WO2019190118A1 - 폴마콕시브 및 프레가발린을 포함하는 통증 치료용 약제학적 조성물 - Google Patents
폴마콕시브 및 프레가발린을 포함하는 통증 치료용 약제학적 조성물 Download PDFInfo
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- WO2019190118A1 WO2019190118A1 PCT/KR2019/003225 KR2019003225W WO2019190118A1 WO 2019190118 A1 WO2019190118 A1 WO 2019190118A1 KR 2019003225 W KR2019003225 W KR 2019003225W WO 2019190118 A1 WO2019190118 A1 WO 2019190118A1
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- pregabalin
- polmacoxib
- pharmaceutical composition
- pain
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Definitions
- the present invention relates to a composition comprising polmacoxib and pregabalin, and more particularly, polmacoxib, which can be usefully used as a nonsteroidal anti-inflammatory agent showing excellent effects with excellent stability and low content. And a broad spectrum anticonvulsant, pregabalin used in the treatment of neuropathological pain.
- Pain is defined as an unpleasant sensory and emotional experience associated with or described as actual or potential tissue damage. It also refers to pain and sensory impairment caused by stimulation of the area in contact with the cerebral cortex and the marginal system area through the neuropath consisting of pain receptors and nerve fibers. It is a warning response that transmits an abnormality inside or outside the body as a defense means to protect the body. Since pain itself is not a disease, eliminating it does not cure the underlying disease.
- the cause can be largely divided into perceptual cases caused by damage or inflammation of somatic or visceral tissue, neuropathy that occurs after nerve damage.
- the neuropathy is a pain due to peripheral nerve or central nervous system dysfunction. If the pain lasts for a long time or the irritation is too severe, it can interfere with daily life, and may cause anxiety and fear. Because of this, people with chronic pain often have depression, so these characteristics should be taken into account when treating.
- Pregabalin has the compound name (S)-(+)-3- (aminomethyl) -5-methyl-nucleic acid ((S)-(+)-3- (aminomethyl) -5-methyl-hexanoic acid) and It has a structure of the following formula (1).
- Pregabalin binds to the alpha-2-delta ( ⁇ 2 ⁇ ) subunit of the calcium channel, thereby reducing calcium ion influx at the nerve cell ends, including glutamate and noradrenalin.
- the secretion of excitatory neurotransmitters is known to restore neuronal function to normal levels.
- Pregabalin is an endogenous neurotransmitter involved in the regulation of brain neuronal activity and is an analog of ⁇ -amino butyric acid (GABA) involved in neuronal processing.
- GABA ⁇ -amino butyric acid
- Pregabalin has been shown to activate L-glutamate decarboxylase (GAD), has a dose dependent protective effect against seizures, and is a central nervous system (CNS) active compound.
- GAD L-glutamate decarboxylase
- CNS central nervous system
- pregabalin may be useful in anticonvulsant therapy due to the activation of GAD, which is one of the major inhibitory neurotransmitters in the brain released by 30% brain synapse (gamma-aminobutyric acid) This is because it causes an inhibitory postsynaptic potential as an amino acid neurotransmitter.
- Such pregabalin drugs can be used to treat epilepsy, neuropathological pain, generalized anxiety discorders, fibromyalgia, and the like.
- neuropathological pain Among the possible causes of neuropathological pain are diabetic polyneuropathy, post shingles neuralgia, tumors, chemotherapy, trigeminal neuralgia, alcohol abuse, vitamin B deficiency, hallucinations, borelia infection, complex pain syndrome, wrist Bone syndrome, back pain and acquired immunodeficiency.
- Pregabalin drugs are white or pale yellow crystalline powders that are well soluble in water. The drug shows rapid and high absorption in the body, resulting in a peak blood concentration in about 1.3 hours and a bioavailability of about 90%. In addition, most are excreted in the urine through the kidney and the half-life is about 5 to 6.5 hours. Since pregabalin is absorbed by the L-amino acid transport system, the absorption is not uniform in the gastrointestinal tract, and because the most absorption occurs in the upper part of the small intestine where L-amino acid transporters are concentrated, the average absorption period is 6 hours. It is as follows. For this reason, many pharmaceutical companies are currently developing tablet formulations such as pregabalin sustained-release tablets and gastric tablets beyond low productivity capsules.
- Polmacoxib is a drug that is currently being sold as a product called Aselex capsules, and its structure is represented by the following Chemical Formula 2.
