KR19990069304A - Sustained release implant composition for inflammation treatment - Google Patents

Abstract

The present invention relates to a sustained-release implant composition for treating inflammation, in particular, using two biodegradable polymers having different degrees of decomposition, to prepare microspheres containing different drugs, respectively, and mixed these microspheres with water-soluble polymers. The present invention relates to a sustained release inflammation therapeutic agent prepared in a bar, sheet or strip form.

Description

Sustained release implant composition for inflammation treatment

The present invention relates to a sustained-release implant composition for treating inflammation, in particular, using two biodegradable polymers having different degrees of decomposition, to prepare microspheres containing different drugs, respectively, and mixed these microspheres with water-soluble polymers. The present invention relates to a sustained release inflammation therapeutic agent prepared in a bar, sheet or strip form.

The present invention primarily aims at effectively preventing and treating inflammatory diseases caused by hematologic and local bacterial infections, infections caused by surgery, and diseases involving pain, and secondly, the two active ingredients can be independently released. It is a formulation for topical administration, characterized in that. More specifically, by using two kinds of biodegradable polymers having different degradation patterns, microspheres having different active ingredients are prepared, mixed with water-soluble polymers, and molded into a bar, sheet or strip in a convenient form. A drug delivery agent administered topically, is a sustained release drug delivery formulation that allows the release of a drug biphasic for a desired period, depending on the degree of degradation of the polymer base and the size of the microspheres used.

Inflammatory implants prepared in this way are suitable for bacterial infections that have the disadvantage of overdosing antibiotics in the long term due to difficulty in keeping the drug above the effective concentration at the site of infection because the drug is not delivered locally when taking the drug. One-time administration can maintain the drug at the site of the lesion for longer than the effective concentration, and is applicable to concomitant formulations in which the formulation of the two active ingredients is not possible to release the drug independently, as well as post-treatment with biodegradable substances. Topical biodegradable formulations that do not need to be removed.

In addition, the combination of active ingredients of the same series together for the purpose of the combination of the two active ingredients to effectively treat the two indications of synergistic action, anti-inflammatory treatment, pain relief, etc. One ideal formulation.

Infection by microorganisms is a disease that occurs frequently in humans and is characterized by pain and inflammation.

In the treatment of microbial infection, it is important to maintain the antimicrobial agent at the site of bacterial infection at the site of infection, and the antimicrobial agent is preferably administered parenterally.

In particular, the treatment of two or more active ingredients in combination is rational in many respects.

First, some infections are usually caused by two or more bacteria, in which case it is effective to treat them in combination with an antimicrobial agent that is selectively sensitive to each bacteria. For example, infections that occur after intestinal rupture of the large intestine are mainly aerobic, anaerobic, and aerobic Gram-positive cocci (streptococci), aerobic bacillus such as Bacteroides fragilis , and Gram-positive rodents such as Clastridium . In this case, aminoglycosides and antibacterial agents against aerobic bacteria. The use of a mixture of clindamycin or metronidazole, an antimicrobial agent against anaerobic microorganisms, including praxilis, has a high therapeutic effect.

Second, in the case of severe infections of unknown origin, it is desirable to use a wide range of antimicrobial agents that can be applied to all possible bacteria.

Third, in the case of certain infections, treatment with the same class of antimicrobial agents is not only synergistic, but also very effective in preventing the emergence of resistant strains, which generally lead to bacterial resistance to natural antibiotics. This is because the use of several antimicrobial agents in combination can prevent the emergence of resistant bacteria most effectively.

This combination of two or more active ingredients is very useful for many indications that require local treatment.

A typical example is periodontal disease, which is a local bacterial infection disease caused by the toxin, a metabolite of bacteria growing in the gingival fissures. If the gums swell, develop gingivitis with bleeding and severe bad breath, and if the periodontitis continues, the collagen supporting the periodontal membrane is destroyed and the alveolar bone supporting the tooth dissolves, which causes the periodontal ligament to separate and form the periodontal sac. It develops into advanced periodontal disease that damages teeth.

