JP3894282B2 - Pharmaceutical composition containing a viscoelastic substance and a drug - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition for preventing and / or treating infection and inflammation associated with intraocular surgery and intra-articular injection.
[0002]
[Prior art]
At present, viscoelastic substances such as sodium hyaluronate and chondroitin sulfate are frequently used in clinical medicine for the purpose of maintaining space, protecting the surface, or reducing friction. In particular, it is a basic drug indispensable for viscoelastic materials in ophthalmic surgery, for example, anterior segment surgery such as cataract surgery.
[0003]
For example, in cataract surgery, it is used for the purpose of preventing the anterior chamber from disappearing when an intraocular lens is inserted. Recently, it is also used for holding the anterior chamber at the time of anterior capsulotomy and protecting the corneal endothelium at the time of ultrasonic emulsification (Ophthalmic surgery, P209-214, Vol. 13, No. 2, 2000). In cataract surgery, viscoelastic substances are injected into the anterior chamber or capsular bag in almost all cases.
[0004]
In addition, the precision and safety of the operation are enhanced by maintaining the intraocular space by using a viscoelastic substance. In particular, there is an era in which cataract surgery cannot be performed without a viscoelastic substance. In addition, new concepts such as corneal endothelium protection (ie, soft shell technique) using a low molecular weight surface-protective viscoelastic substance have been established.
[0005]
Furthermore, such viscoelastic materials are also used for orthopedic treatment of joint diseases. For example, administration of a viscoelastic substance into a joint cavity by injection is used as a therapeutic agent for knee osteoarthritis, shoulder periarthritis, and rheumatoid arthritis.
[0006]
When a viscoelastic material is used in such a surgical operation in an aseptic space such as an eyeball or a joint cavity, there is a possibility that bacteria or the like may enter a part of the living body that has been sterile before the operation. In addition, it is considered that the intraocular residual of the viscoelastic substance applied in the eye causes postoperative inflammation and increases postoperative intraocular pressure.
[0007]
A general anterior segment surgery is completed after the viscoelastic material in the eye is removed by suction. However, complete removal of the viscoelastic substance from the eye is difficult, and each formulation maker has revealed that the viscoelastic substance remains in the anterior chamber for a certain period of time. The viscoelastic substance remaining in the anterior chamber is discharged out of the eye mainly by the flow of anterior chamber water, but a small amount is decomposed by enzymes in the eye. For example, biscort (trademark, approval number 21100AMY00233000), a designated pharmaceutical product for ophthalmic surgical protective agents, has an elimination half-life from the anterior chamber of about 4 hours when injected intraocularly.
[0008]
Conventionally, antibacterial drugs are applied when viscoelastic substances are applied to such a sterile space, or when infection after surgery is expected. For example, if it is in the eyeball, the antibacterial agent is applied systemically by internal use or infusion or locally by use of eye drops.
[0009]
For example, the most serious complication after cataract surgery is endophthalmitis. When endophthalmitis develops, various antibacterial therapies are given by instillation, internal use, infusion, and intraocular injection. However, once endophthalmitis develops, resistance to these therapies arises, resulting in a state in which vitrectomy (ie intraocular separation) must be performed. Furthermore, even if it is healed, visual acuity is rarely improved to the extent expected before cataract surgery, and even worse than the pre-operative condition, and even blindness.
[0010]
In this way, external local treatments such as internal use of antibacterial drugs, infusions, and eye drops have a high risk of disturbing normal resident bacterial layers and generating resistant bacteria. It is a big problem in the field. There is also a possibility that the viscoelastic substance itself used in the body wraps bacteria and isolates it from physiological sterilization and bactericidal action.
[0011]
[Problems to be solved by the invention]
In view of the above situation, it is an object of the present invention to prevent and / or prevent bacterial infection and / or inflammation in procedures such as using viscoelastic materials in sterile spaces, particularly in procedures such as intraocular surgery and intra-articular injection. Or to provide a pharmaceutical composition that can be treated.
[0012]
[Means for Solving the Problems]
In order to achieve the above object, the present inventors have found the following means as a result of intensive studies. That is, it is a pharmaceutical composition containing a drug and a viscoelastic substance.