- the compound name of polmacoxib is 5- (4- (aminosulfonyl) phenyl) -2,2-dimethyl-4- (3-fluorophenyl) -3 ( 2H) -furanone.
- As a selective inhibitor of COX-2 it has reduced gastrointestinal toxicity compared to conventional NSAIDs and is effective in inflammatory diseases, inflammation-related diseases, pain, solid cancers, angiogenesis-related diseases, Alzheimer's disease, seizures and convulsions, strokes, epilepsy, etc. It is known that there is (Korean Patent No. 10-0495389).
- COX-2 (cyclooxygenase) is responsible for the production of prostaglandin.
- compositions in which the combination of polmacoxib and pregabalin can achieve additional effects in severe to moderate pain, especially in the presence of inflammatory components, and to demonstrate the combination thereof. .
- the present inventors formulated two different active ingredients in a single dosage form to further enhance the synergistic effect on the pain of the combination of polmacoxib and pregabalin and the ease of taking the drug compared to the existing product. Was intended.
- the present invention provides a pharmaceutical composition for treating pain, comprising polmacoxib and pregabalin.
- the composition can be used for the treatment of acute or chronic pain caused by inflammatory or neuropathic conditions.
- neurogenic pain including diabetic neuropathy, pain due to generalized anxiety disorder, fibromyalgia, hyperalgesia, allodynia, cancer pain Pain, osteoarthritis, rheumatoid arthritis, spondylitis, frozen shoulder, lumbodynia or sciatica can be applied as indications.
- the ratio of polmacoxib to pregabalin may be 1: 1 to 1: 600 weight ratio.
- the ratio of polmacoxib to pregabalin may be in a 1: 1 to 300: 1 weight ratio, and may have a 2: 1 to 2: 300 weight ratio.
- composition based on the total weight of the composition, it may comprise 0.1 to 10% by weight of polmacoxib and 10 to 50% by weight of pregabalin.
- the excipient may further comprise a pharmaceutically acceptable excipient.
- the excipient consists of ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, carboxy methyl cellulose sodium, polyethylene oxide, carbomer, sodium alginate, mannitol, croscarmellose sodium, sodium bicarbonate and magnesium stearate It may include one or more selected from the group.
- the composition may be provided in the form of a tablet, capsule or suspension.
- polmacoxib and pregabalin may be in the form of a mixed tablet, capsule or suspension, and the tablet may include a double tablet, a multi-layer tablet or a single tablet.
- polmacoxib, pregabalin, or a mixture thereof may be formed as a double-layered double-layered or multi-layered multi-layered tablet in a state divided into different layers.
- the sustained release layer may include pregabalin
- the immediate release layer may include polmacoxib.
- it may further include a pharmaceutically acceptable coating base.
- it may further comprise a pharmaceutically acceptable carrier.
- the composition is similar to the drug release pattern of Lyrica capsule and Aselex tablet, which are oral formulations containing commercial pregabalin.
- Lyrica capsule and Aselex tablet which are oral formulations containing commercial pregabalin.
- each drug effect is complementary with only one or two doses per day, minimizing each drug interaction in the formulation. Can be sustainably exercised.
- composition according to the present invention has stability against physical factors from the outside, and the flowability of the particles can be improved to improve uniformity, so that handling is easy and productivity can be improved.
- Figure 3 is a graph showing the polmacoxib comparative dissolution pattern of Experimental Example 2.
- Figure 6 is a graph showing the polmacoxib comparative dissolution pattern of Experimental Example 4.
- FIG. 12 is a graph showing a comparative dissolution pattern of Experimental Example 8.
- FIG. 14 is a graph showing the comparative dissolution pattern of Experimental Example 10.
- FIG. 15 is a graph showing the comparative dissolution pattern of Experimental Example 11.
- FIG. 16 is a graph showing pregabalin comparative elution patterns of Experimental Example 11 and Experimental Example 12.
- FIG. 17 is a graph showing the polmacoxib comparative elution pattern of Experimental Example 12.
- the term “pharmaceutical composition” may be used in combination with “pharmaceutical composition” and “pharmaceutically acceptable composition” and may be relatively nontoxic and innocuous to the subject to be administered.
- any side effect resulting from the composition will mean any organic or inorganic compound formulation that does not degrade the efficacy of the drug, does not cause serious irritation to the subject to which the compound is administered, and does not impair the biological activity and properties of the compound. Can be.