Treatments for advanced periodontal disease include removal of plaque in periodontal pockets, scaling, mechanical therapy using root root gliding, and chemotherapy for washing the infected area with antibiotic solutions or administering antibiotics systemically. There is a problem that the antibiotic does not reach the deep area of the gingival swallowing can not continue.

As an improved method, a topically administered implant (implant) has been developed and commercialized that can directly administer a drug into the periodontal pocket. However, most of the therapeutic agents are anti-inflammatory drugs containing only bioactive substances that have antibiotic action. The development of a therapeutic agent consisting of two active ingredients to alleviate the pain associated with and to treat an infected site is insufficient.

Also in the case of rheumatoid arthritis, the joint cartilage and surrounding tissues are destroyed by chronic hypertrophy and inflammatory reactions of the blood membrane.In the early stages, joint swelling and pain are caused and joint deformation and stiffness occur as inflammation progresses. The ultimate goal of treating arthritis is to reduce pain and inflammation and to prevent joint deformation.

Commonly used arthritis therapies include systemic treatment, drug therapy and topical treatment for joints. Aspirin is well known as a single drug that has a strong analgesic and anti-inflammatory effect. However, aspirin has side effects that cause gastrointestinal disorders. Instead, acetylsalyclic acid, phenylbutazone, indomethacin, ibuprofen, fenprofen calcium, Tolmetin sodium, naproxen, piroxicam, and steroid drugs are being used. However, since these drugs have analgesic action but no anti-inflammatory action, the combination with drugs having anti-inflammatory action is required to treat arthritis. To this end, there is a need for a formulation of a drug that can release the two drugs independently by comparing the toxicity and benefits of drugs.

Currently used topical treatment is a method of injecting steroid drugs in the joint area, but this method has the disadvantage of secondary infection due to the repeated administration of the drug with the cumbersome administration of the drug every 10 days. Therefore, even in the treatment of arthritis, there is an urgent need for an agent that can be continuously released into a drug having a long-term effective concentration even at a single dose and can be naturally removed from the body after drug release.

On the other hand, osteomyelitis, one of the bacterial infectious diseases of the orthopedic part, is also a disease requiring a topical dosage form. Osteomyelitis is an inflammation caused by Staphylococcus aureus (Staphylococcus aureus), Escherichia coli (Eschericha coil), Streptococcus genus (Streptococcus), Streptococcus pneumoniae (Pneumococcus), Pseudomonas aeruginosa (Pseudomonas aeruginosa), hohyeol Species (Hemophylus) bacteria, mainly primary It is known to be a hematogenous disease that causes mild bacteremia in the primary lesion and subsequently occurs through the bloodstream, and is highly likely to recur due to infection of pathogenic bacteria even after surgical treatment. Bone-causing osteomyelitis, a type of bone anatomy, forms a biofilm at the site of infection, and antibiotics at concentrations above the minimum inhibitory concentration (MIC) are used to remove the bacteria that accumulate on the biofilm. Should be. However, even though antibiotics penetrate better into infected bones than in normal bones, there is a limitation that conventional antibiotics, such as systemic administration by injection, do not reach the affected area locally.

Currently used osteomyelitis treatments include surgical treatment to remove drainage and bones, and then use irrigation to clean the inflammatory site with an excess of antibiotics mixed with saline or purified water, followed by continuous injection or oral administration. There is systemic administration. However, these treatments are not effective because the concentration of antibiotics at the site of infection is lower than in the case of body tissues, and they have serious side effects such as soft tissue damage at the site of administration and kidney and liver toxicity due to overdose of antibiotics. The hassle of administration and long term administration is a problem.

Accordingly, there is an urgent need for the introduction of a topical delivery drug that introduces an implant surgically rather than systemic administration. For this purpose, it has good physical properties to control the rate of drug release and good adhesion and adhesion to the site of administration. It requires pharmaceutical properties that do not cause hypersensitivity reactions and do not need to be removed after treatment. In addition, as described above, there is a need for a formulation of a combination preparation which can exhibit an independent release pattern while simultaneously using two active ingredients in order to enhance the therapeutic effect.

If such formulations are designed, the combination of anti-inflammatory analgesics and local anesthetics, combined with antimicrobial and antibiotic treatment, eases the pain associated with infection, and is useful for the formation of secondary antibiotics against resistant bacteria caused by primary antibiotics. It is expected to improve the antibiotic treatment that has many limitations.

