WO2018186650A2 - Comprimé composite double pour administration orale contenant du tramadol et du célécoxib - Google Patents

Comprimé composite double pour administration orale contenant du tramadol et du célécoxib Download PDF

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WO2018186650A2
WO2018186650A2 PCT/KR2018/003905 KR2018003905W WO2018186650A2 WO 2018186650 A2 WO2018186650 A2 WO 2018186650A2 KR 2018003905 W KR2018003905 W KR 2018003905W WO 2018186650 A2 WO2018186650 A2 WO 2018186650A2
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WO
WIPO (PCT)
Prior art keywords
tramadol
celecoxib
release layer
oral administration
tablet
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PCT/KR2018/003905
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English (en)
Korean (ko)
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WO2018186650A3 (fr
Inventor
김승현
황성주
안준현
현상민
곽상원
선보경
Original Assignee
주식회사 킴스헬스케어
연세대학교 산학협력단
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Priority to US16/500,311 priority Critical patent/US20200323780A1/en
Priority claimed from KR1020180038579A external-priority patent/KR102033716B1/ko
Publication of WO2018186650A2 publication Critical patent/WO2018186650A2/fr
Publication of WO2018186650A3 publication Critical patent/WO2018186650A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to dual combined tablets for oral administration including tramadol and celecoxib, and more particularly, to dual combined tablets for oral administration maintaining a constant dosage interval while showing independent release characteristics of the immediate release layer and the sustained release layer. It is about.
  • Celecoxib is a very poorly soluble drug, solubility in water (20 °C, 3.3mg / L), especially because of its long half-life (about 11 hours), lasts about 12 hours with a single dose, but tramadol In the case of very well soluble in water and half-life (about 6 hours) of blood short duration is also very short. Therefore, the combination of these two drugs is difficult to formulate due to the difference in release rate. In particular, in the preparation of a complex composition of two drugs, there is a high risk of not obtaining sufficient efficacy as expected when prepared by simple combination without considering the release rate at all.
  • the present invention reduces the drug dose of tramadol than the normal dose and sustained release to reduce side effects caused by tramadol (eg, nausea, vomiting, constipation, dizziness, respiratory anxiety, etc.), and at the same time, sustained analgesic effects and relatively low side effects of celecoxib
  • the present invention relates to a two-layer complex tablet that compensates for the reduced analgesic effect.
  • the present invention is designed to solve the above problems, slowing down the release rate of tramadol to adjust the drug duration similar to the duration of celecoxib and at the same time reduce the dose of tramadol complex anti-inflammatory Its purpose is to provide analgesics, to provide a mixed composition for the treatment of acute pain, and to increase the convenience of taking by taking two drugs in one combination.
  • the present invention has been made in order to achieve the above object, a sustained release layer containing tramadol as an active ingredient; And an immediate release layer containing celecoxib as an active ingredient, wherein the ratio of the content of tramadol to celecoxib is a molar ratio of 1: 4.5 to 1: 10.5.
  • a sustained release layer containing tramadol as an active ingredient and an immediate release layer containing celecoxib as an active ingredient, wherein the ratio of the content of tramadol to celecoxib is a molar ratio of 1: 4.5 to 1: 10.5.
  • the composite tablet is characterized by improving the dosage compliance so that the tramadol is sustained and the celecoxib is immediately released to differentiate the release rate, so that it can be taken twice a day.
  • the content of the tramadol and celecoxib is a dual complex tablet for oral administration, characterized in that 1: 5 to 1: 13.5 weight ratio.
  • the sustained release layer is characterized in that it comprises a cellulose derivative, polyether, polyacrylic acid, polyvinyl alcohol or a mixture thereof as a drug release control agent for controlling the release rate of tramadol.
  • the sustained release layer is a drug release controlling agent for controlling the release rate of tramadol cellulose derivative comprising hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose; Polyethers including polyethylene oxide and polypropylene oxide; Polyacrylic acid including carbomer; And it is characterized in that it comprises one or more selected from the group consisting of polyvinyl alcohol.
  • the drug release control agent is characterized in that it comprises 20 to 30 parts by weight and 30 to 40 parts by weight of hydroxypropyl methyl cellulose and polyethylene oxide compared to 100 parts by weight of the total sustained-release layer.
  • the tramadol content of the sustained release layer is characterized in that it is included in the range that the single dose does not exceed 35 mg.