- the term 'administered subject' may be used in combination with 'administered subject' and 'administered organism', and may mean any animal including humans in which acute or chronic pain is caused or may be caused. have.
- the present invention provides a pharmaceutical composition for pain treatment comprising polmacoxib and pregabalin.
- Polmacoxib and pregabalin co-formulations when mixed with other pharmaceutically acceptable additives, may have the effect of increasing the stability against changes over time by reducing the modification of the active ingredient.
- the composition may be in liquid or solid form and provided in any convenient form, such as in the form of tablets, pellets, granules, capsules, suspensions, emulsions or powders suitable for reconstitution with water or other suitable liquid medium.
- the composition may be formed in the form of tablets, capsules, suspensions and the like.
- polmacoxib and pregabalin may be prepared in the form of a tablet, tablet, capsule, or suspension, wherein the tablet may comprise the form of a monolayer, bilayer or multilayer tablet, wherein the tablet is a double tablet.
- Multi-layered tablets or monolithic tablets may also be formed as a capsule formulation, for example filled in the form of particles, granules, pellets.
- pregabalin may be prepared in the form of a capsule formulation having less influence from external physical factors during the manufacturing process for reasons of raw material properties.
- it can be prepared in the form of tablets to minimize the production of the flexible material by manufacturing with a tableting pressure that can improve the instability.
- the long-term stay in the stomach due to the nature of the mechanism of absorption of the pregabalin component can effectively act on the absorption of the drug, it can be prepared in the formulation of gastric floating tablets.
- polmacoxib, pregabalin or a mixture thereof may be formed as a double-layered double-layered or multi-layered multi-layered tablet in a state divided into different layers.
- it may be formed of a bilayer or multiple layers consisting of a sustained release layer and an immediate release layer structure, wherein the sustained release layer may include pregabalin, and the immediate release layer may include polmacoxib.
- the sustained release layer may include pregabalin
- the immediate release layer may include polmacoxib.
- after forming a layer of polmacoxib and pregabalin mixture granules in the immediate release layer, and then chopped, to form a layer of pregabalin granules in the sustained release layer may be prepared by a tablet press.
- a polmacoxib-containing layer may be formed in the immediate release layer, and a pregabalin layer may be formed in the sustained release layer to produce a tableting machine.
- the bilayer manufacturing method may be prepared by forming a lower layer with pregabalin and its mixture granules, and then pulmacoxib and its mixture with granules, and using a tableting machine, but is not limited thereto.
- the inner layer may be formed in a microcoated double release type (DRM) including the pregabalin layer of the outer layer in the pregabalin layer of the inner layer or the pregabalin layer of the outer layer in the layer of polmacoxib.
- DRM microcoated double release type
- the ratio of polmacoxib to pregabalin is, for example, from 1 to 300: 1 to 600 weight ratio, for example from 1: 1 to 1: 300 weight ratio, for example from 2: 1 to 2: 2. May be 300.
- pregabalin may also be included, for example, from 0.1 to 10% by weight of polmacoxib and from 10 to 50% by weight of pregabalin relative to the total weight of the composition. For example, it may be included in 0.3 to 1.0% by weight of polmacoxib and 10 to 30% by weight of pregabalin relative to the total weight of the composition. In addition, for example, 1-5 mg, such as 1-2 mg and pregabalin 75-300 mg, such as 75-150 mg, may be included in the composition.
- excipients include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyethylene oxide, Selected from the group consisting of carbomer, sodium alginate, mannitol, cross carmellose sodium, sodium hydrogen carbonate, and magnesium stearate It may include one or more. Among them, for example, it may include one or more selected from the group consisting of hydroxypropyl methyl cellulose, di-mannitol, hydroxypropyl cellulose, croscarmellose sodium, sodium bicarbonate, magnesium stearate.
- mannitol 200SD having a uniform and water-insoluble polymer may be used, but is not limited thereto.
- the composition is a bilayer formulation consisting of a sustained release layer and an immediate release layer
- the sustained release matrix excipient hydroxy propyl methyl cellulose, polyethylene oxide (PEO), carbomer, sodium alginate, ethyl cellulose, hydroxy propyl
- PEO polyethylene oxide
- carbomer sodium alginate
- ethyl cellulose hydroxy propyl
- It may include one or more selected from the group consisting of cellulose and carboxy methyl cellulose sodium, and the like, for example, may include hydroxy propyl methyl cellulose.
