Pharmaceutical composition

Abstract

The purpose of the present invention is to provide a new pharmaceutical composition capable of suppressing pain after tooth extraction. This pharmaceutical composition that is to be embedded in a tooth extraction socket and that contains celecoxib is capable of suppressing pain after tooth extraction.

Description

Pharmaceutical composition

[0001] The present invention relates to a pharmaceutical composition for analgesia applied to pain after tooth extraction.

[0002] Tooth extraction is one of the most commonly performed oral surgical procedures. Since tooth extraction is highly invasive, pain after tooth extraction is the most common and important postoperative complication, and is also said to be the reason why many patients avoid treatment. Among them, the extraction of mandibular wisdom teeth, especially impacted mandibular wisdom teeth, is highly invasive when accompanied by bone resection or crown division, so pain after tooth extraction is likely to appear significantly at each stage. Pain after tooth extraction is one of the most common and important postoperative complications, and is also said to be the reason why many patients avoid treatment.

[0003] As analgesics used for the treatment of pain after tooth extraction, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and traditional Chinese medicine (Lixiaosan) are recognized. For moderate to severe pain such as the extraction of impacted mandibular wisdom teeth, acidic NSAIDs such as loxoprofen sodium are often selected (Non-Patent Document 1). On the other hand, acetaminophen may also be selected for patients with complications of peptic ulcer or aspirin asthma (Non-Patent Document 2).

[0004] In addition, in order to identify the optimal analgesic for pain relief after the extraction of impacted mandibular wisdom teeth, drugs including celecoxib (Non-Patent Document 3), NSAIDs such as valdecoxib and ibuprofen, and opioids such as oxycodone have also been studied.

[0005] On the other hand, it is necessary to consider side effects when prescribing analgesics after surgery. In the case of NSAIDs, attention should be paid to gastrointestinal disorders, kidney and liver function disorders, platelet function disorders, etc. (Non-Patent Document 4).

[0006] Masakazu, Yoshiteru Honda, Kazuko Iwai, Naoko Murakami, Kazutoshi Ota, Masanori Shinohara, Hideyuki Saito, A Study on the Analgesic Effect of Loxoprofen Sodium After Outpatient Oral Surgery, Jpn. J. Pharm. Health Care Sci. 32(9) 917-922 (2006) Satoru Shintani, Ken Komura, Hideaki Kubota, et al (2012) Clinical Evaluation of JNS013 (Tramadol Hydrochloride / Acetaminophen Combination Tablets) for Post-Extraction Pain: A Double-Blind Comparative Study with Single Administration of Each Combination Component. Journal of the Japanese Society of Oral and Maxillofacial Surgeons 58:110-122 Xie L, Yang RT, Lv K, et al (2020) Comparison of Low Pre-Emptive Oral Doses of Celecoxib Versus Acetaminophen for Postoperative Pain Management After Third Molar Surgery: A Randomized Controlled Study. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg 78:75.e1-75.e6. https: / / doi.org / 10.1016 / j.joms.2019.09.02Gupta A, Bah M (2016) NSAIDs in the Treatment of Postoperative Pain. Curr Pain Headache Rep 20:62. https: / / doi.org / 10.1007 / s11916-016-0591-7

[0007] Loxoprofen sodium is the most frequently prescribed analgesic for post-extraction pain because it has a strong analgesic effect despite having relatively few gastrointestinal side effects. However, even when loxoprofen sodium is prescribed, the analgesic effect may not be sufficient, and side effects may occur. This tendency is particularly pronounced when prescribed for highly invasive post-extraction pain requiring extraction socket suturing (post-extraction pain of mandibular wisdom teeth, especially impacted mandibular wisdom teeth). For such highly invasive post-extraction pain, it is common to be prescribed around 20 tablets for a single extraction, and the large dosage raises concerns about side effects. Despite this, the only treatment taken when sufficient analgesic effect is not achieved is symptomatic treatment such as cooling. Thus, there is still room for improvement in analgesic control for post-extraction pain.

[0008] Therefore, the object of the present invention is to provide a novel pharmaceutical composition that can suppress post-tooth extraction pain.

[0009] The inventors attempted to embed a pharmaceutical composition containing a selective COX-2 inhibitor into the tooth extraction socket before suturing. This attempt was inspired by the treatment of periodontal disease in which antibiotics are applied to periodontal pockets to suppress bacterial infection within the pocket, and was carried out for a purpose different from that of the present invention, which is to suppress bacterial infection in the tooth extraction socket. From clinical experience, it is recognized among dentists that the anti-inflammatory effect of the above-mentioned periodontal disease treatment is slow. The attempt to embed a pharmaceutical composition containing a selective COX-2 inhibitor into the tooth extraction socket was intended to avoid the risk of dry socket formation due to the inability of normal healing mechanisms to function due to a strong anti-inflammatory effect, and was based on the expectation of a slow anti-inflammatory effect.

[0010] However, it was observed that embedding a pharmaceutical composition containing a selective COX-2 inhibitor into the tooth extraction socket dramatically improved the analgesic effect without forming a dry socket. This effect was observed in the reduced amount of loxoprofen prescribed, which was completely unexpected considering the extremely small amount that can be administered locally compared to the oral dose.

[0011] This invention was completed through further investigation based on these findings.