[0013]
DETAILED DESCRIPTION OF THE INVENTION
According to an embodiment of the present invention, a pharmaceutical composition containing a drug and a viscoelastic substance is provided. The present invention is based on the finding of the present inventors that the viscoelastic substance may be involved in the colonization and growth of bacteria that have invaded.
[0014]
The inventors have elucidated the onset mechanism of endophthalmitis by experiments so far mainly following the development process. That is, as a result of experiments using an in vitro endophthalmitis model using rabbits, although the degree of inflammation varies greatly depending on the difference in bacterial species and the amount of bacteria, basically the inflammation spread of endophthalmitis It was clearly observed in the outflow pathway of the anterior aqueous humor. It was suggested that bacteria and bacterial toxins may be excreted by this route. Here, the outflow route of the anterior aqueous humor is a route connecting the anterior chamber-corner angle-fiber column body-Schlemm's canal-collecting duct-aqueous humor vein.
[0015]
That is, the distribution of bacteria in the experimental model was very little found in the vitreous. Although the anterior chamber was filled with pus during high-grade inflammation, the bacteria basically settled and proliferated so as to crawl the front of the iris. This is clinically considered to reflect the fact that culturing from within the eye is difficult to obtain with specimens in the vitreous and anterior aqueous humor. It was suggested that even if bacteria were not obtained clinically as a specimen, the bacteria may have settled on the surface of the intraocular lumen (for example, the iris surface, etc.). (Ophthalmology Annual Meeting 2001)
[0016]
Intraocular infection in a special environment of aphakic eyes can be explained as follows: (1) The change in lens-iris near distance increases the influx of bacteria into the lens; (2) The possibility of bacterial growth in the lens cortex in the lens capsule ( In other words, the lens capsule itself is a huge invasion prevention film against bacteria), and 3) The possibility of turbulence, turbulence or stagnation of the intraocular aqueous humor outflow due to a drastic decrease in the lens volume may be promoted. It is believed that there is. Another factor that creates a state that is not a normal phakic eye is thought to be the inhibition of normal aqueous humor self-purification by viscoelastic substances. By clarifying the mechanism of the development of such endophthalmitis, the present inventors have achieved the present invention.
[0017]
There are roughly two types of viscoelastic materials that can be used in the embodiments of the present invention. That is, a high molecular viscoelastic substance having a strong space retention ability and a low molecular viscoelastic substance having an excellent surface protecting ability. Any viscoelastic material belonging to any of these categories can be used in the present invention.
[0018]
The viscoelastic substance used in the embodiments of the present invention generally includes intraocular surgery such as hyaluronic acid or its non-toxic salt, chondroitin sulfate or its non-toxic salt, hydroxypropyl methylcellulose (HPMC), etc. And / or any viscoelastic material used in intra-articular injection.
[0019]
The term “antibacterial agent” used in the embodiments of the present invention indicates a substance having antibacterial and antifungal effects, and may be a substance produced by a living organism or a synthesized substance. For example, examples of such antibacterial agents include streptomycin, dihydrostreptomycin, dihydrodeoxystreptomycin, fradiomycin, neomycin, paromomycin, aminocidin, kanamycin, kanamycin B, tobramycin, dibekacin, amikacin, gentamicin, micronomycin, ribostamycin, Aminoglycoside antibiotics such as bekanamycin and sisomicin, tetracycline antibiotics such as chlortetracycline, oxytetracycline, tetracycline, doxycycline and minocycline, chloramphenicol antibiotics such as chloramphenicol and thianphenicol, erythromycin , Spiramycin, acetylspiramycin, midecamycin, leucomycin, kitasama Macrolide antibiotics such as syn, josamycin and oleandomycin, lincomycin antibiotics