- the drug may be suspended in the gastrointestinal tract for a certain period of time, thereby causing the generation of gas on the surface of the tablet to increase the floating property, and excipients containing sodium hydrogen carbonate Can be used.
- the sustained release agent added together with the excipient is 10 to 70%, for example 30 to 50%, based on the total weight of the sustained release layer. It may be included as.
- sodium bicarbonate which enhances the suspension of tablets, may increase the disintegration of tablets when added in an amount greater than an appropriate amount, thus preventing the release of drugs, for example, 1 to 15% by weight of the total composition, eg For example, it may be included in 8 to 12%.
- the composition may include a coating base to ensure long-term stability of the polmacoxib having light-sensitive properties and pregabalin is affected by the stability by external factors such as moisture, temperature.
- a coating base for example, a water-soluble coating base may be used, and a coating base commonly used may be used.
- it may include a coating base comprising a polyvinyl alcohol derivative, methacrylic acid derivatives and polyacrylic acid derivatives, for example Opadry®, Kollicoat® and a group consisting of hydroxy propyl methyl cellulose (HPMC)
- a coating base comprising a polyvinyl alcohol derivative, methacrylic acid derivatives and polyacrylic acid derivatives, for example Opadry®, Kollicoat® and a group consisting of hydroxy propyl methyl cellulose (HPMC)
- Opadry® containing polyvinyl alcohol having a relatively good moisture and light shielding effect can be used.
- it may further comprise a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier those commonly used in the preparation may be used, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia Rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup ( syrup, methyl cellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil ), Etc., but is not limited thereto.
- Pharmaceutically acceptable substances commonly used, such as preservatives may be included as additional additives.
- Such additives may be included within a content range that minimizes the effect on the active ingredient of the composition according to the invention, for example 5 to 90% by weight, for example 40 to 90% by weight relative to the total weight of the composition. .
- the composition may act on pain caused by inflammatory or neuropathic, for example, acute pain, chronic pain.
- inflammatory or neuropathic for example, acute pain, chronic pain.
- neurogenic pain including diabetic neuropathy, pain due to generalized anxiety disorder, fibromyalgia, hyperalgesia, allodynia, cancer Effective effect as an analgesic for treating pain, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, lumbarnia or sciatica Can be represented. It can also be used for the treatment of severe to moderate pain of inflammatory elements such as, for example, rheumatoid arthritis, ankylosing spondylitis, sciatica and fifty shoulders.
- the pharmaceutical or pharmaceutical composition according to the present invention may be in any form suitable for application to humans, including infants, children and adult animals, and may be prepared by standard processes known to those skilled in the art.
- the pregabalin active ingredient which has a lack of stability, and the formulation suitability test were used to select excipients without drug-excipient interactions and to minimize their types.
- the excipients shown in Table 1 as the main ingredients of polmacoxib and pregabalin, the granules were combined, dried, sized, mixed, and filled in capsules.
- the mesh network was used as 30 mesh.
- Example 1 In vitro comparative dissolution test was carried out for the formulation of Example 1 according to the second method (paddle method, device 2) standard of the Korea Pharmacopoeia dissolution test method.
- a commercially available one was used.
- a comparative dissolution test was carried out using aselex capsule, a product of Asa, for polmacoxib as a reference, and a comparative dissolution of Lyrica capsule product as a reference for pregabalin. The test was conducted.
- the dissolution test solution for the polmacoxib component As the dissolution test solution for the polmacoxib component, the first solution of the eleventh revised disintegration test method of pH 1.2, the elution solution of Example 1 and the control drug having the largest dissolution difference, was used, and the test temperature was 37 ⁇ 0.5 ° C. , The rotation speed was 50rpm, the results are shown in Table 2 and FIG.
- the elution test solution for the pregabalin component was the first solution of the 11th Amendment Disintegration Test of the Korean Pharmacopoeia at pH 1.2, the 0.05th Amendment of the 17th Pharmacopoeia at pH 4.0, 0.05 acetate / sodium acetate buffer pH 4.0, pH 6.8 Since the similar pattern is shown in all the four eluents of the second solution or water of the eleventh revised disintegration test method of the Korean Pharmacopoeia of the Republic of Korea was tested with the initial eluent 0.06 N HCL, the results are shown in Table 3 and FIG.
- the dissolution rate is expressed as an average, and the unit is%.