[0012] That is, the present invention provides inventions in the following embodiments: Item 1. A pharmaceutical composition for implantation into a tooth extraction socket, comprising a selective COX2 inhibitor. Item 2. The pharmaceutical composition according to Item 1, wherein the tooth extraction socket is a mandibular wisdom tooth extraction socket. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the content of the selective COX2 inhibitor is 0.1 to 5% by weight. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the dose of the selective COX2 inhibitor per tooth extraction socket is 0.1 to 10 mg. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, wherein the selective COX2 inhibitor is selected from the group consisting of celecoxib, etodolac, lornoxicam, meloxicam, nabumetone, and zaltoprofen. Item 6. The pharmaceutical composition according to any one of Items 1 to 5, which is semi-solid. Item 7. The pharmaceutical composition according to any one of Items 1 to 6, which comprises a water-soluble thickener. Item 8. A pharmaceutical composition according to any one of claims 1 to 7, comprising polyethylene glycol and / or a nonionic surfactant. Claim 9. A pharmaceutical composition according to any one of claims 1 to 8, to be used in combination with an oral analgesic for 1 to 15 doses over 5 days after tooth extraction. Claim 10. A pre-filled syringe formulation filled with a pharmaceutical composition according to any one of claims 1 to 9. Claim 11. A method for treating a tooth socket, comprising embedding a selective COX2 inhibitor into the tooth socket in a patient after tooth extraction. Claim 12. Use of a selective COX2 inhibitor for the manufacture of a pharmaceutical composition for embedding into a tooth socket. Claim 13. A selective COX2 inhibitor for use in embedding into a tooth socket.

[0013] The present invention provides a novel pharmaceutical composition that can suppress post-tooth extraction pain.

[0014] The sustained-release properties of the pharmaceutical compositions in Examples 1 and 2 are shown.

[0015] The pharmaceutical composition of the present invention is characterized by containing a selective COX-2 inhibitor as an active ingredient and being used for implantation into a tooth extraction socket. This provides an analgesic effect for post-extraction pain.

[0016] 1. Selective COX2 Inhibitors The pharmaceutical composition of the present invention uses a selective COX2 inhibitor as an analgesic active ingredient to suppress post-tooth extraction bleeding.

[0017] The selective COX2 inhibitor is not particularly limited and examples include celecoxib, etodolac, lornoxicam, meloxicam, nabumetone, and zaltoprofen. These selective COX2 inhibitors may be used individually or in combination of two or more. Among these selective COX2 inhibitors, celecoxib is preferred.

[0018] The amount of selective COX2 inhibitor contained in the pharmaceutical composition of the present invention is not particularly limited and can be appropriately designed according to the formulation form and dosage. Specific amounts of selective COX2 inhibitor in the pharmaceutical composition of the present invention include, for example, 0.01 to 0.5% by weight, preferably 0.03 to 0.4% by weight, more preferably 0.04 to 0.3% by weight, 0.05 to 0.3% by weight, even more preferably 0.08 to 0.3% by weight, 0.1 to 0.3% by weight, 0.1 to 0.25% by weight, or 0.1 to 0.2% by weight, 0.18 to 0.3% by weight, or 0.2 to 0.3% by weight.

[0019] 2. Water-soluble thickener In preferred embodiments, the pharmaceutical composition of the present invention includes a water-soluble thickener as an additive. When the pharmaceutical composition of the present invention includes a water-soluble thickener, it more preferably further includes polyethylene glycol and / or a nonionic surfactant, and even more preferably further includes polyethylene glycol and a nonionic surfactant.

[0020] The water-soluble thickeners used in the present invention are not particularly limited, but examples include cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyacrylic acid, sodium alginate, sodium chondroitin sulfate, sodium hyaluronate, and gelatin. These water-soluble thickeners may be used individually or in combination of two or more.

[0021] Among these water-soluble thickeners, cellulose derivatives are preferred. Cellulose derivatives are polymers in which some of the hydrogen atoms of the hydroxyl groups of cellulose are substituted with substituents selected from the group consisting of methyl groups, ethyl groups, propyl groups, hydroxypropyl groups, and carboxymethyl groups.

[0022] The cellulose derivatives used in the present invention are not particularly limited as long as they are pharmaceutically acceptable, but specifically include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose, hydroxyethyl cellulose, hydroxymethylcellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylcellulose, and salts thereof (specifically, alkali metal salts such as sodium salts and potassium salts). These cellulose derivatives may be used individually or in combination of two or more.

[0023] Among these cellulose derivatives, hydroxypropyl methylcellulose is preferred. The degree of substitution of hydroxypropyl methylcellulose used in the present invention is not particularly limited, but examples include 1828, 2208, 2906, and 2910. These hydroxypropyl methylcelluloses may be used individually or in combination of two or more. Among these hydroxypropyl methylcelluloses, the 2910 degree of substitution is preferred.

[0024] The viscosity grade of the cellulose derivative used in the present invention is not particularly limited, but examples include 600 to 100,000 mP·s, preferably 1,000 to 50,000 mP·s, more preferably 2,000 to 10,000 mP·s, even more preferably 3,000 to 6,000 mP·s, and even more preferably 3,500 to 5,000 mP·s. The viscosity grade of the cellulose derivative refers to the viscosity of a 2% by weight solution in water at 20°C. The viscosity of a predetermined concentration solution refers to the value measured according to "2.53 Viscosity Measurement Method" of the Seventeenth Edition of the Japanese Pharmacopoeia, in accordance with the description in the Seventeenth Edition of the Japanese Pharmacopoeia.