  • the tramadol content of the sustained release layer is a single dose of 25mg, it is characterized in that it contains 50mg per day.
  • the present invention it is possible to provide a composition for treating pain having a sustained analgesic effect for 12 hours while reducing the side effects of tramadol by releasing the water-soluble tramadol and releasing the poorly soluble celecoxib.
  • the number of medications can be reduced to increase the convenience of taking.
  • formulations suitable for long-term patients with analgesic anti-inflammatory drugs such as rheumatoid arthritis and spondylitis patients can be provided.
  • 1 is a side view and a plan view of a dual composite tablet of tramadol and celecoxib according to an embodiment of the present invention.
  • FIG 3 is a tramadol elution graph of Examples 7 to 12 of the comparative example 2 and the tramadol monolayer of the present invention.
  • Figure 4a is an elution graph of the celecoxib immediate release layer in the double composite tablet of Examples 13-16 of the present invention.
  • Figure 4b is an elution graph of the tramadol sustained release layer in the double composite tablet of Examples 13-16 of the present invention.
  • 5 and 6 show hind paw images of rats before and after development of rheumatoid arthritis, respectively.
  • FIG. 8 is a perspective view of a conditional place preference box for mental dependency measurement experiments that are one of the side effects of tramadol.
  • Figure 9 is a graph showing the results of the mental dependence measurement experiment in accordance with an embodiment of the present invention.
  • the present invention a sustained release layer containing tramadol as an active ingredient; And an immediate release layer containing celecoxib as an active ingredient, wherein the ratio of the content of tramadol to celecoxib is a molar ratio of 1: 4.5 to 1: 10.5. Relates to tablets.
  • the present invention uses tramadol and celecoxib as active ingredients to prepare a medicament for the treatment of pain, and the two drugs have a great difference in dissolution rate in the human body, thereby effectively exhibiting the efficacy of the drug.
  • mutual control of the release rate is necessary. Therefore, the dosage compliance can be taken twice a day by dividing the tramadol with good solubility in water into a slow-release layer and a slow-soluble celecoxib in an immediate release layer for 12 hours. Can be improved.
  • the content was adjusted so as not to exceed 35 mg per tablet (Tablet).
  • the binder used in the celecoxib immediate release layer of the present invention is povidone, copovidone, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum
  • At least one selected from among the disintegrants include crospovidone, sodium starch glycolate, croscarmellose sodium, L-hydroxypropyl cellulose, calcium carboxymethylcellulose grain starch, alginic acid, sodium alginate, guar gum
  • Excipients include lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, potassium chloride, magnesium chloride, calcium hydrogen phosphate, calcium phosphate, citric acid, microcrystalline cellulose, colloidal silica as lubricant , Magnesium trisilicate, starch, talc, tricalcium phosphate
  • celecoxib immediate release layer of the present invention for the celecoxib immediate release layer of the present invention, celecoxib as a main component, polyvinylpyrrolidine as a binder, croscarmellose sodium as a disintegrant, and for direct use It is preferable to include an excipient microcrystalline cellulose, a surfactant sodium laruryl sulfate, a lubricant aerosol and magnesium stearate.
  • each component is 60.0-70.0 wt% of celecoxib, 1.0-4.0 wt% of polyvinylpyrrolidine, croscarmellose sodium 4.0-6.0 wt%, microcrystalline cellulose 20.0-30.0 wt%, sodium laruryl sulfate 0.5-1.0 wt%, aerosol 0.1-0.5 wt%, magnesium stearate ( magnesium stearate) and may contain 0.7 to 1.0 percent by weight.
  • the composition of the celecoxib immediate release layer is 66.7% by weight of celecoxib (celecoxib) polyvinylpyrrolidine 3.3% by weight, croscarmellose sodium 5% by weight, microcrystalline cellulose (micro crystalline cellulose) 20.7% by weight, sodium lauryl sulfate (3.3% by weight), aerosol (aerosol) 0.3% by weight, magnesium stearate (magnesium stearate) is preferably included.
  • Excipients used in the tramadol sustained-release layer of the present invention is selected from lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, potassium chloride, magnesium chloride, calcium hydrogen phosphate, calcium phosphate, citric acid, microcrystalline cellulose
  • cellulose derivatives hydroxy ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxy propyl methyl cellulose
  • polyethers polyethylene oxide, polypropylene oxide
  • polyacrylic acid At least one selected from carbomers and polyvinyl alcohols, and lubricants include colloidal silica, magnesium trisilicate, starch, talc, tricalcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, Sodium stearyl fumarate, magnesium carbonate, acid It may include at
