claim 1, wherein said pH adjusting agent comprises sodium hydroxide, potassium hydroxide, phosphate buffer, boric acid buffer; the water is water for injection.

5. The nucleoside antiviral drug gel of claim 1, wherein said deoxyguanosine or a derivative thereof has a final molar concentration of 30 to 85mM or a final mass concentration of 0.8 to 2.3%; the mass concentration of the nucleoside antiviral drug is 0.01-0.5%; the ratio of the final molar concentration of the alkali metal ions to the final molar concentration of the deoxyguanosine or the derivative thereof is 1-2.5, wherein the final mass concentration of potassium ions is 0.1-0.85%, and the final mass concentration of sodium ions is 0.065-0.5%; the dosage of the pH regulator is properly added according to the pH value of the prepared solution until the pH value of the solution is neutral.

6. A process for preparing a nucleoside antiviral drug gel as claimed in any one of claims 1 to 5, which comprises: taking deoxyguanosine or a derivative thereof, a nucleoside antiviral drug, an alkali metal salt for providing alkali metal ions and water for injection in the concentration as defined in claim 5, heating to dissolve, adding a pH regulator to adjust the pH to 7.4, autoclaving, and cooling to room temperature to form gel.

7. The method of claim 6, wherein the heating temperature is 80-90 ℃.

8. A nucleoside antiviral pharmaceutical gel obtained by the process as claimed in claim 6 or 7.

9. The nucleoside antiviral drug gel according to claim 1 or 8, wherein said drug gel exhibits viscous fluid characteristics at low frequency with a loss angle of 0.3 to 0.95; the rubber is characterized by visco-elastic body under shearing force and has deformation recovery performance.

10. Use of the nucleoside antiviral pharmaceutical gel as claimed in claim 1 or 8 for the preparation of a medicament for the treatment of infections of the eye, skin and mucosal tissue.