[0025] When the pharmaceutical composition of the present invention contains a water-soluble thickener, the amount contained in the pharmaceutical composition is not particularly limited, but for example, it may be 0.2 to 20% by weight, preferably 0.6 to 10% by weight, more preferably 1 to 6% by weight, even more preferably 2 to 4% by weight, and even more preferably 2.4 to 3.6% by weight.

[0026] 3. Polyethylene glycol In preferred embodiments, the pharmaceutical composition of the present invention contains polyethylene glycol as an additive. When the pharmaceutical composition of the present invention contains polyethylene glycol, it more preferably further contains a water-soluble thickener and / or a nonionic surfactant, and even more preferably further contains a water-soluble thickener and a nonionic surfactant.

[0027] The average molecular weight of polyethylene glycol used in the present invention is not particularly limited, but examples include 270 to 30,000, preferably 300 to 20,000, more preferably 330 to 10,000, and even more preferably 350 to 5,000, 350 to 1,000, or 350 to 500.

[0028] The method for measuring the average molecular weight of polyethylene glycol follows the test method for polyethylene glycol 200 (p. 1378) listed in the 2006 Standards for Quasi-Drug Raw Materials (Yakuji Nippo Co., Ltd.). Specifically, 42 g of phthalic anhydride is taken and added to a 1 L light-shielded stoppered bottle containing 300 mL of freshly distilled pyridine, which has been accurately measured. The bottle is shaken vigorously to dissolve the phthalic anhydride and left to stand for at least 16 hours. 25 mL of this solution is accurately measured and placed in a pressure-resistant stoppered bottle of approximately 200 mL. Approximately 0.8 g of polyethylene glycol is accurately measured and added to this bottle, which is then tightly sealed. The bottle is then placed in a water bath heated to 98°C ± 2°C. After maintaining the temperature at 98°C ± 2°C for 30 minutes, the bottle is removed from the water bath and left in the air until it reaches room temperature. Next, 50 mL of 0.5 N sodium hydroxide solution is accurately added, and this solution is titrated with 0.5 N sodium hydroxide solution. Five drops of phenolphthalein-pyridine solution (1 → 100) are used as the indicator. However, the endpoint of the titration is defined as the point when the solution exhibits a pale red color that persists for 15 seconds. A blank test is performed in the same manner. The average molecular weight is calculated by substituting the obtained values ​​into the following formula: Average molecular weight = {Amount of sample (g) × 4000} / (a ​​- b) where a: Amount of 0.5N sodium hydroxide solution consumed in the blank test (mL) b: Amount of 0.5N sodium hydroxide solution consumed in the sample test (mL)

[0029] Specific examples of polyethylene glycol include PEG200 (average molecular weight 190-210), PEG300 (average molecular weight 285-315), PEG400 (average molecular weight 380-420), PEG1000 (average molecular weight 950-1050), PEG2000 (average molecular weight 1800-2200), PEG4000 (average molecular weight 2700-3400), PEG6000 (average molecular weight 7400-9000), and PEG20000 (average molecular weight 18000-25000). These polyethylene glycols may be used individually or in combination of two or more types.

[0030] When the pharmaceutical composition of the present invention contains polyethylene glycol, the amount contained in the pharmaceutical composition is not particularly limited, but for example, it may be 5 to 40% by weight, preferably 10 to 30% by weight, more preferably 15 to 25% by weight, and even more preferably 17 to 23% by weight.

[0031] 4. Nonionic surfactant In preferred embodiments, the pharmaceutical composition of the present invention contains a nonionic surfactant as an additive. When the pharmaceutical composition of the present invention contains a nonionic surfactant, it more preferably further contains a water-soluble thickener and / or polyethylene glycol, and even more preferably further contains a water-soluble thickener and polyethylene glycol.

[0032] The type of nonionic surfactant used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, lecithin derivatives, and the like.

[0033] Examples of glycerin fatty acid esters include glyceryl stearate (glyceryl monostearate). Examples of polyglycerin fatty acid esters include polyglyceryl-6 laurate, polyglyceryl-10 myristate, and polyglyceryl-10 isostearate. Examples of polyoxyethylene glycerin fatty acid esters include PEG-5 glyceryl stearate, PEG-15 glyceryl stearate, PEG-5 glyceryl oleate, and PEG-15 glyceryl oleate. Examples of sorbitan fatty acid esters include sorbitan coconut fatty acid, sorbitan palmitate, and sorbitan stearate. Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 40, polysorbate 60, polysorbate 80, PEG-6 sorbitan stearate, and PEG-20 sorbitan isostearate. Examples of polyoxyethylene sorbitol fatty acid esters include sorbeth-6 laurate, sorbeth-6 tetrasorbate, sorbeth-30 tetraoleate, and sorbeth-60 tetraoleate. Examples of polyoxyethylene hydrogenated castor oil include PEG-10 hydrogenated castor oil, PEG-20 hydrogenated castor oil, and PEG-30 hydrogenated castor oil. Examples of polyoxyethylene alkyl ethers include polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether. Examples of polyethylene glycol fatty acid esters include PEG-10 laurate, PEG-10 stearate, PEG-25 stearate, PEG-40 stearate, PEG-45 stearate, PEG-55 stearate, PEG-10 oleate, PEG-150 distearate, and PEG-8 diisostearate. Examples of lecithin derivatives include hydrogenated lecithin and hydrogenated lysolecithin.

