RU2376038C2 - Method for manufacturing of medicinal soft contact lens - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is related to the field of medicine, in particular to ophthalmology, and may be used to create medicinal soft contact lenses (SCL), saturated with antibiotics and used for execution of antibiotic therapy in case of eye diseases and injuries. Method for preparation of medicinal SCL on the basis of polymer hydrogels by means of lens saturation with antibiotics from aqueous solutions, in which SCL are represented by lenses on the basis of cross-linked polymer 2-hydroxyethylmethacrylate, and for lens saturation with antibiotic they use aqueous solution, which contains mixture of antibiotics - fluoroquinolone and cephalosporin with mass ratio of fluoroquinole / cephalosporin from 0.06 to 0.67 and overall concentration of antibiotics in solution from 1.25 to 5.5 wt %. In method of medicinal SCL preparation fluoroquinole is substituted with ofloxacin or levofloxacin, and cephalosporin - with cefotaxim or cefuroxim. As SCL is saturated with fluoroquinole and cephalosporin from solution that contains mixture of antibiotics, sorption of both fluoroquinole and cephalosporin is increased compared to sorption from individual solutions.

EFFECT: invention makes it possible to increase time required to extract fluoroquinole from medicinal SCL 1,4 times, and time required to extract cephalosporin 4 times.

1 tbl, 15 ex

Description

The invention relates to medicine, in particular to ophthalmology, and can be used to create soft contact lenses (MCL) for medical use, used for perioperative antibiotic prophylaxis of infection and therapy for diseases and eye injuries.

It is known that the introduction of an antibiotic into the tissues of the eye using therapeutic MKL saturated with an antibiotic is an effective technique. However, in the manufacture of therapeutic MKL there are difficulties in choosing the optimal combination of antibiotic - polymer material MKL.

When creating therapeutic MKL, the choice of an antibiotic is determined by its antimicrobial activity, its ability to penetrate into the tissues of the eye, the breadth of the spectrum of action - the ability to suppress various microorganisms and the absence of irritating and toxic effects. Given this set of requirements, the choice of antibiotics in ophthalmology is very limited. Currently, it has been established that certain types of fluoroquinolones and cephalosporins [Vokhmyakov A.V., Okolov I.N., Gurchenok P.A. The choice of the optimal antibiotic for the prevention of infectious complications in ophthalmosurgery // Clinical Ophthalmology. - 2007. - T.8. - No. 1. - S. 37-40; Barry P., Seal D., Gettinby G. ESCRS of hrophylaxis of postoperative endophthmitis after cataract surgery; preliminary report of principal results from a European multicenter study // J. Cataract Refract Surgery. - 2006 - Vol.32. - No.3. p.407-409; Montan P., Wejde G., Koranyi G., Rylander M. Prophylactic intracameral cefuroxime. Efficacy in preventing endophthalmitis after cataract surgery // J. Cataract Refract Surgery. - 2002 - Vol. 28. - No.6. - P.977-981]. They are low toxic, effectively penetrate the moisture of the anterior chamber of the eye and have a wide spectrum of action.

Another, no less important, aspect of creating therapeutic MKL is the choice of the polymeric material from which the lens is made. The polymer material must bind the antibiotic due to the formation of hydrogen bonds, donor-acceptor interactions, dipole or ion-dipole interactions, etc. The strength of these bonds determines the rate of antibiotic release from MKL and, under certain conditions, allows for a prolonged mode of action of the drug substance.

It is known that MKL based on polymer hydrogels are able to bind antibiotics when the hydrogel is saturated from an aqueous solution of a drug substance. However, when MKL is saturated with some antibiotics, problems arise due to the fact that many of the most effective drugs are produced by the pharmaceutical industry in the form of dilute aqueous solutions with a substance concentration of 0.3-0.5 wt.%. For this reason, MCL, even under conditions of equilibrium saturation, cannot absorb the required amount of a drug substance to create a therapeutic concentration in the treatment zone. Those antibiotics that are released in a crystalline state, such as cephalosporins, can be used as sufficiently concentrated solutions. Due to this, it is possible to make therapeutic MKL with a high content of a drug substance. However, in this case, it is very difficult to ensure the release of the antibiotic from therapeutic MCL at an adjustable rate. As a rule, an antibiotic is released from therapeutic MKL at a very high speed.