- the disintegrant was adjusted to fill the capsule in the same manner as in Example 1.
- Example 2 A comparative dissolution test was conducted for the preparation in the same manner as in Experimental Example 1.
- test solution for polmacoxib is pH 1.2, the results are shown in Table 5 and FIG. 3, the test solution for pregabalin is pH 0.06 N HCL and is shown in Table 6 and FIG. 4.
- the dissolution difference between pregabalin and the control drug increased by disintegrant.
- the capsules were filled in the same manner as in Example 1 except that the composition of Table 7 was treated with 16 or 20 mesh mesh.
- Experimental Example 4 A formulation was prepared in tablets for each hardness, and the comparative dissolution test was conducted in the same manner as in Experimental Example 1 for the polmacoxib component.
- Example 4 After preparing tablets by hardness according to the composition, the first solution of the Korean Pharmacopoeia 11th Amendment Disintegration Test of pH 1.2 and the Japanese Pharmacopoeia 17th Amendment of pH 4.0, 0.05 mol / L acetic acid and acetic acid Comparative dissolution test was conducted in the same manner as Experimental Example 1 in the second solution or water of the Korean Pharmacopoeia 11th Amendment Disintegration Test method of sodium buffer pH 4.0, pH 6.8. Lyrica capsule was used as a reference drug. The results are shown in Table 11, Table 12, FIG. 7 and FIG.
- Example 5 A tablet was prepared in the same manner as in Example 4, except that the composition of Table 14 was used to further improve tableting properties. Specifically, the content of excipients was increased and silicon dioxide was added.
- Example 6 A comparative dissolution test was conducted for the formulation in the same manner as in Experimental Example 1. PH 1.2 or water was used as the elution test solution, Aselex tablet was used as a reference for polmacoxib, and Lyrica capsule was used as a reference for pregabalin.
- the comparative dissolution test results for the polmacoxib component are shown in Table 15 and FIG. 9, and the comparative dissolution test results for the pregabalin component are shown in Table 16 and FIG. 10.
- the bilayer composite tablet containing the pregabalin layer which shows slow release property, and the pregabalin and polmacoxib layer which show immediate release was prepared.
- the composition was prepared to show a rapid release drug release by adding an amount equivalent to half of the main component polmacoxib and pregabalin to the upper layer in the immediate release layer, and the amount corresponding to the other half of pregabalin in the lower layer in the lower layer An exothermic base was added to prepare a double layer composite.
- As the sustained release base hydroxy propyl methyl cellulose, carbomer and PEO were used.
- Composite tablets were prepared in the same manner as in Example 7, except for following the composition of Table 18.
- As the sustained release base hydroxy propyl methyl cellulose, sodium alginate and carboxy methyl cellulose sodium were used.
- the dissolution test of Examples 7 and 8 was conducted in the same manner as in Experimental Example 1, and the dissolution test was performed by increasing the dissolution paddle rpm from 50 rpm to 100 rpm to measure gastrointestinal motility resistance.
- the change in dissolution rate due to the change of rotational speed is within 4 to 8%, so it is considered that the possibility of rapid drug release due to the movement of the gastrointestinal tract is low.
- Tablets were prepared using only the composition of the sustained release layer of the compositions of Examples 7 and 8, and the dissolution test was conducted in the same manner as in Experimental Example 1.
- the overall pregabalin elution results of the bilayer tablets showed controlled release rather than sustained-release (SR) forms, so as to confirm the dissolution patterns of the lower-layer sustained release.
- the test was conducted. The results are shown in Table 21 and FIG.
- Pregabalin in the bilayer composite composition was added to the sustained-layer portion without dividing the upper, lower, immediate release layer, and sustained-release layer into a tablet as shown in Table 22.
- Sodium alginate which is a sustained-release base, may influence the change of the composition of the composition by moisture absorption during the progress of the stability test.
- hydroxypropyl methyl cellulose, carbomer, and PEO were used as the sustained-release base.
- the optimal composition was selected based on the results of Experimental Example 10.
- Tablets were prepared according to the compositions in Table 24 for the preparation of compositions for reducing the size of tablets without affecting dissolution rate. As shown in the table, the final tablet weight was reduced by reducing the amount of immediate release layer while simultaneously reducing the amount of excipients contained in the sustained release layer.
- in order to improve the instability due to the tableting pressure of the pregabalin main component was prepared for each tablet hardness. Specifically, tablets of 5 kp and 9 kp hardness were prepared, respectively.