[0034] Furthermore, the HLB value of the nonionic surfactant is not particularly limited, but examples include 8 to 20, preferably 10 to 18, more preferably 13 to 17, and even more preferably 14 to 16.

[0035] The HLB (Hydrophilic-Lipophilic Balance) value is a value that indicates the affinity of a mono-nonionic surfactant for water and oil. In this disclosure, the HLB value of the nonionic surfactant is a value obtained by a measurement method that conforms to the actual measurement of HLB values ​​by emulsification method described in "Handbook - Cosmetics and Pharmaceutical Raw Materials - Revised Edition," Nikko Chemicals Co., Ltd., revised edition published February 1, 1977, pp. 854-855. Specifically, a nonionic surfactant whose HLB value is to be measured is combined with polyoxyethylene sorbitan monostearate (NIKKOL TS-10, HLB 14.9) as a standard substance. The total amount of these two emulsifiers is kept constant, and only the ratio is changed to emulsify liquid paraffin (HLB 10.1), which is the substance to be emulsified. After standing for 24 hours, the optimal ratio of surfactant at which stability is obtained is determined from the amount of creaming, turbidity, and water separation in the lower layer, and the HLB value x of the surfactant is calculated using the following formula (1): y = (x × amount used (mass%) + z × amount used (mass%)) / 100 ... formula (1) In formula (1), x represents the HLB value of the nonionic surfactant (the substance to be measured), y represents the HLB value of the liquid paraffin, and z represents the HLB value of polyoxyethylene sorbitan monostearate (the standard substance). The HLB value of the liquid paraffin can be determined in a similar manner by combining sorbitan monostearate (NIKKOL SS-10, HLB 4.7) and polyoxyethylene sorbitan monostearate (NIKKOL TS-10, HLB 14.9).

[0036] The above-mentioned nonionic surfactants may be used individually or in combination of two or more types.

[0037] Among these nonionic surfactants, polyoxyethylene sorbitan fatty acid esters are preferred, more preferably polysorbate 40, polysorbate 60, polysorbate 80, PEG-6 sorbitan stearate, PEG-20 sorbitan isostearate, and even more preferably polysorbate 40, polysorbate 60, polysorbate 80, and PEG-20 sorbitan isostearate.

[0038] When the pharmaceutical composition of the present invention contains a nonionic surfactant, the amount contained in the pharmaceutical composition is not particularly limited, but for example, it may be 0.1 to 10% by weight, preferably 0.3 to 5% by weight, more preferably 0.5 to 3% by weight, even more preferably 1 to 2% by weight, and even more preferably 1.2 to 1.8% by weight.

[0039] 5. Water The pharmaceutical composition of the present invention, in a preferred embodiment, contains water as a base material. The water content is not particularly limited, but for example, it may be 40 to 99% by weight, preferably 50 to 90% by weight, more preferably 60 to 85% by weight, and even more preferably 70 to 80% by weight.

[0040] 6. Other Components The pharmaceutical composition of the present invention may further contain, or may not contain, other additives and / or other bases depending on the formulation form, etc., in addition to the above-mentioned active ingredients and additives that may be added as needed, such as polyethylene glycol, nonionic surfactants and / or cellulose derivatives, as long as they do not impair the effects of the present invention. Other additives and bases, whether present or absent, are not particularly limited to those that are pharmaceutically acceptable. Examples include surfactants, oily bases (higher (6-34 carbon) monohydric alcohols, cholesterol, fatty acid alkyl esters, vegetable oils, animal oils, mineral oils, higher fatty acids with 12-34 carbon atoms, silicone oils, etc.), monohydric lower (1-5 carbon) alcohols, polyhydric alcohols (dihydric alcohols such as ethylene glycol, 1,3-butylene glycol, isoprene glycol, dipropylene glycol, etc., trihydric alcohols such as glycerin, etc.), isotonic agents (ionic isotonic agents such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and nonionic isotonic agents such as mannitol, sorbitol, glucose, xylitol, trehalose, maltose, maltitol, etc.), chelating agents, pH adjusters, buffering agents, preservatives, antioxidants, stabilizers, etc. These other additives and / or other bases may be used individually or in combination of two or more. The content of these other additives and other bases may be appropriately determined depending on the type of other additives and other bases used, the formulation of the pharmaceutical composition of the present invention, etc.

[0041] Furthermore, the pharmaceutical composition of the present invention may or may not contain other pharmacological components in addition to the above-mentioned active ingredients, as long as they do not impair the effects of the present invention. Such pharmacological components, whether present or absent, are not particularly limited as long as they are pharmaceutically acceptable, but examples include hemostatic agents, antibacterial agents, vasoconstrictors, vitamins, etc. These pharmacological components may be used individually or in combination of two or more. The content of these components may be appropriately determined depending on the type of component used.

[0042] 7. pH The pH of the pharmaceutical composition of the present invention is not particularly limited as long as it can be applied to the extraction socket. Specific pH (25°C) includes 6.8 to 7.5.

[0043] 8. Dosage form The pharmaceutical composition of the present invention contains the above active ingredient, and its dosage form is not particularly limited as long as it can be filled into the extraction socket.