For this purpose, first, the polymer base containing the drug should be inserted into the body to release the drug, decompose in vivo, be biocompatible, safe, and have a physical and functional substance capable of controlling drug release. .

As a local drug delivery system used as a controlled release system containing a bioactive substance, US Pat. No. 5,599,553 mixes minocycline HCl and polycaprolactone. A periodontitis therapeutic agent prepared by the present invention is disclosed. There have also been reports of topical administration of osteomyelitis, in which antibiotic-containing polymethylmethacrylate beads were inserted into the bone cavity before and after surgery [Tsukayama et al, Orthopedics , 11, 1285]. , 1988], the use of non-degradable polymethylmethacrylate as a polymer base has the need to be removed by reoperation after a certain period of time, leaving the possibility of secondary bacterial infection during reoperation.

As a result, many formulations prepared in the form of fine particles or films after homogeneous mixing of gentamycin with high-molecular-weight and low-molecular-weight biodegradable polylactic acid are reported. (Mauduit et al., J. Control. Rel. 23 , 209-230 (1993)), however, this formulation has the limitation that the initial release of the drug is very high and the release of the drug is not uniform or complete.

One product currently being commercialized based on biodegradable materials is the SEPTACIN implant developed by Scios Nova (USA). This product is formulated with gentamycin in the biodell drug carrier using biodegradable polymer polyanhydride, which maintains high concentration of local drug and low circulating By maintaining the level) it was intended to improve the problem.

However, these formulations are intended only for the release of one active ingredient. When two or more active ingredients are applied to the formulation, the respective ingredients are not independently released and are not completely released. Therefore, new drug carriers must be introduced for the release of two or more active ingredients.

As a combination formulation that releases two active ingredients, a formulation using a biodegradable polymeric material is disclosed in US Pat. No. 4,933,182, which is a topical administration implant formulation for treating topical bacterial diseases such as periodontitis. To prepare a fine particles by mixing with a water-insoluble biodegradable polymer and dispersed in a water-soluble polymer base containing a second drug is a formulation prepared. In this formulation, the first drug is released slowly, primarily as the second drug contained in the water-soluble polymer base is first released in large quantities, and then the biodegradable polymer base is degraded. In this formulation, the difference in solubility between the water-soluble polymer and the water-insoluble biodegradable polymer is used to obtain the independent release of the two drugs.

In addition, U.S. Patent No. 5,268,178 attempts to release the drug abnormally by mixing the high molecular weight and low molecular weight biodegradable polymer bases with different mixing ratios of the two polymers and the two drugs. I couldn't.

Therefore, in the present invention, by using two or more microspheres containing different drugs with different degrees of decomposition using the degree of decomposition, which is an inherent property of biodegradable polymers, to achieve independent release of two or more drugs In order to prepare a formulation having biphasic by controlling the rate of drug release according to the size by varying the microsphere manufacturing conditions.

It is an object of the present invention to provide a sustained release implant composition for the treatment of inflammation, in which two or more active ingredients can be released independently and show continuous efficacy.

1 is a graph showing the drug release of the formulation according to the type of water-soluble polymer.

2 (a) and 2 (b) are graphs showing drug release of microspheres according to size.

3 is a graph showing drug release of microspheres according to the types of biodegradable polymers.

4 to 9 are graphs showing drug release of strips or bars prepared in Examples 1-6.

According to the above object, in the present invention (1) a first microsphere consisting of the first drug and the first biodegradable polymer; (2) a second microsphere having a different degree of decomposition than the first microsphere, consisting of a second drug different from the first drug and a second biodegradable polymer; And (3) a water-soluble polymer, there is provided a sustained release implant composition for treating an ideal drug-releasing inflammation.

Hereinafter, the present invention will be described in more detail.