- a tablet was prepared according to the Example 11 formulation by hardness and the dissolution test was performed. The results are shown in Table 25 and FIG. 15.
- Example 11 and Example 12 The dissolution test was conducted in the same manner as in Experiment 1 for the tablet.
- the comparative dissolution test results for the pregabalin component are shown in Table 27 and FIG. 16, and the comparative dissolution test results for the polmacoxib component are shown in Table 28 and FIG. 17.
- Example 12 (9 kp) Average 0 11.6 16.5 24.7 38.1 49.3 58.8 - 67.0 - 87.1 101.4
- Example 11 (9 kp) Average 0 10.1 16.3 25.3 39.2 50.8 60.3 - 69.2 - 87.9 104.4
- the composition according to the present invention can be seen that the drug release pattern is similar to the commercially available oral formulation of lyrica capsule and Aselex tablets containing pregabalin.
- pregabalin has the characteristic that it may cause stability problems due to the increase of the flexible material due to external physical factors such as tableting pressure, so that appropriate tableting pressure was applied to compensate for this, and compared with the capsule formulation.
- the tablet form may be excellent in terms of stability in the production of the formulation.
- the capsule formulation it was confirmed that the uniformity of the particles without the variation of mass during filling due to the excellent flowability.
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Abstract
Description
구분 | 시간(분) | 0 | 5 | 10 | 15 | 30 | 45 | 60 |
실시예 1 | 평균 | 0 | 67.0 | 85.7 | 87.9 | 90.2 | 92.5 | 94.0 |
대조약(아셀렉스캡슐) | 평균 | 0 | 37.2 | 56.8 | 72.4 | 84.3 | 88.5 | 91.7 |
구분 | 시간(분) | 0 | 5 | 10 | 15 | 30 | 45 | 60 |
실시예 1 | 평균 | 0 | 60.2 | 96.8 | 99.3 | 100.3 | 100.8 | 101.2 |
대조약(리리카캡슐) | 평균 | 0 | 61.7 | 96.0 | 98.9 | 100.6 | 100.2 | 100.7 |
구분 | 시간(분) | 0 | 5 | 10 | 15 | 30 |
실시예 2 | 평균 | 0 | 64.9 | 94.5 | 98.0 | 101.5 |
대조약(아셀렉스캡슐) | 평균 | 0 | 41.4 | 64.9 | 77.5 | 92.7 |
구분 | 시간(분) | 0 | 5 | 10 | 15 | 30 | 45 | 60 |
실시예 2 | 평균 | 0 | 34.9 | 85.4 | 91.1 | 94.8 | 95.2 | 95.4 |
대조약(리리카캡슐) | 평균 | 0 | 72.7 | 96.7 | 98.3 | 98.6 | 99.3 | 99.6 |
구분 | 시간(분) | 0 | 30 | 60 | 120 | 240 | 360 | 480 | 960 | 1440 | |
실시예7 | pH1.2 | 평균 | 0 | 59.0 | 62.1 | 66.4 | 73.0 | 78.5 | 83.9 | 100.3 | 107.4 |
실시예8 | 평균 | 0 | 59.0 | 61.3 | 65.2 | 72.4 | 77.7 | 82.5 | 98.0 | 104.0 |
rpm 100 | 시간(분) | 0 | 30 | 60 | 120 | 240 | 360 | 480 | 960 | 1440 | |
실시예7 | pH1.2 | 평균 | 0 | 55.9 | 61.0 | 66.5 | 72.9 | 77.6 | 82.9 | 97.4 | 103.3 |