A known method of manufacturing therapeutic MKL by saturation with fluoroquinolone from an aqueous solution with an antibiotic concentration of 0.3 wt.% [Karigard S.S., Jones L.W., Moresoli C. Ciprifloxacin interaction with silicon-based and conventiotional hydrogel contact lenses // Eye Contact Lens. - 2003 .-- Vol.29. - No.2. - P.83-89]. In this method, hydrogel lenses based on nonionic and ionic polymers of 2-hydroxyethyl methacrylate (HEMA) were used as MKL. The disadvantage of therapeutic MKL made by this method is that they are able to absorb and then release a relatively small amount of fluoroquinolone (ciprofloxacin). MCLs based on nonionic and ionic HEMA polymers release 0.168 mg and 0.127 mg of ciprofloxacin, respectively. Such amounts of ciprofloxacin do not allow the creation of therapeutic concentrations of the antibiotic in the tissues of the eye. This is also due to the fact that ciprofloxacin hardly overcomes the blood-ophthalmic barrier. Cephalosporins, when used in the form of concentrated solutions, can be sorbed by the lenses in much larger quantities, but as mentioned above, therapeutic MCLs cannot secrete an antibiotic of this type at an adjustable rate (see control examples 1-3).

The closest in technical essence to the present invention is a method (prototype) for the preparation of therapeutic MKL, according to which Acuvue lenses made of etafilcon-A material (ionic copolymer of 2-hydroxyethyl methacrylate and methacrylic acid) are saturated from aqueous solutions of antibiotics, including fluoroquinolones (ciprofloxacin and ofloxacin) [Hehl EM, Beck RL, Luthard K., Guthoff R., Drewelow B. Improved penetration of aminoglicosides and fluoroquinolones into the aqueous humor of patients by means of Acuvue contact lenses // Eur. J. Clin. Pharmacol - 1999. - Vol. 55. - No.4. - P. 317-323]. In the case of ofloxacin, it is possible to obtain therapeutic MKL, which ensures the creation of a therapeutic concentration of antibiotic in the moisture of the anterior chamber of the eye.

The disadvantage of therapeutic MKL made by the specified method is the very rapid release of the antibiotic from the lens, which does not allow to realize a prolonged mode of antibiotic release in the eye tissue.

The aim of the present invention is to provide therapeutic MKL capable of absorbing increased amounts of antibiotics and releasing them at an adjustable rate.

The goal is achieved due to the fact that the material of soft contact lenses is a cross-linked polymer of 2-hydroxyethyl methacrylate, and to saturate the lens with an antibiotic, an aqueous solution containing a mixture of antibiotics - fluoroquinolone and cephalosporin is used at a mass ratio of fluoroquinolone / cephalosporin from 0.06 to 0.67 and the total concentration of antibiotics in solution from 1.25 to 5.50 wt.%. Data on the sorption and desorption of antibiotics by soft contact lenses are presented in the table.

The essence of the invention lies in the fact that in the manufacture of therapeutic MKL, ofloxacin or levofloxacin is used as fluoroquinolone, and cefotaxime or cefuroxime is used as cephalosporin at a mass ratio of fluoroquinolone / cephalosporin from 0.06-0.67 and the total concentration of antibiotics in the aqueous solution of MK used for from 1.25 to 5.50 wt.%.

The authors of the present invention found that when MCL is saturated with fluoroquinolone and cephalosporin from a solution containing a mixture of antibiotics, there is an increase in the sorption of both fluoroquinolone and cephalosporin in comparison with the sorption of antibiotics from individual solutions.

The synergistic effect in the processes of antibiotic sorption is manifested only at the above ratio of fluoroquinolone / cephalosporin concentrations in the aqueous solution used to saturate MCL. When using concentration ratios of fluoroquinolone / cephalosporin of less than 0.06 or more than 0.67, the synergistic effect is weakened, while the sorption of fluoroquinolone can be even lower than in the case of using an individual solution of fluoroquinolone (see control examples 5-7).