such as lincomycin and clindamycin, benzylpenicillin, phenoxymethylpenicillin, pheneticillin, propicillin, phenpenicillin, methicillin, oxacillin, cloxacillin, dicloxacillin Flucloxacillin, ampicillin, amoxicillin, cyclacillin, hetacillin, mecillinam, pibmesilinum, pivampicillin, tarampicillin, bacampicillin, carbenicillin, calindacillin, calfecillin, ticarcillin, sulbenicillin, piperacillin, and pipelocillin Cephaloridine, cefazolin, cephaloglycin, cephalexin Cefadroxyl, cefatrizine, cefaclor, cefamandol, cefuroxime, cefothium, cefoxitin, cefmethazole, cefsulosin, cefoperazone, ceftizoxime, cefotaxime, ceftazidime, cefixime, cefbuperazone, cefotetane, cefminox, ratofoxime, Monobactam antibacterials, nystatin, amphotericin B, tricomycin, pimacillin, griseofulvin, flucytosine, clotrimazole, miconazole, econazole, isoconazole, ketoconazole, fluconazole and itraconazole and other antifungal agents, sulfathiazole, sulfamethizole, sulfisomidine , Sulfamethoxazol Sulfa drugs such as sulfamethoxypyrimidine, sulfamethoxine, sulfaphenazole, sulfamonomethoxine, sulfaphenazole, sulfisoxazole and sulfamonomethoxine, 4,4'-diaminodiphenyl Sulfone agents such as sulfone, glucosulfone sodium, sulfoxone sodium and thiazole sulfone, anti-tuberculosis drugs such as paraaminosalicylic acid, isoniazid, etionamide, porothionamide and ethambutol, nalidixic acid, pipemidic acid, ofloxacin, norfloxacin, enoxacin, ciprofloxacin, Quinolone antibacterials such as tosufloxacin, levofloxacin and sparfloxacin, nitrofurantoin, furazolidone, niphrate, niphraden, nitrofurazone and niflofurone Nitrofuran compounds such as shim, dihydrofolate reductase inhibitors such as trimethoprim and pyrimesamine, and cycloserine, fosfomycin, bacitracin, vancomycin, biomycin, capreomycin, fusidic acid, rifampicin, polymyxin B, colistin and gramicidin S, etc. Any antibacterial agent that is commonly used may be used.
[0020]
Anti-inflammatory agents used in embodiments of the present invention include steroids such as dexamethasone, fluorometholone and betamethasone, and aspirin, mefenamic acid, indomethacin, indomethacin farnesyl, sulindac, acemetacin, diclofenac sodium, mofezolac, nabumetone, thiaprofenic acid, oxaprozin , Non-steroidal antipyretic analgesics such as napyroxen, pranopyrophene, zaltoprofen, ibuprofen, ketoprofen, loxoprofen sodium, flurbiprofen axetil, ampiroxicam, sulpyrine, thiaramide hydrochloride, acetaminophen and azulenesulfonic acid, etc. It may be any anti-inflammatory agent that is used routinely.
[0021]
The pharmaceutical composition according to an embodiment of the present invention can be used in ophthalmic internal eye surgery such as cataract, glaucoma and vitreous surgery, and orthopedic procedures such as intra-articular injection for the treatment of various joint diseases. .
[0022]
For example, in the case of ophthalmic surgery, particularly cataract surgery, maintaining the anterior chamber is one major barrier to the surgery. That is, when the closed space called the eyeball is incised, the content liquid (that is, the anterior aqueous humor) flows out due to the intraocular pressure, and the eyeball collapses. Since the cataract operation is such an intraocular operation, it is an essential condition for the operation to protect the intraocular lumen (particularly the anterior chamber) as a working space from collapse. Another characteristic technique for cataract surgery is insertion of an intraocular lens. Also in this case, it is very important to form a space for inserting a lens in the lumen (that is, the lens capsule). In such a case, the pharmaceutical composition of the present invention can be used satisfactorily.
[0023]
Regarding the mixing of a viscoelastic substance and an antibacterial agent, a pharmaceutical composition for intraperitoneal administration is disclosed in Japanese Patent Laid-Open No. 9-208476 and a composition for oral cavity in Japanese Patent Laid-Open No. 10-182390. However, both are intended for therapeutic use in the affected area, and also for the slow release of medicinal ingredients from viscoelastic substances. Accordingly, in the present application, the purpose of use, the site of use, and the effects obtained are different from the invention described in the claims we seek.