  • composition of the sustained release layer of tramadol of the present invention is composed of tramadol as a main component, pregelatinized starch as a filler, hydroxypropylmethylcellulose and polyethylene oxide as a drug release controlling agent, and aerosil as a lubricant. aerosol and magnesium stearate.
  • the tramadol sustained-release layer composition is tramadol 6.0 ⁇ 12.0 wt%, pregelatinized starch (pre gelatinized starch) 10.0 ⁇ 30.0 wt%, hydroxypropylmethyl cellulose (hydroxypropylmethylcellulose) 20.0 ⁇ 30.0 wt%, polyethylene oxide (polyethylene oxide) 30.0 to 40.0% by weight, aerosol (aerosol) may include 1 to 2.5% by weight, magnesium stearate (magnesium stearate) may include 1 to 5% by weight.
  • the tramadol sustained-release layer composition is 10.0% by weight of tramadol (tramadol), 16.0% by weight of pregelatinized starch, 32.0% by weight of hydroxypropylmethylcellulose, 36.0% by weight of polyethylene oxide, aero It is preferable to include 2.0% by weight of aerosol and 4.0% by weight of magnesium stearate.
  • a method for producing a dual oral combination formulation containing tramadol and celecoxib as an active ingredient to slow down the side effects of tramadol and obtain a continuous analgesic effect, sustained release of tramadol and celecoxib
  • the drug can be adjusted for 12 hours to achieve a continuous analgesic effect, reducing the side effects that can occur during long-term use of analgesics and combining the two drugs to improve medication compliance.
  • the present invention relates to a method of preparing a complex for treating pain, comprising the following process steps:
  • composition of celecoxib monolayer, tramadol monolayer and bilayer composite tablet was summarized in Table 1, Table 2 and Table 3, respectively.
  • Table 1 shows the composition of the celecoxib monolayer formulations of Examples 1-6.
  • Table 2 shows the composition of the tramadol monolayer formulations of Examples 7-12.
  • Table 3 shows the composition of the composite layer formulations of Examples 13-16.
  • the dissolution rate of tramadol and celecoxib was measured for the tramadol sustained-release layer, the celecoxib sustained-release layer, and Comparative Examples 1 and 2 using the apparatus of the USP Method 2 (paddle method).
  • tramadol 900 ml of D.W and 900 ml of 1% sodium lauryl sulfate solution for celecoxib were used as eluents.
  • the solution was maintained at a temperature of 37 ⁇ 2 ° C. and stirred at 50 rpm during the test. Twelve identical tablets or capsules were each placed in a standard elution vessel and each hour a 2 ml fraction of the solution was obtained from each vessel, which was filtered through a 0.45 um PTFE filter to determine the concentration via HPLC-UV.
  • FIG. 2 is a graph showing the dissolution of celecoxib in Comparative Examples 1 and Examples 1 to 6 of the celecoxib monolayer.
  • the initial dissolution rate of celecoxib in the immediate release formulation showed a dissolution rate of 80% or more within 15 minutes.
  • Examples 1, 3, 4, and 5 there was a marked difference in Comparative Example 1 and the initial dissolution rate, whereas in Examples 2 and 6, the initial dissolution rate within 15 minutes was similar to that of Comparative Example 1.
  • Examples 2 and 6 it was confirmed that the formulation suitable for the celecoxib immediate layer.
  • FIG 3 is a graph showing the dissolution of tramadol for Comparative Examples 2 and Examples 7 to 12 of the tramadol monolayer.
  • the dissolution rate after 4 hours and 8 hours in the sustained release formulation was 70% and 90%, respectively.
  • the dissolution rate of Comparative Example 2 did not show a significant difference, but in Examples 7 to 10, in the previous studies, tramadol in two-layer composite tablets was 70% or more at 2 hours and 4 hours. The dissolution rate was over 90%, confirming that the emission control was not properly performed. Therefore, it was confirmed that Examples 11 and 12 are formulations suitable for the tramadol sustained release layer.
  • Figure 4a is a dissolution graph for celecoxib in the immediate release layer in a bilayer composite tablet.
  • the dissolution rate of celecoxib was 90% or more after 1 hour, but Examples 13 and 14 were 80% or more in the initial 15-minute dissolution rate.
  • Example 13 showed a higher dissolution rate than Example 14, and it was confirmed that Example 13 was the optimal formulation.
  • Example 4B is a dissolution graph for tramadol of the immediate release layer in a double composite tablet.
  • Examples 13 and 15, 14 and 16 showed similar dissolution rates, and Examples 13 and 15 showed lower dissolution rates than 14 and 16, respectively.
  • the dissolution rate of Examples 13 and 15 did not show a large difference, it was confirmed that Example 13 was the optimum formulation because it was better controlled in Example 13 than Example 15.
  • Example 13 is an optimal formulation for rapid release of celecoxib and slow release of tramadol.
  • the immediate release layer exhibited elution of at least 80% within 15 minutes and 90% within 45 minutes when tested by the USP II instrument at 37 ° C. and 50 rpm in 900 ml of 1% sodium lauryl sulfate (SLS) at 100 rpm within 100 minutes.