Depending on the specific therapeutic task, within the framework of the revealed ratio of antibiotic concentrations and their total concentration in solution, narrower intervals should be chosen. If it is required to increase the sorption of cephalosporin, then at a concentration of fluoroquinolone in the solution of 0.3-0.5 wt.%, The concentration of cephalosporin should be varied within 0.7-5.0 wt.%. If it is necessary to increase the sorption capacity of MKL with respect to fluoroquinolone, then the concentration of cephalosporin in the solution should not exceed 1.5 wt.% At a concentration in the fluoroquinolone solution of 0.3-0.5 wt.%.

If it is necessary to maximize the duration of the release of antibiotics from therapeutic MKL (the creation of a prolonged action of medicinal substances), solutions should be used to saturate MKL with a concentration of fluoroquinolone of 0.3-0.5 wt.% And cephalosporin concentration of 0.7-1.5 wt.%. If rapid release of antibiotics from therapeutic MKL is required, then solutions with a maximum concentration of antibiotics should be used.

The inventors have found that for the realization of the effects described above, the optimal lenses are hydrogel MKL based on nonionic HEMA polymers. Other types of MKL, including lenses based on other polymer hydrogels, even with a higher water content, do not provide increased sorption of antibiotics and their release from therapeutic MKL in a prolonged mode (see control example 8).

Saturation of MKL with antibiotics is carried out by keeping the lenses in an aqueous solution containing a mixture of fluoroquinolone and cephalosporin at room temperature for at least two hours. In accordance with the present invention, any commercially available lenses made of non-ionic cross-linked HEMA polymers can be used as hydrogel MKLs, such as Benz 38T MKL Concor Concor LLC, Soflens 38 lenses from Bausch & Lomb, Cibasoft lenses Ciba Vision et al. Before saturating with antibiotics, the lenses were kept in distilled water for at least two hours to remove buffer and preservative additives dissolved in the hydrogel.

In the study of sorption of antibiotics and their isolation from LMLC, the following methodology was used.

MKL, which has reached equilibrium saturation in an antibiotic solution, is placed in 100 ml of an isotonic sodium chloride solution at a temperature of 37 ° C and, at certain intervals, 1 ml samples are taken. The optical density of the solution is measured on a spectrophotometer and the antibiotic concentration in the solution is calculated from the calibration data. The experiment is carried out until the increase in the optical density of the solution, i.e. until the complete desorption of the antibiotic from the lens into the solution. The completeness of desorption of the antibiotic from the lens is also controlled by the absence of antibiotic absorption bands in the UV spectrum of the hydrogel. The amount of antibiotic Wo sorbed by the lens is calculated by the formula

Wo = [A] × V,

[A] is the concentration of the antibiotic in solution in mg / ml.

V is the volume of isotonic sodium chloride solution (in ml) into which the antibiotic is desorbed.

Thus, in experiments of this type, the amount of antibiotic bound by the lens is simultaneously determined, and the rate of release of the antibiotic from the lens is estimated by analyzing samples taken from the solution at various time intervals.

Antibiotic concentrations in the solutions were determined using absorption bands in the UV spectra of 250 nm (for cephalosporin) and 289 nm (for fluoroquinolone) as analytical ones. Since these bands in the UV spectrum are not completely separated, the following system of equations was used to calculate the concentration of each antibiotic

D ²⁸⁹ = А _Ф / К _Ф ²⁸⁹ + А _Ц / К _Ц ²⁸⁹

D ²⁵⁰ = А _Ф / К _Ф ²⁵⁰ + А _Ц / К _Ц ²⁵⁰ ,

where D ²⁸⁹ and D ²⁵⁰ are the optical density of the solution at wavelengths of 289 and 250 nm, respectively; _KF ^289, _KF ^250, _D ²⁸⁹ K, R _D ²⁵⁰ - absorption coefficients for cephalosporin fluoroquinolone and at respective wavelengths; And _F , And _C - the concentration of antibiotics. Absorption coefficients (in mg / l) were preliminarily determined using calibration solutions with a known concentration of antibiotics (K _F ²⁸⁹ = 0.0146, K _F ²⁵⁰ = 0.0303, K _C ²⁸⁹ = 0.0289, K _C ²⁵⁰ = 0.0365). Thus, the experimental determination was reduced to measuring the optical density of the solution at two wavelengths and calculating the concentrations of antibiotics using the equations