[0024]
For example, intraocular treatment for endophthalmitis with a mixture of a viscoelastic substance and an antibacterial agent is described in Acta Ophthalmol 1991, Feb; 69 (1): 50-6. This paper states that the use of viscoelastic substances as the administration method of antibacterial agents is useful because it increases the half-life of the antibacterial agents. This technique is also different from the invention disclosed in this application. The pharmaceutical composition used according to embodiments of the present invention is primarily intended for use for the treatment and prevention of endophthalmitis. Therefore, as far as we know, there is no disclosure or implementation of using antibacterial agents or anti-inflammatory agents for viscoelastic materials during cataract surgery and viscoelastic materials during intra-articular injection.
[0025]
The inventors have found that it is useful to mix an antibacterial agent with a viscoelastic substance in order to prevent the formation of an infection caused by bacteria that have entered the closed space. Similarly, the present inventors have found that mixing an anti-inflammatory agent with the pharmaceutical composition of the present invention is very useful for preventing inflammation associated with infection or inflammation due to tissue invasion. . The present invention has been achieved based on such findings.
[0026]
Conventionally, viscoelastic substances are applied to aseptic spaces such as intraocular and joint joints using viscoelastic substances alone. Similarly, application of antibacterial agents to the above-mentioned sites has been performed by systemic administration such as internal use and infusion, or local administration such as eye drops and intraocular injection. Therefore, the idea of using a pharmaceutical composition containing a viscoelastic substance and a drug such as an antibacterial agent or an anti-inflammatory agent is a breakthrough in intraocular surgery and intraarticular injection, and has an excellent effect. It is possible to obtain. That is, it is possible to effectively prevent infectious diseases that can occur after the use of viscoelastic substances and the accompanying inflammation. Furthermore, the pharmaceutical composition of the present invention prevents bacteria from escaping from physiological sterilization and bactericidal action due to the presence of the viscoelastic substance.
[0027]
Here, the entry of bacteria into the closed site is mainly caused by bacteria that have entered from the outside during treatment or surgery. However, the pharmaceutical composition of the present invention is also effective against infection and inflammation caused by endogenous bacteria such as movement of bacterial in the body to the above-mentioned closed site, which is often seen in the case of immunocompromised state.
[0028]
The viscoelastic substances, antibacterial agents and anti-inflammatory agents used in the pharmaceutical composition used in the embodiments of the present invention are not limited to the above, and various modifications may be used without departing from the concept and scope of the present invention. It will be apparent to those skilled in the art that this is possible.
[0029]
The present invention will be further described below by way of examples, but these are described for illustration only and are not intended to limit the present invention.
[0030]
【Example】
Example 1: Measurement of viable bacterial count in the presence of a viscoelastic substance
<Method>
The growth rate of bacteria in the presence of the viscoelastic substance of the present invention was tested. The bacterial species used were Staphylococcus aureus MK99-3 (hereinafter referred to as S. aureus) and Stenotrophomonas maltophilia TK-1, hereinafter referred to as S. aureus. Called Martofilia). Bacterial culture was carried out in a penicillin cup placed on an agar plate. With saline, 0.5 McFarland (McFarland, 1.5 × 10 ⁸ CFU / ML) and those prepared to 0.5 McFarland with Mueller Hinton broth were prepared. As the first group, Hyalon sodium hyaluronate formulation ^R (Pharmacia & Upjohn, hereinafter referred to as HL) 0.1 mL of the bacterial solution was injected into the penicillin cup and allowed to stand, and then 0.1 mL of the bacterial solution was added. As the second group, 0.1 mL of the bacterial solution alone was penicillin cup. The one injected inside was placed in an incubator at 35 ° C. Growth curves were determined after 2, 4, 6 and 20 hours of culture.
[0031]
<Results and discussion>
Proliferation occurred more rapidly in the liquid culture medium prepared than in the liquid culture medium. In physiological saline, S.P. The growth of Aureus was slight, but S. A clear growth was observed in maltophilia. The growth curve when HL was mixed in both physiological saline and liquid medium did not produce a significant difference from the growth curve when HL was not mixed. HL includes S.I. Aureus and S. Bacterial growth effect and bacterial inhibitory effect on maltophilia were not observed (see FIG. 1 and FIG. 2).
[0032]
Several cases of viscoelastic contamination have been reported. From the growth curve obtained from this experiment, it can be seen that HL is sufficiently contaminated because it has neither a bacterial growth effect nor a suppressive effect. Although the hypertrophic state that promotes the growth of bacteria cannot normally occur, It is necessary to pay attention to contamination in bacteria that can grow in a low-impact environment such as maltophilia.