[0044] The pharmaceutical composition of the present invention may be in a liquid state (solution) or semi-solid state (paste) with a fluid property, or may be in a solid state (jelly, pill, tablet, granule, powder, etc.). Further, the pharmaceutical composition of the present invention may be either a solubilized composition or a dispersible composition (an emulsion composition without an oily base or an emulsified composition containing an oily base).

[0045] The pharmaceutical composition of the present invention is preferably a sustained-release composition that slowly releases a selective COX2 inhibitor. When the pharmaceutical composition of the present invention is a sustained-release composition, the pharmaceutical composition of the present invention can be a dispersible composition containing a selective COX2 inhibitor as a disperse phase and an aqueous gel containing a water-soluble thickener and water as a dispersion medium. Preferably, the pharmaceutical composition of the present invention is a dispersible composition containing polyethylene glycol, a nonionic surfactant, and a water-soluble thickener together with water, and contains particles containing a selective COX inhibitor and polyethylene glycol as a disperse phase and an aqueous gel containing a water-soluble thickener and water as a dispersion medium. When the dispersible composition is administered to the extraction socket, the aqueous gel is gradually dissolved in the moisture of the exudate, and the particles containing the selective COX2 inhibitor contact the extraction socket tissue, so that the selective COX2 inhibitor can be continuously absorbed transdermally.

[0046] When the pharmaceutical composition of the present invention has a fluid property, it may be provided in a form pre-filled in a syringe (prefilled syringe preparation).

[0047] In the prefilled syringe preparation, the syringe may further include an extension nozzle for improving operability, or may not include it. The extension nozzle may be integrated with the syringe, or may be provided as a separate member and attached to the syringe during use.

[0048] The extension nozzle can have a length that enables access to the tooth extraction socket at the nozzle tip. The extension nozzle may have the same diameter from the syringe side to the nozzle tip side, or may be tapered with a larger diameter on the syringe side and a smaller diameter on the nozzle tip side.

[0049] The axis of the extension nozzle may be a straight line, a curve, a broken line with a predetermined angle, or a combination of a straight line and a curve (for example, consisting of one straight line and one curve connected to each other, where one of the nozzle tip side and the syringe side is a straight line and the other is a curve; consisting of one curve and two straight lines connected to each end thereof, where the directions of the two straight lines form a predetermined angle, etc.). Also, when the axis of the extension nozzle is a straight line, it may be configured such that the axis of the syringe and the axis of the extension nozzle form a predetermined angle. As the above-mentioned predetermined angle and the curvature of the above-mentioned curve, an angle and a curvature that facilitate access to the tooth extraction socket at the nozzle tip can be appropriately designed.

[0050] In the prefilled syringe, the amount of the pharmaceutical composition filled per syringe may be appropriately set according to the concentration of the active ingredient, dosage, set number of uses, etc. Examples include 0.5 to 3 mL, preferably 1 to 2.5 mL, more preferably 1 to 2 mL. The prefilled syringe preparation is preferably disposable.

[0051] The prefilled syringe can be stored, preferably in a sealed bag and / or under refrigeration, with the syringe cap attached.

[0052] The material of the sealed bag is not particularly limited, but examples include polyolefins (polyethylene, polypropylene, ethylene-vinyl acetate copolymer, metal-crosslinked polyethylene, cyclic polyolefin copolymer, cyclic polyolefin), polyacrylonitrile, polyester, polyamide, polystyrene, vinyl chloride, etc. The sealed bag may consist of a single-layer film of these resins, or it may consist of a multi-layer film containing layers of these resins and a barrier layer (metal vapor-deposited film, metal oxide vapor-deposited film, aluminum foil, ethylene-vinyl alcohol copolymer, polyacrylonitrile, vinylidene chloride, polyvinyl alcohol, etc.). Examples of sealing methods include heat seals and zippers. The refrigeration temperature is preferably 2 to 8°C.

[0053] 9. Manufacturing Method The pharmaceutical composition of the present invention can be manufactured by using the above-mentioned active ingredient and other ingredients as needed, following conventionally known manufacturing procedures depending on the formulation.

[0054] For example, when preparing the pharmaceutical composition of the present invention as a sustained-release composition, the pharmaceutical composition of the present invention can be prepared by preparing a liquid drug composition containing a selective COX2 inhibitor and an aqueous gel composition containing a water-soluble thickener and water, and then adding the liquid drug composition to the aqueous gel composition and mixing. Alternatively, when the pharmaceutical composition of the present invention contains a water-soluble thickener, polyethylene glycol, a nonionic surfactant and water along with a selective COX2 inhibitor, the pharmaceutical composition can be prepared by preparing a liquid drug composition containing a selective COX2 inhibitor, polyethylene glycol and a nonionic surfactant, and an aqueous gel composition containing a water-soluble thickener, a nonionic surfactant and water, and then adding the liquid drug composition to the aqueous gel composition and mixing. The prepared pharmaceutical composition of the present invention should be stored under refrigeration, preferably at 2 to 8°C.

[0055] 10. Uses The pharmaceutical composition of the present invention is used to suppress post-extraction pain by being embedded in the extraction socket. More specifically, the pharmaceutical composition of the present invention can be used to fill the extraction socket after tooth extraction and before suturing, and then to embed it by suturing. The location of the extraction socket is not particularly limited as long as it is a location where suppression of post-extraction pain is required. Generally, post-extraction pain of mandibular wisdom teeth is particularly pronounced, but because the pharmaceutical composition of the present invention has an excellent pain-suppressing effect, it can effectively suppress post-extraction pain of mandibular wisdom teeth as well. From this viewpoint, particularly preferred locations for the extraction socket include the extraction socket of a mandibular wisdom tooth, and more preferably, the extraction socket of an impacted mandibular wisdom tooth.