실시예8 | 평균 | 0 | 52.0 | 63.2 | 68.5 | 74.3 | 75.6 | 82.6 | 93.4 | 101.2 |
하층부분 | 시간(분) | 0 | 30 | 60 | 120 | 240 | 360 | 480 | 600 | 960 | 1440 | |
실시예7 | pH1.2 | 평균 | 0 | 11.5 | 14.9 | 22.5 | 34.6 | 45.8 | 55.4 | 64.5 | 85.2 | 102.8 |
실시예8 | 평균 | 0 | 8.7 | 13.7 | 21.4 | 34.0 | 45.1 | 54.7 | 63.6 | 83.4 | 99.0 |
pH1.2 | 시간(분) | 0 | 30 | 60 | 120 | 240 | 360 | 480 | 540 | 600 | 720 | 960 | 1440 |
실시예9 | 평균 | 0 | 11.5 | 17.6 | 26.0 | 38.0 | 47.1 | 57.4 | - | 66.0 | - | 82.7 | 98.0 |
실시예10 | 평균 | 0 | 10.9 | 17.2 | 26.6 | 37.5 | 49.1 | 56.9 | - | 64.3 | - | 81.9 | 99.3 |
pH1.2 | 시간(분) | 0 | 30 | 60 | 120 | 240 | 360 | 480 | 540 | 600 | 720 | 960 | 1440 |
실시예11(5kp) | 평균 | 0 | 9.1 | 15.9 | 25.7 | 40.2 | 51.2 | 61.4 | - | 70.5 | - | 90.2 | 106.4 |
실시예11(9kp) | 평균 | 0 | 10.0 | 16.3 | 25.3 | 39.2 | 50.8 | 60.3 | - | 69.2 | - | 87.9 | 104.4 |
pH1.2 | 시간(분) | 0 | 30 | 60 | 120 | 240 | 360 | 480 | 540 | 600 | 720 | 960 | 1440 |
실시예12(9kp) | 평균 | 0 | 11.6 | 16.5 | 24.7 | 38.1 | 49.3 | 58.8 | - | 67.0 | - | 87.1 | 101.4 |
실시예11(9kp) | 평균 | 0 | 10.1 | 16.3 | 25.3 | 39.2 | 50.8 | 60.3 | - | 69.2 | - | 87.9 | 104.4 |
pH1.2 | 시간(분) | 0 | 5 | 10 | 15 | 30 | 45 | 60 |
실시예12 | 평균 | 0 | 45.0 | 63.2 | 73.2 | 88.0 | 93.0 | 95.3 |
대조약아셀렉스정제 | 평균 | 0 | 42.0 | 73.2 | 81.6 | 88.9 | 91.4 | 92.7 |
Claims (16)
- 폴마콕시브(polmacoxib) 및 프레가발린(pregabalin)을 포함하는 통증 치료용 약제학적 조성물.
- 제1항에 있어서,상기 조성물이 염증성 또는 신경병증성으로 유발된 급성 또는 만성 통증 치료용인 것인, 약제학적 조성물.
- 제1항에 있어서,상기 조성물이 당뇨병성 신경장애를 포함하는 신경성 통증(neurogenic pain), 범불안장애(generalized anxiety disorder)로 인한 통증, 섬유근육통(fibromyalgia), 통각과민증(hyperalgesia), 이질통(allodynia), 암통증(cancer pain), 골관절염(osteoarthritis), 류마티스 관절염(rheumatoid arthritis), 척추염(spondylitis), 오십견(frozen shoulder), 요통(lumbodynia) 또는 좌골신경통(sciatica)을 적응증으로 하는 것인, 약제학적 조성물.
- 제1항에 있어서,폴마콕시브 대 프레가발린의 비율이 1 내지 300:1 내지 600 중량비인 것인, 약제학적 조성물.
- 제1항에 있어서,폴마콕시브 대 프레가발린의 비율이 1:1 내지 1:300 중량비인 것인, 약제학적 조성물.
- 제1항에 있어서,폴마콕시브 대 프레가발린의 비율이 2:1 내지 2:300 중량비인 것인, 약제학적 조성물.
- 제1항에 있어서,조성물 총 중량에 대하여, 폴마콕시브 0.1 내지 10중량% 및 프레가발린 10 내지 50중량% 포함하는 것인, 약제학적 조성물.
- 제1항에 있어서,약제학적으로 허용되는 부형제를 추가로 포함하는 것인 약제학적 조성물.
- 제8항에 있어서,상기 부형제가 에틸 셀룰로오스(ethyl cellulose), 히드록시 프로필 셀룰로오스(hydroxypropyl cellulose), 히드록시 프로필 메틸 셀룰로오스(hydroxypropyl methylcellulose), 카복시 메틸 셀룰로오스 나트륨(sodium carboxymethyl cellulose), 폴리에틸렌 옥사이드(polyethylene oxide), 카보머(carbomer), 알긴산나트륨(sodium alginate), 만니톨(mannitol), 크로스 카멜로오스 나트륨(cross carmellose sodium), 탄산수소나트륨(sodium hydrogen carbonate) 및 스테아르산 마그네슘(magnesium stearate)으로 이루어지는 군으로부터 선택되는 하나 이상을 포함하는 것인, 약제학적 조성물.