The compositions of the present invention are formed into films, rods and strips by mixing two or more new forms of drug carriers, called microspheres comprising two or more active ingredients, with water-soluble polymeric materials that provide adhesion and flexibility. The formulation of the present invention can be used by directly inserting or attaching to the site of infection, whereby the first microsphere, which is rapidly degraded, is first degraded or disintegrated by the body fluid component of the lesion to release a large amount of the first drug, and secondary degradation is The late second microspheres are slowly degraded or disintegrated to release the second drug. The degree of decomposition of the first and second microspheres can be controlled by the molecular weight, constituents, crystallinity and size of the microspheres of the biodegradable polymer. The first drug released primarily kills most of the bacteria in the lesion or has an anti-inflammatory analgesic effect in a short time, and the second released drug is slowly released through diffusion or degradation of the biodegradable polymer. Can be maintained continuously above the effective concentration to inhibit or kill the growth of bacteria remaining at the site of infection. Accordingly, the composition of the present invention is a mixed formulation which releases a large amount of drug at the beginning of administration to increase the drug efficacy and maintains the drug at an effective concentration above the long-term lesion for effective treatment as well as to achieve independent release of complex components.

In addition, the present invention was intended to improve the solubility and flexibility by mixing a water-soluble polymer having a tackiness in order to facilitate the initial drug release in a simple and uniform decomposition of the manufacturing process in the preparation of the formulation, water-soluble components such as body fluid in the lesion In contact with water and within a few hours or a day to have a uniform decomposition pattern to evenly release the active ingredient, secondly to slowly release the active ingredient in the microsphere to keep the drug above the effective concentration for a long period of time biphasic).

As the biodegradable polymer base, a polymer of an alpha-hydroxy carboxylic acid derivative that is hydrolyzed by water to produce a material harmless to the human body such as water and carbon dioxide is preferable. In particular, low molecular weight and high molecular weight polyglycolic acid, D, L-polylactic acid, L-polylactic acid, copolymers of lactic acid and glycolic acid to have different decomposition degrees [poly (lactic-co-glycolic acid)] and polycaprolactone (polycaprolactone) are suitable, and these polymers act as carriers of drugs, have release control functions, and are biodegradable and biocompatible.

The average molecular weight of the biodegradable polymer used to prepare the microsphere of the present invention is preferably 1,000 to 500,000 and 2,000 to 200,0000. In particular, the low molecular weight biodegradable polymers used in the first microspheres exhibiting degradation behavior among the two types of microspheres preferably have a weight average molecular weight of 1,000 to 30,000 and more preferably 2,000 to 15,000. . In addition, as the high molecular weight biodegradable polymer used in the second microsphere of the two types of microspheres exhibiting secondary decomposition behavior, the degree of decomposition is lower than that of the low molecular weight biodegradable polymer, and the average molecular weight is 5,000 to 500,000. And it is more preferable that it is crystallinity and the average molecular weights are 30,000-200,000. However, the average molecular weight of the biodegradable polymer used for the first microsphere is preferably smaller than the average molecular weight of the biodegradable polymer used for the second microsphere.

The decomposition behavior of the first and second microspheres can be adjusted according to the constituents and crystallinity in addition to the average molecular weight of the biodegradable polymer.

The drug may be a disinfectant such as an antigen-protein, glyceryl iodide, phenol, etc .; Antibacterial agents and antibiotics such as penicillin, cephalosporin, tetracycline, chloramphenicol, aminoglycoside, and erythromycin; Anti-inflammatory analgesics, such as aspirin, naproxen, ibuprofen, flubiprofen, indomethacin, diclofenac, ketoprofen, pyroxicam, tenoxycam, ibufenac, acetaminophen; Examples of corticosteroids such as pridnisone, dexamethasone, triamcinolone, acetonide, and prostaglandin, and local anesthetics such as tetracaine, lidocaine, dibucaine, procaine, benzocaine, and ethyl aminobenzoate, and paclitaxel, The drug of the present invention is not limited thereto.

As the antimicrobial agent, vancomycin, gentamicin, tobramycin, kanamycin, minocycline, tetracycline, or hydrochloride thereof may be used, and as antibiotics, oploxacin, metronidazole, ampicillin, erythromycin may be used.

In addition, one drug may be used for the first or second drug, or two or more drugs may be mixed and used.