[0056] When the pharmaceutical composition of the present invention is applied to the extraction socket of an impacted mandibular wisdom tooth, the Pell-Gregory classification of the impacted mandibular wisdom tooth is not particularly limited, and the Class may be I, II, or III, and the Position may be A, B, or C.

[0057] The animals to which the pharmaceutical composition of the present invention can be applied are not particularly limited, and examples include humans, other primates, dogs, cats, and other mammals.

[0058] When filling a tooth extraction socket with the pharmaceutical composition of the present invention, the pharmaceutical composition of the present invention may be used alone, or it may be used in combination with bone graft material (such as Telplug, Spongel, Bonarch, etc.).

[0059] 11. Dosage The dosage of the pharmaceutical composition of the present invention is, for example, 0.1 to 10 mg or 0.3 to 10 mg per tooth extraction socket, preferably 0.4 to 10 mg, 0.5 to 10 mg, 0.6 to 10 mg, or 0.7 to 10 mg, more preferably 0.8 to 10 mg, 0.9 to 10 mg, 1 to 10 mg, 1.2 to 10 mg, 1.4 to 10 mg, 1.6 to 10 mg, 1.8 to 10 mg, or 2 to 10 mg, in terms of the dosage of the selective COX2 inhibitor. Furthermore, since the pharmaceutical composition of the present invention has an excellent effect in suppressing post-extraction pain, post-extraction pain can be effectively suppressed even with an even smaller dose of the selective COX2 inhibitor. From this perspective, suitable dose ranges for selective COX2 inhibitors per extraction socket include 0.1-8 mg, 0.1-6 mg, 0.1-5 mg, 0.1-4 mg, 0.1-3 mg, 0.1-2.5 mg, 0.1-1.7 mg, 0.1-1 mg, 0.1-1.5 mg, 0.1-1.2 mg, 0.1-1 mg, 0.1-0.8 mg, 0.1-0.7 mg, or 0.1-0.6 mg.

[0060] The daily oral doses of selective COX-2 inhibitors used for post-extraction pain relief are approximately 400-600 mg for celecoxib, 400 mg for etodolac, 24 mg for lornoxicam, 15 mg for meloxicam, 800 mg for nabumetone, and 240 mg for zaltoprofen. The pharmaceutical composition of the present invention, when administered by embedding it in the tooth socket, can effectively suppress post-extraction pain with a significantly lower dose compared to oral administration.

[0061] 12. Concomitant Drugs The pharmaceutical composition of the present invention can be used in combination with oral analgesics. Examples of oral analgesics include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and Rikkosan. Examples of NSAIDs include loxoprofen and its salts (e.g., loxoprofen sodium), diclofenac and its salts (e.g., diclofenac sodium), and ibuprofen. Among these oral analgesics, NSAIDs are preferred, and loxoprofen or its salts are more preferred, particularly loxoprofen sodium.

[0062] Oral analgesics can be taken as needed. The dose of oral analgesics taken as needed should be set appropriately according to the usual dosage set for each type of oral analgesic, but for example, the total dose for 5 days after tooth extraction can be 1 to 20 doses. The pharmaceutical composition of the present invention has an excellent effect in suppressing post-extraction pain, so the number of times oral analgesics can be taken as needed can be reduced. From this viewpoint, suitable doses of oral analgesics taken as needed for 5 days after tooth extraction include 1 to 15 doses, 1 to 12 doses, 1 to 10 doses, 1 to 8 doses, 1 to 6 doses, and 1 to 5 doses. The dose per dose is the usual dose depending on the type of oral analgesic. Specific doses per dose can be selected as follows: 60 mg for loxoprofen sodium, 25 to 50 mg for diclofenac sodium, 400 mg for ibuprofen, 1000 mg for acetaminophen, and 1.5 g for Rikkosan extract.

[0063] For example, if the dose of selective COX2 inhibitor per extraction socket is in the range of 0.1 to 0.7 mg, the as-needed dose of oral analgesic for the 5 days after tooth extraction may be 5 to 15 doses, preferably 7 to 15 doses; if the dose of selective COX2 inhibitor per extraction socket is in the range of 0.7 to 1.7 mg, the as-needed dose of oral analgesic for the 5 days after tooth extraction may be 1 to 12 doses, preferably 1 to 10 doses, more preferably 1 to 8 doses; if the dose of selective COX2 inhibitor per extraction socket is in the range of 1.7 to 10 mg, the as-needed dose of oral analgesic for the 5 days after tooth extraction may be 1 to 9 doses, preferably 1 to 7 doses, more preferably 1 to 5 doses.

[0064] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0065] [1] Preparation of pharmaceutical compositions Pharmaceutical compositions with the compositions shown in Table 1 were prepared by following the procedure below under sterile conditions.