[0033]
Example 2: Measurement of change in antibacterial action by viscoelastic material
<Method>
Using Bacillus subtilis (ATCC6633, hereinafter referred to as B. subtilis), the change in antibacterial action by the viscoelastic substance was measured. The viscoelastic substances are HL of sodium hyaluronate and opegan high ^R (Santen, hereinafter referred to as OP), biscort of sodium hyaluronate / sodium chondroitin sulfate ^R (Alcon, hereinafter referred to as VS) was used. The antibacterial drug is levofloxacin Cravit ^R (Santen, hereafter referred to as LVFX) and nofloxacin ^R (Ari, hereinafter referred to as NFX) was used. 1.4 x 10 in 4% heart infusion medium ⁸ B. CFU / ML Subtilis was applied in 0.1 mL. Then, the penicillin cup was left still on the culture medium and the chemical solution was injected. The chemicals used the following combinations:
1) A group in which 0.1 mL of each antibacterial agent was injected into a penicillin cup, and each antibacterial agent used 5 concentrations from 10 μg / mL to 0.625 μg / mL (ie, an antibacterial agent single agent group);
2) A group in which 0.1 mL of each viscoelastic substance is injected into a penicillin cup (that is, a viscoelastic substance single agent group);
3) A group in which 0.1 mL of each antibacterial agent prepared to 5 μg / mL or 2.5 μg / mL was gently injected from the top after each viscoelastic substance was injected and allowed to stand in a 0.1 mL penicillin cup (ie, multi-layer group) );
4) A group in which 0.1 mL of each viscoelastic substance and 0.1 mL of each antibacterial agent prepared to 5 μg / mL or 2.5 μg / mL were mixed and then injected into a penicillin cup (ie, a mixed group).
[0034]
Each of these groups was cultured in an incubator at 35 ° C., and the inhibition circle diameter after 24 hours was measured. From the results of the antimicrobial agent single agent group, the standard concentration-inhibition circle diameter curve of each antimicrobial agent was determined.
[0035]
<Results and discussion>
From the blocking circle of the viscoelastic material carrier, HL, OP, VC are Bacterial inhibitory action against subtilis was not seen. The above results are shown in FIG.
[0036]
In comparison with the standard curve of inhibition circle diameter-antibacterial drug concentration in LVFX, when viscoelastic substance is layered on the lower layer and LVFX is layered on the upper layer, all of HL, OP and VC have decreased antibacterial action, In particular, it was remarkable in VC. When the viscoelastic substance and LVFX were mixed, the inhibitory action by the antibacterial agent was slightly decreased compared to the standard curve of the inhibition circle diameter-antibacterial agent concentration for all of HL, OP, and VC (see FIG. 4). See).
[0037]
Compared to the standard curve of inhibition diameter-antibacterial drug concentration in NFX, when viscoelastic substance is layered on the lower layer and NFX is layered on the upper layer, all of HL, OP, and VC show a decrease in the antibacterial action. Especially, it was prominent in VC. When the viscoelastic substance and NFLF were mixed, the inhibitory action by the antibacterial agent was slightly reduced compared to the standard curve of the inhibition circle diameter-antibacterial agent concentration for all of HL, OP, and VC (see FIG. 5). See).
[0038]
In the multistory group, inhibition of the formation of the inhibition circle by the antibacterial drug was observed. From this, it is thought that there exists suppression of the antibacterial agent transfer by a viscoelastic substance.
[0039]
When divided by viscoelastic material, in the multi-layer group, HL and OP saw almost the same reduction in the diameter of the blocking circle, but VC had a further reduction in the diameter of the blocking circle. This may be due to differences in the concentration-molecular weight and viscosity of the viscoelastic substance, but further investigation is necessary, and this may conversely cause the endothelial protective ability of VC. I must. However, it was inferred that in the drug mixture group, all of HL, OP, and VC did not inhibit the antibacterial agent action and were not a chemical suppression but a physical barrier by the layer.