  • SLS sodium lauryl sulfate
  • the sustained layer shows 60% elution for 4 hours and 80% for 8 hours and 100% for 12 hours when tested by USP II instrument at 37 ° C and 75 rpm in 900 ml of distilled water. It can be seen that there is a close dissolution .
  • PWT Paw Withdrawal Threshold
  • the analgesic effect is to approach the sole surface in ascending order from the low-strength filament to each of the different-strength von-frey filaments, applying five mechanical stimuli such that the filament slightly bends to the sole.
  • the intensity of the filament was calculated and evaluated as the pain threshold value.
  • PWT was measured using Von-frey filament before Intraperitoneal injection of Experimental Example 1 and Comparative Examples 1 and 2 described in Table 4 below, and Experimental Example 1 and Comparative Examples 1 and 2 were intraperitoneally administered. 30 minutes after intraperitoneal administration, PWT was measured by the same method as before. Afterwards, the analgesic effect was measured by calculating the change trend of PWT using Equation 1 below.
  • test was performed using the non-parametric statistical method Kruskal-Wallis test and the significance level (p-value) was confirmed.
  • test was performed using the Mann-Whitney U-test and the significance level (p-value) was confirmed.
  • Statistical analysis was performed using the IBM ® SPSS ® Statistics version 24.
  • the average value of the analgesic effect of Experimental Example 1 and Comparative Examples 1 to 3 is shown in Table 5 below.
  • the experimental and comparative examples were tested using the Kruskal-Wallis test based on the result of the population, and the significance level was 0.023 (p ⁇ 0.05).
  • the results of assaying Experimental Example 1 and Comparative Examples 1 to 3 using Mann-Whitney U-test were as shown in FIG. 7. That is, when co-administered celecoxib and tramadol, analgesic effect was shown, and analgesic effect of Experimental Example 1 and Comparative Example 2 was similar, and analgesic effect of Experimental Example 1 and Comparative Example 3 showed a significant difference.
  • the conditional place preference box is divided into three boxes of white, black, and gray as shown in FIG. 8, and the gray box is 28cm long as an intermediate part where the animal can select a white and black box.
  • the black box is made of stainless steel with a rod bottom of 4.8 mm in diameter and 16 mm gap.
  • the white box is made of stainless steel with a 1.25 x 1.25 cm mesh bottom.
  • the gray box is 12cm wide, 22cm high and 21cm high.
  • the white and black boxes are 28cm wide, 21cm high and 21cm high.
  • the sequence of experiments is as follows. 5 weeks old male Sprague-Dawley rats (SD rats) were purchased and subjected to a week-long purifying period, followed by drug or injection physiology during the 1st, 2nd and 3rd preconditioning steps. After the saline was not treated in a gray room, the door (Door) was opened to measure the time to stay in each room for 15 minutes. Then, the average of the measurement results was used to determine the preferred room in the preconditioning step (the longer stay among the white room and the black room), and the rats in the experimental group shown in Table 6 below (Experimental Example 2 and Comparative Examples 4 to 6). The separation was carried out to the next step (conditioning step).
  • the next step is the conditioning step corresponding to the 4th to 11th day, and the corresponding doses of the experimental and comparative examples were measured on the 4th, 6th, 8th and 10th days.
  • 30 minutes after injection into rats they were adapted to an unfavorable room for 30 minutes to relate the tramadol to the unfavorable room.
  • saline injections were administered to rats by ip injection, and after 30 minutes, they were adapted to the preferred room for 30 minutes to relate the saline to the preferred room.
  • the postconditioning step rats were placed in a gray room without drug or injection saline, and the doors were opened to measure the time spent in each room for 15 minutes (see Table 7).
  • the difference between the time spent in a tramadol-associated place (an unpreferred room) in the postconditioning step and the time spent in an unfavorable room in the preconditioning step indicates a change in the conditional place preference by the tramadol, i.e. the psychological dependence of the drug.
  • Table 8 The difference between the time spent in a tramadol-associated place (an unpreferred room) in the postconditioning step and the time spent in an unfavorable room in the preconditioning step indicates a change in the conditional place preference by the tramadol, i.e. the psychological dependence of the drug.
  • the dual combination tablet for oral administration including tramadol 25mg and celecoxib 200mg, characterized by improving the dose compliance so that it can be taken twice a day of the present invention shows an analgesic effect with less side effects indicating mental dependence.
  • the analgesic effect is not inferior to the product of the tramadol dose of 37.5 mg or 100 mg.