[0066] [1-1] Preparation of the drug solution composition A warm bath was prepared by placing about 50-70 mL of water in a 100 mL beaker and heating it to about 50°C with a hot stirrer. 10 mg, 20 mg, or 40 mg of celecoxib was weighed into a centrifuge tube (15 mL), and PEG400 was added in 1 mL increments for a total of 3 mL while stirring with VOLTEX under heating in the warm bath to dissolve the celecoxib. 1.5 mL of 10% by weight polysorbate 80 aqueous solution was added to the centrifuge tube in 0.5 mL increments while stirring with VOLTEX under heating, and then 5.5 mL of 2% by weight polysorbate 80 aqueous solution was slowly added in 0.5 ml increments while stirring with VOLTEX under heating. This yielded drug solutions containing 1,2,5 mg / mL of celecoxib, 30% by weight of PEG400, and 2.6% by weight of polysorbate 80.

[0067] [1-2] Preparation of aqueous gel composition 22 mL of sterile water for injection was prepared in a 100 mL beaker and heated to approximately 50°C using a hot stirrer. While stirring with a stirring bar, 1.5 g of hypromellose was added to the beaker in small amounts. After confirming the dispersion state of the hypromellose (turbidity), 2 mL of PEG400 and 1 mL of 10% by weight aqueous solution of polysorbate 80 were added. The beaker was removed from the hot stirrer, the stirring bar was removed from the beaker, and stirring was continued with a stirring rod. As the turbidity cleared with cooling, the viscosity increased, and a paste-like aqueous gel composition containing 6% by weight of hypromellose, 8% by weight of PEG400, and 0.4% by weight of polysorbate 80 was obtained.

[0068] [1-3] Preparation of Pharmaceutical Composition (in Pre-filled Syringe Formulation) 10 g of the paste-like aqueous gel composition prepared in [1-2] above was placed in a centrifuge tube (50 mL capacity) and heated to 40°C in a water bath. The drug solution composition prepared in [1-1] above was heated to 40°C in a water bath. The drug solution composition was added to the aqueous gel composition, removed from the water bath, and mixed vigorously by shaking until it became a paste as it cooled. After that, it was stored in a refrigerator (2-8°C). After about one day of storage, the air bubbles introduced during shaking were removed. This yielded pharmaceutical compositions (Examples 1-3) with the compositions shown in Table 1.

[0069] The pharmaceutical compositions of Examples 1 to 3 were obtained as sustained-release compositions in emulsion form (colorless, clear to slightly translucent, paste-like, no insoluble matter observed), with particles containing celecoxib as the dispersed phase and an aqueous gel containing hypromellose and water as the dispersion medium. The pH (at 25°C) of the pharmaceutical compositions of Examples 1 to 3 was 6.8 to 7.5.

[0070] Subsequently, 1.5 to 2 mL of the paste-like pharmaceutical composition was filled into a 2.5 mL syringe, and a syringe cap was attached to obtain a pre-filled syringe formulation. The pre-filled syringe formulation was placed in a resealable LDPE bag, sealed, and stored in a refrigerator (2 to 8°C).

[0071]

[0072] [2] Animal Tests [2-1] Preparation of Pharmaceutical Compositions A pharmaceutical solution composition containing 12 mg / mL of celecoxib, 30% by weight of PEG400, and 2.6% by weight of polysorbate 80 was obtained in the same manner as in [1-1] above, except that the amount of celecoxib used was changed to 120 mg. Using a paste-like aqueous gel composition containing 6% by weight of hypromellose, 8% by weight of PEG400, and 0.4% by weight of polysorbate 80, prepared in the same manner as in [1-2] above, a pharmaceutical composition was obtained in the same manner as in [1-3] above. This obtained the pharmaceutical composition of Example 4 in Table 2. The same procedure was also followed except that celecoxib was not used to obtain the composition of Comparative Example 1 in Table 2.

[0073]

[0074] [2-2] Safety Test 1 The pharmaceutical composition of Example 4 was applied to one cheek pouch of 8-10 week old hamsters, and the composition of Comparative Example 1 was applied to the other cheek pouch for 3 days. Mucosal tissue from the application site was collected on the 4th day. The mucosal tissue was then fixed with formalin, dehydrated and degreased, embedded in paraffin, and sliced ​​to obtain paraffin-embedded sections. The paraffin-embedded sections were stained with hematoxin and eosin and evaluated by microscopy. As a result, no noteworthy findings were observed with the pharmaceutical composition of Example 4. Thus, the safety of the pharmaceutical composition of Example 4 was confirmed.

[0075] [2-3] Safety Test 2 The pharmaceutical composition of Example 4 or the composition of Comparative Example 1 was injected subcutaneously into the backs of 10-week-old mice, and skin tissue from the injection site was collected after 7 days. The skin tissue was then fixed with formalin, dehydrated and degreased, embedded in paraffin, and sliced ​​to obtain paraffin-embedded sections. The paraffin-embedded sections were stained with hematoxin and eosin and evaluated by microscopy. As a result, no pathological findings were observed with respect to the pharmaceutical composition of Example 4. Thus, the safety of the pharmaceutical composition of Example 4 was confirmed.

[0076] [3] Sustained-release test The pharmaceutical composition of Example 1 or Example 2 prepared in [1] above was placed in a dialysis membrane bag, sealed, and immersed in albumin buffer. The amount of celecoxib in the albumin buffer was measured over time (1, 2, 4, 7, and 14 days). The measurement results are shown in Figure 1.