In particular, a drug that is initially released in a large amount is preferably an antibiotic having a broad antimicrobial range and an anti-inflammatory drug, and a drug having a specific antibacterial range is preferable as a slowly released drug.

The content of the drug is 1 to 50% by weight with respect to the microspheres, preferably 5 to 30% by weight.

The content of the first and second microspheres in the present invention is 50 to 99% by weight, preferably 50 to 90% by weight based on the total weight of the composition.

Accordingly, the compositions of the present invention have a pharmaceutical feature that allows the combination of fungicides, antimicrobials, antibiotics, anti-inflammatory analgesics and local anesthetics, as well as formulations of antibiotics, including secondary antibiotics against resistant bacteria that arise during long-term antibiotic treatment.

As the water-soluble polymer, a polysaccharide-based polymer may be used, and sodium alginate, pectin, carrageenan, gellan, chitosan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and carbopol are preferable. These water-soluble polymers do not directly affect the hydrolysis of the biodegradable polymer, but can control the drug release rate according to the solubility of the water-soluble polymer, and at the same time increase the flexibility of the film, rod or strip at a temperature of 30 to 37 ℃ Benefit from administration and facilitate molding.

The content of water-soluble polymers has an important influence on the physicochemical properties such as the release rate of the drug and the strength and flexibility of the preparation. Too much content of water-soluble polymers can increase the amount of moisture contained therein, which promotes the degree of decomposition, while too little content of water-soluble polymers reduces the amount of water containing less water, resulting in a longer decomposition period but higher strength and easier breakage. There is inconvenience when using it apart. The content of the water-soluble polymer in the present invention is 1 to 50% by weight, preferably 10 to 50% by weight relative to the total weight of the composition.

In addition to the above components, other additives such as colorants, viscosity regulators, antioxidants, etc. may be added to the composition of the present invention, if necessary, but are not limited thereto.

The composition according to the invention can be processed into the form of a bar, sheet, rod, film or strip and molded into an implant.

Hereinafter, a method for producing a drug-containing microsphere will be described.

The method for preparing the drug-containing microspheres may use a method for preparing the sustained-release microspheres containing water-soluble antibiotics, which the present inventors have already filed in Korean Patent No. 95-10671. That is, the drug is pulverized finely in a mortar or jet mill to adjust the particle size, and then uniformly mixed with the biodegradable polymer and put into dichloromethane to uniformly prepare a biodegradable polymer solution. The biodegradable polymer solution is added to an aqueous polyvinyl alcohol or poloxamer solution to emulsify, dichloromethane is evaporated, filtered off, washed with distilled water and dried to calculate the content and yield. Drug-containing microspheres are prepared using the same method as above using biodegradable polymer materials having different degrees of degradation for other drugs.

The average size of the microspheres prepared according to the above method is preferably 20 to 200 탆 in diameter. The size of the microspheres can be adjusted according to the conditions in the preparation of the microspheres, for example, the size can be reduced by increasing the stirring speed in the emulsification step. In particular, the size of the microspheres is an important factor in determining the release rate and duration of the drug. The larger the size, the slower the release rate and the longer the release period. Therefore, in the present invention, it is possible to control the release rate and duration by adjusting the size of the microspheres by adjusting the conditions in the manufacturing stage of the microspheres.

Therefore, in the present invention, the degree of decomposition of the two microspheres can be controlled by the molecular weight, constituents, crystallinity, and size of the microspheres of the biodegradable polymer, and further, the ideal release of the drug can be controlled.

Hereinafter, a method for preparing an implant formulation will be described.

Two drug-containing microspheres prepared by the above method are mixed with a water-soluble polymer, and then distilled water is added thereto and mixed well to prepare a polymer suspension or a hydrogel. In this case, the amount of distilled water added is an important factor in forming the composition into a film, rod or strip. If the amount of distilled water is too large, it is difficult to form into a film or strip, and if the amount of distilled water is too small, the drug-containing microspheres may be used as a water-soluble polymer Difficult to evenly distribute In consideration of this, it is preferable to add distilled water so that the concentration of the water-soluble polymer in the hydrogel is 50% by weight or less. More preferably, distilled water is added so that the concentration of the water-soluble polymer in the hydrogel is 1 to 20% by weight, and most preferably 5 to 15% by weight.