[0040]
Bacterial infection requires colonization before the growth of bacteria, and once settled bacteria become difficult to disinfect due to the formation of a biofilm or the like. Even in actual ophthalmology, postoperative antibacterial eye drops are used against bacteria that have passed through disinfection and antibacterial drugs. However, since the viscoelastic substance used during the operation cannot be completely removed from the eye, and viscoelastic substances that are likely to remain in the eye have begun to be used, there is a risk that the possibility of colonization of bacteria is increased. This is not only a problem of migration of antibacterial drugs, but also the aqueous humor clearance and the protective action of the viscoelastic substance against the immune reaction.
[0041]
In the study of Oda et al. (2001, Japan Ophthalmological Society) and inventors (Tanaka et al., The Association for Research in Vision and Ophthalmology Annual Meeting 2001 is scheduled to be announced), bacteria administered into the anterior chamber were quickly eliminated. After 24 hours, it is shown that almost disappears from the anterior aqueous humor. The pathological image of the experiment reports that the bacterial culture from the anterior chamber water was negative even when bacteria were colonized and proliferated on the corneal endothelium or iris surface. It is considered that this may be due to aqueous humor flow clearance or phagocytosis by leukocytes.
[0042]
This time, the effectiveness of the antibacterial drug was almost completely maintained by mixing the viscoelastic material with the antibacterial drug. From this, it is suggested that it is possible to prevent bacterial colonization due to inhibition of migration of antibacterial agents by applying an antibacterial agent to the viscoelastic substance itself. It is also expected to have an effect of preventing bacterial colonization due to the aqueous humor clearance and the protective action of the viscoelastic substance against the immune reaction.
[0043]
As a method of drug administration to the eyeball, attention can be paid to the sustained release action of the antibacterial agent by the viscoelastic substance. In particular, applying an antibacterial agent to a viscoelastic substance that will remain on the inner surface of the eye for 24 hours from immediately after surgical invasion can sufficiently exert the effect of the antibacterial agent at the most necessary time and place. Is possible.
[0044]
In the future, the need for viscoelastic materials will increase. Therefore, further development and technological progress are expected. In such a situation, it is desirable from the standpoint of preventing infectious diseases that these viscoelastic substances are provided with an antibacterial action in addition to a physical space retention ability and an endothelial protection ability.
[0045]
Examples of the composition of the present invention are shown below. These examples are used for illustrative purposes only and are not intended to limit the invention in any way.
[0046]
Example 3: Composition
1. Ophthalmic composition
Viscoelastic substances are widely used to protect the corneal endothelium during the formation of the anterior chamber and the posterior capsule bag during cataract surgery. Such a procedure is indispensable in the current global standard cataract surgery including Japan, and is included in insurance medical care in Japan.
[0047]
Infectious diseases such as endophthalmitis are one of the most serious complications of intraocular surgery with cataract at the head. At the time of the occurrence of these infectious diseases, antibacterial eye drops, intraocular antibacterial drug injection, and vitrectomy are performed, but the visual prognosis is poor. Conventionally, viscoelastic substances have been used without being mixed with drugs, and their molecular weight ranges from 10,000 to 20 million. In the present invention, any of these substances can be used.
[0048]
According to the embodiment of the present invention, a pharmaceutical composition obtained by mixing an antibacterial agent or an anti-inflammatory agent with a viscoelastic substance without changing the conventionally used concentration is used during cataract surgery. Moreover, at the time of the mixing, it is desirable that the antibacterial agent is mixed so as to maintain a concentration satisfying the intraocular effective concentration. Two examples of ophthalmic compositions are shown below.
[0049]
<Composition 1>
Example 1 is shown below.
[0050]
In 1 ml of composition
Sodium hyaluronate 30mg,
Chondroitin sulfate sodium 40mg
Contains 2 μg of levofloxacin.
[0051]
The above mixing examples were set with reference to the concentration of the viscoat (trademark) viscoelastic material conventionally used in the ophthalmic field and the conventionally used clabit ophthalmic solution (trademark, sold by Santen Pharmaceutical Co., Ltd.). Each concentration is an effective intraocular concentration. For the intraocular effective concentration of levofloxacin, see “Pharmacologic action and intraocular dynamics of levofloxacin eye drops”, ANTIBIOTICS & CHEMOTHERAPY Vol. 16, no. Refer to 8, 76-84 (2000) for details.