[0077] As shown in Figure 1, both the pharmaceutical compositions of Example 1 and Example 2 were confirmed to be able to sustainably release celecoxib. In particular, both pharmaceutical compositions were able to sustainably release celecoxib up to 4 days later. In other words, it could be inferred that when applied to an extracted tooth socket, celecoxib would be sustainably released for at least 4 days after extraction (up to 5 days if the day of extraction is considered day 1).

[0078] [4] Clinical Trials [4-1] Subjects Subjects were individuals who met all of the following selection criteria and did not fall under any of the following exclusion criteria .

[0079] Selection Criteria (1) Individuals scheduled to have one mandibular wisdom tooth extracted (unilateral) (2) Individuals classified as Class I or II in the Pell-Gregory classification (horizontal position) (3) Individuals classified as Position A or B in the Pell-Gregory classification (vertical position) (4) Individuals aged 18 or older at the time of obtaining consent (5) Individuals who have given written consent of their own free will to participate in this clinical study

[0080] Exclusion Criteria (1) Individuals with severe and / or poorly controlled co-existing medical conditions (e.g., systolic blood pressure exceeding 160 mmHg or diastolic blood pressure exceeding 95 mmHg despite aggressive blood pressure therapy, renal failure requiring dialysis, history of transplantation within 180 days prior to the start of investigational drug administration, cerebrovascular accident requiring treatment within 180 days prior to the start of investigational drug administration, or major invasive surgery within 30 days prior to the start of investigational drug administration) (2) Individuals with a known history of hypersensitivity to at least one of the components of celecoxib, polysorbate 80, hypromellose, and PEG400 (3) Individuals with aspirin-induced asthma or a history thereof (4) Individuals who use analgesics (including topical analgesics / anti-inflammatory drugs (patches / poultices) in the case of opioids) at least once a week for pain (regardless of whether it is cancer pain or non-cancer pain; e.g., migraine, stiff neck pain, lower back pain, etc.) (5) (6) Individuals whom the principal investigator determines cannot be properly evaluated due to dementia, psychiatric symptoms, drug addiction, alcohol addiction, etc. (7) Pregnant or breastfeeding women (8) Individuals who have received radiation therapy to the site where wisdom tooth extraction is planned (9) Individuals with a history of taking drugs related to drug-induced osteonecrosis of the jaw (10) Others whom the principal investigator or other relevant personnel of this clinical study deem unsuitable

[0081] [4-2] Protocol This study was a Phase I, open-label, single-center, single-arm study involving patients undergoing mandibular wisdom tooth extraction. After extraction of the mandibular wisdom teeth of the subjects, one of the pharmaceutical compositions from Examples 1 to 3 was filled into the extraction socket in the doses shown in Table 3, and the wound was sutured. After tooth extraction, the subjects were prescribed loxoprofen sodium 60 mg (Loxonin tablets) as a single-dose medication.

[0082] The day of tooth extraction was designated as day 1, and subjects recorded the degree of pain and the amount of Loxonin tablets taken as needed. The degree of pain was evaluated using a Visual Analog Scale (VAS) where "0" represented no pain and "100" represented the worst pain. The resulting VAS value was divided by 10 and rounded to the nearest whole number to obtain the pain score.

[0083] By day 8, the principal investigator determined whether or not dry socket had developed in the extraction socket.

[0084] [4-3] Results The following table shows the gender, age, Pell-Gregory classification (Class-Position), surgical time taken for tooth extraction, pharmaceutical composition used, celecoxib dose per extraction socket (mg), pain VAS score, and loxoprofen dose (tablets) of the subjects.

[0085]

[0086] As shown in Table 3, post-extraction pain of mandibular wisdom teeth was well controlled in the subjects. Generally, more than 15 tablets of loxoprofen are prescribed by the fifth day after mandibular wisdom tooth extraction, but with the exception of one subject in the low-dose group (celecoxib dose of 0.5 mg per extraction socket), the subjects' as-needed dose of loxoprofen was less than the typical prescribed amount, reflecting the good suppression of post-extraction pain. In particular, post-extraction pain was further suppressed when the celecoxib dose per extraction socket was 0.7 mg, 1 mg, and 2 mg, and was especially suppressed when the celecoxib dose per extraction socket was 2 mg. Furthermore, dry socket was not observed in any of the cases.

Claims

1. A pharmaceutical composition for implantation into tooth extraction sockets, containing a selective COX-2 inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the extraction socket is the extraction socket of a mandibular wisdom tooth.

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of the selective COX2 inhibitor is 0.1 to 5% by weight.

4. The pharmaceutical composition according to claim 1 or 2, wherein the dose of the selective COX2 inhibitor per tooth extraction socket is 0.1 to 10 mg.

5. The pharmaceutical composition according to claim 1 or 2, wherein the selective COX2 inhibitor is selected from the group consisting of celecoxib, etodolac, lornoxicam, meloxicam, nabumetone, and zaltoprofen.

6. The pharmaceutical composition according to claim 1 or 2, which is semi-solid.

7. The pharmaceutical composition according to claim 1 or 2, comprising a water-soluble thickening agent.

8. The pharmaceutical composition according to claim 1 or 2, comprising polyethylene glycol and / or a nonionic surfactant.

9. The pharmaceutical composition according to claim 1 or 2, which is used in combination with an oral analgesic for as-needed use, administered 1 to 15 times over a 5-day period following tooth extraction.

10. A pre-filled syringe formulation filled with the pharmaceutical composition according to claim 1 or 2.

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