The hydrogel is evenly spread on an acrylic plate or a metal plate, covered with a polyester film coated with silicon on it, and then pressed with a roller to make the thickness uniform. The polyester film is then removed and dried in air to yield a film.

Considering the size of the lesion site, the thickness of the final formulation film, rod or strip is preferably 5 mm or less, more preferably 1 to 4 mm. In addition, the dosage form is preferably 5 to 10 mm wide and 1 to 3 mm long, 6 mm wide and 2 mm long.

In addition, the bar and the rod are 1 to 3 mm in diameter, 6 to 15 mm in length, preferably 2 mm, and 10 mm in length while inserting a hydrogel containing active ingredients, microspheres of different components, into the syringe and then pushing the piston. The phosphorus rod is prepared.

The film or strip may be coated with an aqueous solution of a divalent or trivalent cation salt to remove tack after hydration and to prolong the decomposition time of the strip. Preferred cationic salts are calcium chloride, magnesium chloride, barium chloride and aluminum chloride, in particular calcium chloride is suitable for use in formulations which are hydrated by saliva within a short period of up to 3 hours, and barium chloride is formulated for 1-2 weeks. It is suitable for long term formulations to be maintained. The concentration of these divalent or trivalent cation salts in an aqueous solution is preferably 1 to 10%, more preferably 2 to 5%. Coating methods include a method of dipping a film or strip in an aqueous salt solution and then drying and a method of spraying an aqueous solution of salt in a film or strip, and a method of coating by sprue is preferable.

In addition, since the solubility in water and the swelling rate vary depending on the type of cationic metal, an appropriate metal ion can be selected in consideration of the treatment period.

In the present invention, by using a biodegradable polymer material that is a medical polymer that is decomposed in the body for the independent drug release of the two active ingredients as a polymer base and by introducing a microsphere drug carrier containing two or more active ingredients independently, the release of the drug According to the dispersing and decomposition mechanism, rather than simple dispersion, ideally sustained release and independent release of two or more active ingredients are achieved, resulting in long-term release with uniform and complete release.

Therefore, the implant formulation prepared as described above may be inserted near the site of onset, that is, near the lesion, and slowly release the drugs over a long period of time in succession with two drugs in a single insertion to treat a local infectious disease.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to these examples.

Preparation Example 1: Preparation of anti-inflammatory analgesic-containing microspheres

1.6 g of polylactic acid having a molecular weight of 3,000 and 0.4 g of ibuprofen powder having a particle size of 10 μm or less were added to 2 ml of dichloromethane to prepare a polylactic acid solution in which ibuprofen was dispersed. This solution was added to 500 ml of 5% polyvinyl alcohol aqueous solution, stirred at a speed of 600 rpm to emulsify, and dichloromethane was slowly evaporated at room temperature to prepare microspheres. The microspheres were filtered, washed with distilled water and dried to obtain ibuprofen-containing polylactic acid microspheres. The microspheres obtained have an average particle size of 100 μm and a drug content of about 27 to 28% by weight.

Preparation Example 2, 3: Preparation of microspheres containing anti-inflammatory analgesic

A microsphere was prepared according to the same method as in Preparation Example 1, except for the composition of Table 1 below.

Furtherance Size (μm) Drug content (%) Biodegradable polymer drug Kinds Molecular Weight Preparation Example 2 Copolymers of lactic and glycolic acids (50:50) 6,700 Diclofenac 120 24-25 Preparation Example 3 D, L-polylactic acid 7,200 Indomethacin 100 22-23

Preparation Examples 4 to 7: Preparation of antibiotic-containing biodegradable microspheres

A microsphere was prepared according to the same method as in Preparation Example 1, except for the composition of Table 2 below.

Furtherance Size (μm) Drug content (%) Biodegradable polymer drug Kinds Molecular Weight Preparation Example 4 D, L-polylactic acid 7,200 Minocycline Hydrochloride 100 17-18 Preparation Example 5 D, L-polylactic acid 12,500 Ofloxacin 120 27-28 Preparation Example 6 Copolymer of lactic acid and glycolic acid (75:25) 100,000 Vancomycin 80-90 27-28 Preparation Example 7 Lactic and Glycolic Acid Copolymers (50:50) 72,500 Ampicillin 90 14-15

Preparation Examples 8 to 10: Preparation of microspheres according to the stirring speed

A microsphere was prepared according to the same method as in Preparation Example 1, except for the composition and stirring speed of Table 3 below.