A _Ф = 18.8 (D ²⁸⁹ -0.44D ²⁵⁰ )

A _C = 36.5 (D ²⁵⁰ -0.033A _F )

The desorption rate was characterized by the time of isolation of half the amount of antibiotic contained in the lens from the LMLC before the start of the desorption process - t _1/2 .

t _{1/2 was} calculated from graphical dependencies plotted in the coordinates log (W / Wo) -lgt, where W is the amount of antibiotic released from LMLC into physiological saline at time t.

The invention is illustrated by the following examples.

Example 1 (control).

MKL Company "Concor Firm" Benz 38T Concor, made from a cross-linked GEMA polymer and having a water content of 38 wt.%, Was placed in 200 ml of distilled water for 20 hours to remove buffering and preserving additives. The washed lens was immersed in 5 ml of a 1.5% solution of cefotaxime for 18 hours. Sorption of the antibiotic was carried out at room temperature. An antibiotic-saturated lens? removed from the solution, droplets from the surface of the MCL were removed with filter paper, and then the lens was immersed in 100 ml of isotonic sodium chloride solution, preheated to 37 ° C. At certain intervals, samples were taken from the solution and their spectrophotometric analysis was performed for the content of the antibiotic. Samples were taken until the antibiotic was completely released from MKL. The value of t _{1/2 was} calculated from the kinetic dependence of desorption at a value of log (W / Wo) equal to -0.301. The results are shown in the table.

Example 2 (control).

The experiment was carried out as in example 1, but a 5% solution of cefotaxime was used as an antibiotic. The results are shown in the table.

Example 3 (control).

The experiment was carried out as in example 1, but a 5% solution of cefuroxime was used as an antibiotic. The results are shown in the table.

Example 4 (control).

MKL company Vistakon Acuvue, made from a cross-linked ionic copolymer of HEMA and methacrylic acid and having a water content of 58 wt.%, Was placed in 200 ml of distilled water for 18 hours to remove buffering and preserving additives. The washed lens was immersed in 5 ml of 0.3% ofloxacin solution for 16 hours. Further, the experiment was carried out as in example 1. The results are shown in the table.

Example 5 (control).

The experiment was carried out in the same way as in example 1, but a mixture of levofloxacin and cefotaxime at concentrations of 0.5 and 0.4 wt.%, Respectively, and wt. ratio 1.25. The results are shown in the table.

Example 6 (control).

The experiment was carried out in the same way as in example 1, but as an antibiotic, a mixture of levofloxacin and cefotaxime was used at concentrations of 0.5 and 9.5 wt.%, Respectively. ratio 0.053. The results are shown in the table.

Example 7 (control).

The experiment was carried out as in example 1, but a 0.5% solution of levofloxacin was used as an antibiotic. The results are shown in the table.

Example 8 (control).

The experiment was carried out in the same way as in example 1, but the Concor Benz 55T lens made of a copolymer of HEMA and N-vinylpyrrolidone and having a water content of 55 wt.%, And as an antibiotic, 0.3%, was used as MKL ofloxacin solution. The results are shown in the table.

Example 9 (control).

The experiment was carried out in the same way as in example 8, but the lens of LLC Concor Firm Concor Benz 38T was used as the MCL. The results are shown in the table.

Example 10

The experiment was carried out as in example 1, but as an antibiotic, a solution containing a mixture of fluoroquinolone and cephalosporin was used at the following antibiotic concentrations: ofloxacin - 0.3 wt.%, Cefotaxime - 1.05 wt.%. The saturation of the lens was produced within 8 hours. The results are shown in the table.