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Abstract

La présente invention concerne un comprimé composite double pour administration orale, comprenant : une couche à libération prolongée contenant du tramadol en tant que principe actif ; et une couche à libération immédiate contenant du célécoxib en tant que principe actif, le comprimé composite double étant une préparation orale qui est prescrite pour soulager les symptômes ou les signes de l'arthrose (arthrite dégénérative), de la polyarthrite rhumatoïde, de la spondylarthrite ankylosante, pour soulager la douleur aiguë chez l'adulte (douleur post-opératoire ou post-extraction), la dysménorrhée primaire, ou la douleur aiguë ou chronique sévère et modérée. Grâce à la présente invention, on peut donc obtenir une composition pour le traitement de la douleur qui réduit les effets secondaires du tramadol et a un effet antidouleur continu pendant 12 heures par libération prolongée de tramadol soluble dans l'eau et libération immédiate de célécoxib peu soluble. En outre, le nombre de médicaments administrés diminue grâce à l'intégration de deux types de médicaments dans une seule préparation complexe, ce qui permet d'améliorer la commodité d'administration de ces médicaments.
PCT/KR2018/003905 2017-04-03 2018-04-03 Comprimé composite double pour administration orale contenant du tramadol et du célécoxib WO2018186650A2 (fr)

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US16/500,311 US20200323780A1 (en) 2017-04-03 2018-04-03 Bilayer combination tablet for oral administration containing tramadol and celecoxib

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KR10-2017-0042927 2017-04-03
KR20170042927 2017-04-03
KR10-2018-0038579 2018-04-03
KR1020180038579A KR102033716B1 (ko) 2017-04-03 2018-04-03 트라마돌과 셀레콕시브를 포함한 경구투여용 이중 복합정제

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113521292A (zh) * 2020-04-15 2021-10-22 江苏恒瑞医药股份有限公司 一种cox-2抑制剂和曲马多的复方制剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2311446A1 (fr) * 2009-10-16 2011-04-20 Laboratorios Del. Dr. Esteve, S.A. Compositions comprenant du Tramadol et du Célécoxib pour le traitement de la douleur
KR101710792B1 (ko) * 2015-07-14 2017-02-28 주식회사 유영제약 세레콕시브 및 트라마돌을 함유하는 약제학적 조성물

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113521292A (zh) * 2020-04-15 2021-10-22 江苏恒瑞医药股份有限公司 一种cox-2抑制剂和曲马多的复方制剂

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