Furtherance Stirring Speed (rpm) Size (μm) Drug content (%) Biodegradable polymer drug Kinds Molecular Weight Preparation Example 8 D, L-polylactic acid 12,500 Ofloxacin 900 60-80 27-28 Preparation Example 9 D, L-polylactic acid 12,500 Ofloxacin 1,500 20-40 26-27 Preparation Example 10 Copolymer of lactic acid and glycolic acid (75:25) 100,000 Ofloxacin 1,500 30-60 26-27

Comparative Example 1: Drug Release Test of Formulation According to Water-Soluble Polymer Type

Carbopol, sodium alginate or pectin was added to the microspheres of Preparation Example 1 or 5, and 1.5 g of distilled water was added thereto, followed by mixing well to prepare a hydrogel. The hydrogel is placed in an acrylic box 10 cm wide, 10 cm long and 0.5 mm high, with a closed base, evenly folded, covered with a silicone coated polyester film on it, pressed with a roller, and then removed from the polyester film at room temperature. Dried. The film was cut to a suitable size of about 6 mm wide and 2 mm long to obtain a strip.

The formulation was placed in a 50 ml conical tube, filled with 10 ml of phosphate buffer solution (pH 7.4) and stirred at 50 rpm in a 37 ° C. constant temperature water bath. The amount of drug released was measured every 24 hours with an ultraviolet / visible spectrophotometer.

The measurement result is as showing in FIG.

As can be seen in Figure 1, the difference in drug release amount depending on the type of water-soluble polymer, but does not significantly affect the release pattern of the microspheres.

Comparative Example 2: Drug Release Test of Formulation According to Microsphere Size

The release amount of the microspheres of Preparation Example 5, 6, 8, 9 or 10 was measured in the same manner as in Comparative Example 1.

The measurement results are as shown in Figs. 2 (a) and 2 (b).

As can be seen in Figures 2 (a) and 2 (b), the faster the stirring speed, the smaller the size of the produced microspheres, the larger the initial emission amount and the shorter the release period can be seen.

Comparative Example 3: Drug Release Test of Formulation According to Biodegradable Polymer Type

The release amount of the microspheres of Preparation Example 1, 3, 5 or 6 was measured in the same manner as in Comparative Example 1.

The measurement result is as showing in FIG.

As can be seen in Figure 3, the larger the molecular weight of the biodegradable polymer, the drug is released for a long time and the release period may be controlled according to the composition of the polymer.

Example 1 Preparation of Strips Containing Anti-inflammatory Analgesics and Antibiotics

0.4 g of each of the microspheres of Preparation Examples 1 and 4 was mixed well with 0.2 g of sodium alginate, and 1.5 g of distilled water was added thereto, followed by mixing well to prepare a hydrogel. The hydrogel is placed in an acrylic box 10 cm wide, 10 cm long and 0.5 mm high and closed underneath, evenly folded, covered with a silicone coated polyester film on it, pressed with a roller, and then removed from the polyester film at room temperature. Dried. The film was cut to a suitable size of about 6 mm wide and 2 mm long to obtain a strip.

Example 2 Preparation of a Rod Containing Anti-inflammatory Analgesics and Antibiotics

0.45 g of each of the microspheres of Preparation Examples 1 and 5 was mixed well with 0.1 g of pectin, and then 2.0 g of distilled water was added thereto and mixed well to prepare a microsphere-containing polymer hydrogel. The hydrogel was placed in a syringe and the piston was pushed in to obtain a rod having a diameter of 2 mm and a length of 10 mm.

Example 3: Preparation of a Strip Containing Anti-inflammatory Analgesics and Antibiotics

Strips were prepared in the same manner as in Example 1 except for using microspheres and Carbopol of Preparation Examples 2 and 6 instead of the microspheres and Sodium Alginate of Preparation Examples 1 and 4.