Example 11

The experiment was carried out in the same way as in example 1, but a solution containing a mixture of fluoroquinolone and cephalosporin was used as antibiotic at the following antibiotic concentrations: levofloxacin - 0.5 wt.%, Cefotaxime - 0.75 wt.%. The results are shown in the table.

Example 12

The experiment was carried out as in example 1, but as an antibiotic, a solution containing a mixture of fluoroquinolone and cephalosporin was used at the following antibiotic concentrations: levofloxacin - 0.5 wt.%, Cefotaxime - 1.5 wt.%. The results are shown in the table.

Example 13

The experiment was carried out in the same way as in example 1, but a solution containing a mixture of fluoroquinolone and cephalosporin was used as antibiotic at the following antibiotic concentrations: levofloxacin - 0.5 wt.%, Cefotaxime - 2.5 wt.%. The results are shown in the table.

Example 14

The experiment was carried out in the same way as in example 1, but a solution containing a mixture of fluoroquinolone and cephalosporin was used as an antibiotic at the following antibiotic concentrations: levofloxacin - 0.5 wt.%, Cefotaxime - 5.0 wt.%. The results are shown in the table.

Example 15

The experiment was carried out as in example 1, but as an antibiotic, a solution containing a mixture of fluoroquinolone and cephalosporin was used at the following antibiotic concentrations: levofloxacin - 0.5 wt.%, Cefuroxime - 2.5 wt.%. The results are shown in the table.

The above examples show that when sorption of fluoroquinolone and cephalosporin from a solution containing a mixture of antibiotics, there is an increase in the sorption of both fluoroquinolone and cephalosporin in comparison with sorption from individual solutions, while the time of isolation of fluoroquinolone from therapeutic MCL can be increased by 1.4 times, and cephalosporin 4 times. Compared with the prototype method, the time for the isolation of fluoroquinolone (ofloxacin) from therapeutic MKL is increased 10 times (see examples 4 and 10). It should also be noted that the use of two antibiotics for the manufacture of therapeutic MKL simultaneously increases the efficiency of using therapeutic MKL by expanding the spectrum of antimicrobial action of the antibiotic mixture.

The claimed invention meets the criterion of "novelty", because the inventors for the first time proposed a method for manufacturing therapeutic MKL by saturating a drug with an aqueous solution containing a mixture of two antibiotics (fluoroquinolone and cephalosporin) of a certain composition, which enhances the sorption of each of the antibiotics in comparison with sorption from individual solutions and increases the time for the release of antibiotics from the treatment MKL, i.e. there is an effect of prolonged action of drugs.

The claimed invention meets the criterion of "inventive step", because it does not use well-known technical solutions. In comparison with the prototype method, instead of Acuvue lenses made from the HEMA ion copolymer, lenses made from the nonionic crosslinked polymer HEMA are used as MKL, and instead of the individual fluoroquinolone solution used to saturate the MKL, a solution containing a mixture of antibiotics fluoroquinolone and cephalosporin is used when the mass ratio of fluoroquinolone / cephalosporin is from 0.06 to 0.67 and the total concentration of antibiotics in solution is from 1.25 to 5.50 wt.%.

Compliance with the criterion of "industrial applicability" is determined by the possibility of widespread use of the invention in clinical practice due to the use of commercially available MKL and antibiotics and the simple manufacturing technology of therapeutic MKL, which can be implemented in any ophthalmic clinic.

Claims (2)

1. A method of manufacturing a therapeutic soft contact lens based on a polymer hydrogel by saturating the lens with antibiotics from aqueous solutions, characterized in that the material of the soft contact lenses is a cross-linked polymer of 2-hydroxyethyl methacrylate, and to saturate the lens with an antibiotic, an aqueous solution containing a mixture of antibiotics - fluoroquinolone and cephalosporin with a mass ratio of fluoroquinolone: cephalosporin from 0.06 to 0.67 and a total concentration of antibiotics in solution from 1.25 to 5.50 wt.%. 2. A method of manufacturing a therapeutic soft contact lens according to claim 1, characterized in that ofloxacin or levofloxacin is used as fluoroquinolone, and cefotaxime or cefuroxime as cephalosporin.