- 제1항에 있어서,정제, 캡슐제 또는 현탁제의 형태인 것인, 약제학적 조성물.
- 제10항에 있어서,폴마콕시브 및 프레가발린이 혼합된 정제, 캡슐 또는 현탁제 형태이고,상기 정제는 이중정, 다층정 또는 단일정의 형태를 포함하는 것인, 약제학적 조성물.
- 제1항에 있어서,폴마콕시브, 프레가발린 또는 이들의 혼합물이 각기 다른 층으로 구분된 상태인 이중층 구조의 이중정 또는 다층 구조의 다층정으로 형성된 것인, 약제학적 조성물.
- 제1항에 있어서,서방층 및 속방층으로 구분되어 있는 이중층으로 형성된 것인, 약제학적 조성물.
- 제13항에 있어서,상기 서방층이 프레가발린을 포함하고, 상기 속방층이 폴마콕시브를 포함하는 것인, 약제학적 조성물.
- 제1항에 있어서,약제학적으로 허용되는 코팅기제를 더 포함하는 것인, 약제학적 조성물.
- 제1항에 있어서,약제학적으로 허용되는 담체를 추가로 포함하는 것인, 약제학적 조성물.
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JP2020545470A JP2021517115A (ja) | 2018-03-30 | 2019-03-20 | ポルマコキシブ及びプレガバリンを含む疼痛治療用薬剤学的組成物 |
EP19777560.4A EP3777849A4 (en) | 2018-03-30 | 2019-03-20 | PHARMACEUTICAL COMPOSITION, COMPRISING POLMACOXIB AND PREGABALIN, FOR THE TREATMENT OF PAIN |
US16/982,137 US11602517B2 (en) | 2018-03-30 | 2019-03-20 | Pharmaceutical composition, comprising polmacoxib and pregabalin, for treatment of pain |
CA3093899A CA3093899A1 (en) | 2018-03-30 | 2019-03-20 | Pharmaceutical composition, comprising polmacoxib and pregabalin, for treatment of pain |
CN201980020180.0A CN111867578A (zh) | 2018-03-30 | 2019-03-20 | 包含帕马考昔及普瑞巴林的用于治疗疼痛的药剂学组合物 |
BR112020017773-3A BR112020017773A2 (pt) | 2018-03-30 | 2019-03-20 | Composição farmacêutica compreendendo polmacoxibe e pregabalina para tratamento de dor |
US18/155,240 US20230293476A1 (en) | 2018-03-30 | 2023-01-17 | Pharmaceutical composition, comprising polmacoxib and pregabalin, for treatment of pain |
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US18/155,240 Continuation US20230293476A1 (en) | 2018-03-30 | 2023-01-17 | Pharmaceutical composition, comprising polmacoxib and pregabalin, for treatment of pain |
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- 2018-03-30 KR KR1020180037054A patent/KR102631399B1/ko active IP Right Grant
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2019
- 2019-03-20 JP JP2020545470A patent/JP2021517115A/ja active Pending
- 2019-03-20 CN CN201980020180.0A patent/CN111867578A/zh active Pending
- 2019-03-20 CA CA3093899A patent/CA3093899A1/en active Pending
- 2019-03-20 US US16/982,137 patent/US11602517B2/en active Active
- 2019-03-20 WO PCT/KR2019/003225 patent/WO2019190118A1/ko unknown
- 2019-03-20 EP EP19777560.4A patent/EP3777849A4/en active Pending
- 2019-03-20 BR BR112020017773-3A patent/BR112020017773A2/pt unknown
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2023
- 2023-01-17 US US18/155,240 patent/US20230293476A1/en not_active Abandoned
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Also Published As
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KR20190114403A (ko) | 2019-10-10 |
US20230293476A1 (en) | 2023-09-21 |
EP3777849A4 (en) | 2022-02-23 |
CA3093899A1 (en) | 2019-10-03 |
EP3777849A1 (en) | 2021-02-17 |
CN111867578A (zh) | 2020-10-30 |
JP2021517115A (ja) | 2021-07-15 |
US11602517B2 (en) | 2023-03-14 |
BR112020017773A2 (pt) | 2020-12-22 |
KR102631399B1 (ko) | 2024-02-01 |
US20210113515A1 (en) | 2021-04-22 |
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