Examples 4 to 8: Preparation of Strips or Bars Containing Anti-inflammatory Analgesics and Antibiotics

Strips or bars were prepared in the same manner as in Examples 1 or 2 except for the compositions in Table 4 below.

Microsphere Composition Water soluble polymer Composition ratio of microspheres and water-soluble polymers Formulation Example 4 Preparation Example 5 Preparation Example 7 Sodium alginate 40/40/20 strip Example 5 Preparation Example 3 Preparation Example 6 Cabopol 40/40/20 strip Example 6 Preparation Example 4 Preparation Example 5 pectin 45/45/10 bar Example 7 Preparation Example 1 Preparation Example 5 Sodium alginate 40/40/20 strip Example 8 Preparation Example 1 Preparation Example 5 Cabopol 40/40/20 strip

Example 9: Drug Release Test

Drug release test of the strip or bar prepared in Examples 1 to 6 was carried out in the same manner as in Comparative Example 1.

The measurement result of drug release amount is as showing in FIGS.

As can be seen in Figures 4 to 9, microspheres containing different drugs have independent release patterns according to the degree of decomposition of the polymer and have a desired drug release period according to the degree of decomposition of the polymer.

The composition of the present invention, by independently releasing two or more drugs at the site of infection, keeps the drug at an effective concentration for longer than the effective concentration even at a single administration, and can be applied to a combination preparation of two active ingredients.

In particular, the composition of the present invention is useful for bacterial infection disease, the formulations containing the same series of drugs together is very effective because the drugs can exhibit a synergistic effect with each other, and together with other classes of drugs, such as antibiotics and anti-inflammatory drugs The combination preparation is very useful for the simultaneous treatment of two indications, such as anti-inflammatory treatment and pain relief, and is useful for formulating with secondary antibiotics against resistant bacteria caused by primary antibiotics. Therefore, the composition of the present invention solves the problem of long-term administration in excess of the difficulty in maintaining the drug at an effective concentration or more at the site of infection by conventional methods.

In addition, the composition of the present invention does not need to be removed separately after treatment by using a biodegradable substance.

Claims (9)

(1) a first microsphere consisting of a first drug and a first biodegradable polymer; (2) a second microsphere having a different degree of decomposition than the first microsphere, consisting of a second drug different from the first drug and a second biodegradable polymer; And (3) A sustained release implant composition for treating inflammation that ideally releases a drug, comprising a water-soluble polymer. The method of claim 1, A composition wherein the degree of degradation of the first or second microspheres is controlled by the molecular weight, constituents, crystallinity, and size of the microspheres of the biodegradable polymer. The method of claim 1, The first or second biodegradable polymer is a polyglycolic acid, D, L-polylactic acid, L-polylactic acid, a copolymer of lactic acid and glycolic acid or polycaprolactone. The method of claim 1, A composition wherein the first or second biodegradable polymer has an average molecular weight in the range of 2,000 to 200,000. The method of claim 1, A composition wherein the average size of the first or second microspheres is between 20 and 200 μm in diameter. The method of claim 1, The first or second drug may be an antigen-protein, glyceryl iodine, phenol, penicillin, cephalosporin, chloramphenicol, aminoglycoside, vancomycin, gentamycin, tobramycin, ganamycin, minocycline, tetracycline, oploxacin, Metronidazole, Ampicillin, Erythromycin, Aspirin, Naproxen, Ibuprofen, Flubiprofen, Indomethacin, Diclofenac, Ketoprofen, Pyroxycam, Tenoxycamp, Ibufenac, Acetaminophen, Pridnisolone, Dexamethasone , Triamcinolone acetonide, prostaglandin, tetracaine hydrochloride, lidocaine, dibucaine, procaine, benzocaine, ethyl aminobenzoate, paclitaxel and salts thereof. The method of claim 1, The water-soluble polymer is a polysaccharide-based polymer, sodium alginate, pectin, carrageenan, gellan, chitosan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or carbopol. The method of claim 1, 50 to 99% by weight of microspheres and 1 to 50% by weight of a water-soluble polymer. The method of claim 1, The composition is further coated with a polyvalent metal cation.