[0052]
<Composition 2>
Next, Example 2 is shown.
[0053]
In 1 ml of admixture
Sodium hyaluronate 100mg,
Contains 1 μg of ofloxacin.
[0054]
By the above, it is possible to prevent the occurrence of infectious diseases including endophthalmitis after cataract surgery.
[0055]
2. Joint composition
In joint diseases such as knee osteoarthritis, shoulder periarthritis, and rheumatoid arthritis, ADL disorder due to joint pain is a major problem. Conventionally, in order to reduce joint pain caused by destruction of articular cartilage, viscoelastic substances are injected into joint spaces all over the world. Again, bacteria may enter the joint cavity that is inherently sterile by the procedure. It is well known that bacterial infection of joints immediately causes pyogenic arthritis, and the prognosis is extremely poor even when systemic or local administration of antibacterial drugs is given, resulting in severe joint dysfunction. This is what most orthopedic surgeons fear. Mixtures of antibacterials and viscoelastic substances are also expected to prevent such bacterial infections of joints.
[0056]
Furthermore, inflammation of the joint synovium becomes a problem as a side effect when the viscoelastic substance is injected into the joint. From a preventive standpoint against inflammation of the articular periosteum, a mixture of an anti-inflammatory agent and a viscoelastic substance is considered to be effective.
[0057]
Conventionally used viscoelastic substances are used without being mixed with a drug, and their molecular weight ranges from 10,000 to 20 million, but any substance can be used in the present invention.
[0058]
Moreover, it is possible to use for joint cavity injection according to the aspect of the present invention by mixing an antibacterial agent or an anti-inflammatory agent with a viscoelastic substance without changing the concentration used conventionally. Below, the example of the composition for joints is shown.
[0059]
<Composition 3>
In 1 mL of composition
Sodium hyaluronate 25mg
Contains 500 mg of lincomycin hydrochloride.
[0060]
By mixing these materials, a third example of the composition of the present invention is produced. Such a pharmaceutical composition can prevent the occurrence of infectious diseases including arthritis after treatment.
[0061]
【The invention's effect】
As described above, according to the present invention, it is possible to prevent and / or treat infectious diseases caused by bacteria that have entered during use of a viscoelastic substance. In addition, the process of bacterial colonization and growth that occurs upon application of a viscoelastic substance alone can be stopped. Moreover, generation | occurrence | production of the resistant microbe which can arise by only using a small amount of antibacterial agents for a use site | part, ie, the whole body or local therapy from the outside, such as an internal use of an antibacterial agent, an infusion, and eye drops, can be prevented.
[0062]
In addition, according to the present invention, it is possible to prevent and / or treat inflammation that occurs during use of a viscoelastic substance or during treatment.
[Brief description of the drawings]
FIG. The graph which shows the growth curve of Aureus.
FIG. The graph which shows the growth curve of maltophilia.
FIG. The graph which shows the viscoelastic substance blocking circle of Subtilis.
FIG. The graph which shows the correlation with the diameter of the LVFX inhibition circle | round | yen of subtilis, and a drug concentration.
FIG. The graph which shows the correlation with the diameter of the LVFX inhibition circle | round | yen of subtilis, and a drug concentration.

Claims (4)

A pharmaceutical composition for cataract surgery or glaucoma surgery used as a surgical protection agent during cataract surgery or glaucoma surgery and for preventing and / or treating bacterial infection and / or inflammation at the surgical site:
Viscoelastic materials as ophthalmic surgical protection agents;
An antibacterial agent mixed in the viscoelastic material;
And is applied so as to be in direct contact with the anterior chamber, corneal endothelium, lens capsule, and aqueous humor outflow tract, which are the surgical sites.   The ophthalmic surgical composition according to claim 1, wherein the viscoelastic substance is selected from the group consisting of hyaluronic acid and its non-toxic salt, chondroitin sulfate and its non-toxic salt, hydroxypropylmethylcellulose, and mixtures thereof.   The ophthalmic surgical composition according to claim 2, wherein the viscoelastic substance is a mixture of sodium hyaluronate and sodium chondroitin sulfate.   The composition for ophthalmic surgery according to any one of claims 1 to 3, further comprising an anti-inflammatory agent.

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